Methods of classifying periorbital dyschromia and systems therefor

Description

FIELD OF THE INVENTION

The present application is directed, generally, to methods and systems for classifying periorbital dyschromia on a person. More specifically, the present application discloses methods and systems for classifying different types of periorbital dyschromia based on visual characteristics, histology, the presence, absence and/or abundance of biomarkers and genetic indicators.

BACKGROUND OF THE INVENTION

A person's eyes are a prominent and noticeable facial feature. Thus, any desirable or undesirable aesthetic features associated with the eyes may influence an individual's perception of herself or himself or the impression that the individual makes on others. Undesirable aesthetic features may include lines, wrinkles and discoloration of the skin. For example, some people may find periorbital dyschromia, sometimes referred to as dark circles or under-eye dark circles, to be aesthetically undesirable and/or they may associate the appearance of periorbital dyschromia with fatigue and/or age. It should come as no surprise then that throughout history a variety of ways to accentuate and/or beautify the eyes have been devised. A common approach to improve the appearance of periorbital dyschromia is to use a cosmetic composition such as a concealer or the like to hide the discoloration. Using make up to hide a perceived flaw may provide a temporary cosmetic benefit, but most conventional make up products require daily application and, in some instances, may even require reapplication throughout the day. Thus, a more permanent solution is desired to reduce and/or eliminate some of the undesirable aesthetic features commonly found around the eye.

As mentioned above, a particularly undesirable aesthetic eye feature is periorbital dyschromia. In an effort to find a solution to the problem of periorbital dyschromia, researchers have previously tried to identify its underlying causes. One theory suggests that periorbital dyschromia occurrence is based on the difference between the thickness of the skin in the periorbital region (i.e., the skin around the eye) and the thickness of the skin in other areas of the face such as the cheeks. It is known that the skin surrounding the eyes is typically thinner than other facial skin (e.g., on the order of 0.33 to 0.36 ram or 3 to 5 times thinner than the rest of the skin of the face). As a result, some conventional theories posit that the skin around the eyes may be easily dehydrated and particularly vulnerable to adverse impact of external factors such as heat, stress, tobacco, UV rays, and excessive facial expressions. According to these theories, the skin tissues around the eye area may undergo multiple variations throughout the day, such as vascularization, hydration and turgescence, which contributes to swelling/puffiness and/or the appearance of dark circles under the eyes. While the thinness of the skin in the periorbital region may play a role in the occurrence of periorbital dyschromia, it is not a suitable characteristic for distinguishing different types of periorbital dyschromia. This is because most people generally have thinner skin in the periorbital region compared to other areas of the face, yet not all people have the same type of periorbital dyschromia or, in sonic instances, any periorbital dyschromia at all. Thus, there remains a need to find suitable characteristics for distinguishing different types of dark circles.

Another theory attributes the occurrence of periorbital dyschromia to hyperpigmentation, or the overproduction of melanin in the skin under the eye. But recent studies have revealed that the cause of under-eye dark circles is more often the result of a combination of factors such as deep vascular congestion/superficial vascularity, hyperpigmentation, skin translucency, and structural shadowing, alone or in combination. The belief that a variety of factors are responsible for causing periorbital dyschromia has led to attempts to classify periorbital dyschromia into discrete types according to the different underlying factor(s) believed to be responsible for the discoloration. But these attempts have failed to provide a commercially viable method of classifying periorbital dyschromia or a system that is suitable for developing and marketing cosmetic products that target periorbital dyschromia. In some instances, there were too many classes of periorbital dyschromia, which requires a manufacturer to develop more cosmetic products or line ups and/or market a more complex treatment method. In some instances, the system used to classify the types of periorbital dyschromia may be too complex to allow consumer to self-diagnose, for example, at home or in a commercial environment such as a retail store.

Another theory suggests that chromophores such as melanin and hemoglobin present in the undereye region contribute to the occurrence of periorbital dyschromia. Melanin is a naturally produced pigment in the skin, and hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all humans. It is commonly believed that melanin and hemoglobin are primarily responsible for the skin tone of a person. Thus, some recent attempts to classify dark circles have included analyzing relatively small areas of skin on the lower eyelid with a device that correlates certain wavelengths of reflected light into measurements of melanin and/or hemoglobin present in the skin. While this approach may be suitable for providing an indication of the melanin and/or hemoglobin content of the particular area of skin analyzed, it has several drawbacks. For example, the amount of melanin and/or hemoglobin present in the skin or in the blood vessels in under-eye skin can vary based on a wide variety of environment and/or biological influences, which current analytical approaches do not consider. Additionally, current approaches to classifying dark circles based on melanin and hemoglobin levels may not take into account one or more of a variety of other factors believed to contribute to periorbital dyschromia, which are important to include in a robust classification method and/or system suitable for use in commerce. Previous attempts to analyze periorbital dyschromia based on melanin and hemoglobin measurements also focused on the skin of the lower eyelid. Since it is not uncommon for periorbital dyschromia to occur in the periorbital region above the eye and in portions of the undereye region, but not the entire undereye region, it is important to holistically analyze periorbital dyschromia in the periorbital region.

It is currently recognized that periorbital dyschromia is a multifactorial pathogenesis that is not well elucidated. Past attempts to classify periorbital dyschromia may have shown that there are different types of periorbital dyschronia, but they still have failed to provide a suitable method or system of classifying the different types. Further, there is a need for products, product line ups and/or treatment regimens that are particularly suited for treating different types of periorbital dyschromia. For example, some researchers may have recognized that there are different types of periorbital dyschromia, but they still propose treating different types of periorbital dyschromia with the same composition or material. Other researchers have suggested that a “one size fits all” approach to treating periorbital dyschromia may not be suitable, due to the numerous and not well understood differences in the underlying causes of periorbital dyschromia, but they do not proffer a suitable alternative. Thus, there remains a need for a suitable method and system of classifying periorbital dyschromia, and, in particular, one that is more suitable for commercial use. Otherwise, manufacturers may find it too difficult and/or unpredictable to design and market products and treatment regimens for the diverse array of consumers who typically use their products. Similarly, in some instances, it may be desirable for consumers to self-diagnose, and thus it would be desirable for the method and system to be user friendly, for example, in a commercial setting such as a retail store.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

FIG. 1 is an illustration of various portions of a human face.

FIGS. 2A and 2B illustrate examples of the portion of the periorbital region affected by Type I periorbital dyschromia.

FIGS. 3A and 3B illustrate examples of portion of the periorbital region affected by Type II periorbital dyschromia.

FIGS. 4A and 4B illustrate examples of portion of the periorbital region affected by Type III periorbital dyschromia.

FIGS. 5A, 6A and 7A are images of a test subject captured with a digital camera.

FIGS. 5B, 6B and 7B are Brown channel images of a test subject.

FIGS. 5C, 6C and 7C are Red channel images of a test subject.

FIGS. 5D, 6D and 7D illustrate the location of the periorbital dyschromia seen in FIGS. 5B, 6B and 7B, respectively.

FIGS. 5E, 6E and 7E illustrate the location of the periorbital dyschromia seen in FIGS. 5C, 6C and 7C, respectively.

FIG. 8 is a 20× micrograph of a skin tissue sample from a subject exhibiting No Dyschromia.

FIG. 9 is a 20× micrograph of a skin tissue sample from a subject exhibiting Type I periorbital dyschromia.

FIG. 10 is a 20× micrograph of a skin tissue sample from a subject exhibiting Type II periorbital dyschromia.

FIG. 11 is a 20× micrograph of a skin tissue sample from a subject exhibiting Type III periorbital dyschromia.

FIG. 12 illustrates the Fontana-Masson positive bodies observed per field of view for each type of periorbital dyschromia and a No Dyschromia condition.

FIG. 13 illustrates the normalized PTCA amount measured for each type of periorbital dyschromia and a No Dyschromia condition.

FIG. 14 illustrates an example of a masked region corresponding to Zone 1.

FIG. 15 illustrates an example of a masked region corresponding to Zone 2.

FIG. 16 illustrates an example of a masked region corresponding to Zone 4.

FIG. 17 illustrates an example of a masked region corresponding to the cheek.

FIG. 18 illustrates an example of a masked region corresponding to the cheek.

FIG. 19 shows a comparison of the R values for different types of periorbital dyschromia in Zone 1.

FIG. 20 is a comparison of the B values for different types of periorbital dyschromia in Zone 1.

FIG. 21 is a comparison of the G values for different types of periorbital dyschromia in Zone 1.

FIG. 22 is a comparison of the B/G ratios for different types of periorbital dyschromia in Zone 1.

FIG. 23 is a comparison of the R values for different types of periorbital dyschromia in Zone 2.

FIG. 24 is a comparison of the G values for different types of periorbital dyschromia in Zone 2

FIG. 25 is a comparison of the B values for different types of periorbital dyschromia in Zone 2.

FIG. 26 is a comparison of the B/G ratios for different types of periorbital dyschromia in Zone 2.

FIG. 27 is a comparison of the R values for different types of periorbital dyschromia in Zone 4 (i.e., Zones 1 and 2, in combination).

FIG. 28 is a comparison of the G values for different types of periorbital dyschromia in Zone 4 (i.e., Zones 1 and 2, in combination).

FIG. 29 is a comparison of the B values for different types of periorbital dyschromia in Zone 4 (i.e., Zones 1 and 2, in combination).

FIG. 30 is a comparison of the B/G ratios for different types of periorbital dyschromia in Zone 4 (i.e., Zones 1 and 2, in combination).

SUMMARY OF THE INVENTION

In order to provide a solution to the aforementioned problems, disclosed herein is a method of classifying periorbital dyschromia comprising providing a first predetermined imaging value for a first type of periorbital dyschromia, a second predetermined imaging value for a second type of periorbital dyschromia, and a third predetermined imaging value for a third type of periorbital dyschromia. The method includes indentifying skin in a periorbital region of a person comprising periorbital dyschromia and measuring an imaging value of at least a portion of the identified skin. The measured imaging value is compared to the predetermined imaging values, and the person is classified as having the first type of periorbital dyschromia when the measured image value corresponds to the first predetermined imaging value, as having the second type of periorbital dyschromia when the measured imaging value corresponds to the second predetermined imaging value, or as having the third type of periorbital dyschromia when the measured imaging value corresponds to the third predetermined imaging value.

DETAILED DESCRIPTION OF THE INVENTION

All percentages are by weight of the personal-care composition, unless otherwise specified. All ratios are weight ratios, unless specifically stated otherwise. All numeric ranges are inclusive of narrower ranges; delineated upper and lower range limits are interchangeable to create further ranges not explicitly delineated. The number of significant digits conveys neither limitation on the indicated amounts nor on the accuracy of the measurements. All measurements are understood to be made at about 25° C. and at ambient conditions, where “ambient conditions” means conditions under about one atmosphere of pressure and at about 50% relative humidity.

Definitions

“Connectivity map” and “C-map” refer broadly to devices, systems, articles of manufacture, and methodologies for identifying relationships between cellular phenotypes or cosmetic conditions, gene expression, and perturbagens, such as cosmetic actives. A description of connectivity mapping and methods of using connectivity mapping to identify genes and/or compositions of interest can be found in U.S. Publication No. 2012/0283112 titled “Systems and Methods For Identifying Cosmetic Agents For Skin Care Compositions” filed by Binder, et al., on Feb. 22, 2012 and U.S. Publication Nos. 2013/0259816, 2013/0261006, 2013/0261024 and 2013/0261007 all filed by Hakozaki, et al., on Mar. 27, 2013.

“Cosmetic” means providing a desired visual effect on an area of the human body. The visual cosmetic effect may be temporary, semi-permanent or permanent. Some non-limiting examples of “cosmetic products” include products that leave color on the face, such as foundation, mascara, concealers, eye liners, brow colors, eye shadows, blushers, lip sticks, lip balms, face powders, solid emulsion compact, and the like.

“Cosmetic agent” means any substance, as well any component thereof, intended to be rubbed, poured, sprinkled, sprayed, introduced into, or otherwise applied to a mammalian body or any part thereof. Cosmetic agents may include substances that are Generally Recognized as Safe (GRAS) by the US Food and Drug Administration, food additives, and materials used in non-cosmetic consumer products including over-the-counter medications. In some embodiments, cosmetic agents may be incorporated in a cosmetic composition comprising a dermatologically acceptable carrier suitable for topical application to skin. A cosmetic agent includes, but is not limited to, (i) chemicals, compounds, small or large molecules, extracts, formulations, or combinations thereof that are known to induce or cause at least one effect (positive or negative) on skin tissue; (ii) chemicals, compounds, small molecules, extracts, formulations, or combinations thereof that are known to induce or cause at least one effect (positive or negative) on skin tissue and are discovered, using the provided methods and systems, to induce or cause at least one previously unknown effect (positive or negative) on the skin tissue; and (iii) chemicals, compounds, small molecules, extracts, formulations, or combinations thereof that are not known have an effect on skin tissue and are discovered, using the provided methods and systems, to induce or cause an effect on skin tissue.

Some examples of cosmetic agents or cosmetically actionable materials can be found in: the PubChem database associated with the National Institutes of Health, USA; the Ingredient Database of the Personal Care Products Council; and the 2010 International Cosmetic Ingredient Dictionary and Handbook, 13^th Edition, published by The Personal Care Products Council; the EU Cosmetic Ingredients and Substances list; the Japan Cosmetic Ingredients List; the Personal Care Products Council, the SkinDeep database; the FDA Approved Excipients List; the FDA OTC List; the Japan Quasi Drug List; the US FDA Everything Added to Food database; EU Food Additive list; Japan Existing Food Additives, Flavor GRAS list; US FDA Select Committee on GRAS Substances; US Household Products Database; the Global New Products Database (GNPD) Personal Care, Health Care, Food/Drink/Pet and Household database; and from suppliers of cosmetic ingredients and botanicals.

Other non-limiting examples of cosmetic agents include botanicals (which may be derived from one or more of a root, stem bark, leaf, seed or fruit of a plant). Some botanicals may be extracted from a plant biomass (e.g., root, stem, bark, leaf, etc.) using one more solvents. Botanicals may comprise a complex mixture of compounds and lack a distinct active ingredient. Another category of cosmetic agents are vitamin compounds and derivatives and combinations thereof, such as a vitamin B3 compound, a vitamin B5 compound, a vitamin B6 compound, a vitamin B9 compound, a vitamin A compound, a vitamin C compound, a vitamin E compound, and derivatives and combinations thereof (e.g., retinol, retinyl esters, niacinamide, folic acid, panthenol, ascorbic acid, tocopherol, and tocopherol acetate). Other non-limiting examples of cosmetic agents include sugar amines, phytosterols, hexamidine, hydroxy acids, ceramides, amino acids, and polyols.

“Data architecture” refers generally to one or more digital data structures comprising an organized collection of data. In some embodiments, the digital data structures can be stored as a digital file (e.g., a spreadsheet file, a text file, a word processing file, a database file, etc.) on a computer readable medium. In some embodiments, the data architecture is provided in the form of a database that may be managed by a database management system (DBMS) that is be used to access, organize, and select data (e.g., instances and gene expression signatures) stored in a database.

“Disposed” refers to an element being located in a particular place or position relative to another element.

“Effective amount” means an amount of a compound or composition sufficient to significantly induce a positive or desired benefit, (e.g., a positive skin or feel benefit, reverse the expression of a gene, group of genes and/or gene signature), including independently or in combinations the benefits disclosed herein, but low enough to avoid serious side effects, i.e., to provide a reasonable benefit to risk ratio, within the scope of sound judgment of the skilled artisan.

“Gene expression signature” refers to a rationally derived list, or plurality of lists, of genes representative of a skin tissue condition or a skin agent. In specific contexts, the skin agent may be a benchmark skin agent or a potential skin agent. Thus, the gene expression signature may serve as a proxy for a phenotype of interest for skin tissue. A gene expression signature may comprise genes whose expression, relative to a normal or control state, is increased (up-regulated), whose expression is decreased (down-regulated), and combinations thereof. Generally, a gene expression signature for a modified cellular phenotype may be described as a set of genes differentially expressed in the modified cellular phenotype over the unmodified cellular phenotype. A gene expression signature can be derived from various sources of data, including but not limited to, from in vitro testing, in vivo testing and combinations thereof. In some embodiments, a gene expression signature may comprise a first list representative of a plurality of up-regulated genes of the condition of interest and a second list representative of a plurality of down-regulated genes of the condition of interest.

“Gene expression profiling” refers to the measurement of the expression of multiple genes in a biological sample using any suitable profiling technology. For example, the mRNA expression of thousands of genes may be determined using microarray techniques. Other emerging technologies that may be used include RNA-Seq or whole transcriptome sequencing using NextGen sequencing techniques. Gene expression profiling may be used to generate a gene expression signature.

“Joined” means configurations whereby an element is directly secured to another element by affixing the element directly to the other element, and configurations whereby an element is indirectly secured to another element by affixing the element to intermediate member(s) that in turn are affixed to the other element.

“Keratinous tissue,” means keratin-containing tissue layers disposed as the outermost protective covering of mammals which includes, but is not limited to, skin, hair, and nails.’

“Lateral” means a direction that is generally perpendicular to an imaginary centerline that bisects the human body into right and left mirror images. Directions that are within forty-five degrees of being perpendicular to the imaginary centerline are considered lateral.

“Longitudinal” means a direction that is generally parallel to an imaginary centerline that Bisects the human body into right and left mirror images. Directions that are within forty-five degrees of being parallel to the imaginary centerline are considered longitudinal.

“Microarray” refers broadly to any ordered array of nucleic acids, oligonucleotides, proteins, small molecules, large molecules, and/or combinations thereof on a substrate that enables gene expression profiling of a biological sample. Non-limiting examples of microarrays are available from Affymetrix, Inc.; Agilent Technologies, Inc.; Illumina, Inc.; GE Healthcare, Inc.; Applied Biosystems, Inc.; Beckman Coulter, Inc.; etc.

“Periorbital” means around the orbit of the eye. The periorbital region of a person is the area of the face generally disposed around the eye socket and typically lies between the bottom of the brow and the top of the cheek in the longitudinal direction and between the bridge of the nose and the temple in the lateral direction.

“Periorbital dyschromia” is a condition that occurs when the tone of skin in the periorbital region of person is noticeably different from the tone of skin in a nearby portion of the face, such as the cheek, nose, forehead, temple and/or another portion of the periorbital region. Perioribital dyschromia is bilateral, (i.e., it occurs in the periorbital region of both sides of the face). Periorbital dyschromia may appear as a result of hyperpigmented and/or hypopigmented skin disposed in the periorbital region. Periorbital dyschromia may be identified and/or classified according to one or more of the indicators described in more detail below. Periorbital dyschromia herein is classified into one of three types (i.e., Type I, Type II or Type III). The three types of periorbital dyschromia are described and defined in more detail below, and can be readily determined in accordance with the methods herein.

“Personal care composition” means a cosmetic composition or a skin care composition suitable. Is it to be appreciated that a personal care composition may provide both a cosmetic benefit and a skin health benefit,

“Reverse,” when referring to the gene expression of a gene, means that the expression of the gene is changed such that it is opposite of the expression indicated in a gene signature in a significant way (e.g., p-value <0.1, p-value <0.05, p-value <0.01, p-value <0.001, or p-value <0.0001 as determined by a statistical test like ANOVA or to a t-test). For example, if a gene expression signature indicates that a particular gene is up-regulated, then reversing the expression of the gene can mean that the gene is down-regulated relative to the indicated gene expression signature with a p-value of less than 0.05 as determined by a statistical test like ANOVA or t-test. When referring to gene expression signatures, the term “reversing” depends on the method used to determine the change in gene expression signature. For example, when using connectivity mapping, a connectivity score is generated to represent an amount of differential expression relative to a known gene expression signature, e.g., stored in a data architecture, and the connectivity score can be used as a measure of the amount of reversal in a gene expression signature in a significant way (e.g., p-value <0.1, p-value <0.05, p-value <0.01, p-value <0.001, or p-value <0.0001.

“Skin” means the outermost protective covering of mammals that is composed of cells such as keratinocytes, fibroblasts and melanocytes. Skin includes an outer epidermal layer and an underlying dermal layer. Skin may also include hair and nails as well as other types of cells commonly associated with skin, such as, for example, myocytes, Merkel cells, Langerhans cells, macrophages, stem cells, sebocytes, nerve cells and adipocytes.

“Skin care” means regulating and/or improving skin condition. Some nonlimiting examples of skin care benefits include improving skin appearance and/or feel by providing a smoother, more even appearance and/or feel; increasing the thickness of one or more layers of the skin; improving the elasticity or resiliency of the skin; improving the firmness of the skin; and reducing the oily, shiny, and/or dull appearance of skin, improving the hydration status or moisturization of the skin, improving the appearance of fine lines and/or wrinkles, improving skin texture or smoothness, improving skin exfoliation or desquamation, plumping the skin, improving skin barrier properties, improve skin tone, reducing the appearance of redness or skin blotches, and/or improving the brightness, radiancy, or translucency of skin. Some nonlimiting examples of “skin care products” include skin creams, moisturizers, lotions, and body washes.

“Skin-care active” means a compound or combination of compounds that, when applied to skin, provide an acute and/or chronic benefit to skin or a type of cell commonly found therein. Skin-care actives may regulate and/or improve skin or its associated cells (e.g., improve skin elasticity; improve skin hydration; improve skin condition; and improve cell metabolism).

“Skin-care composition” means a composition that regulates and/or improves skin condition.

“Skin tone” refers to the perceived color or pigmentation of skin, especially with regard to the evenness of the coloration or pigmentation. “Skin tone” may also include other characteristics of skin that contribute to a consumer perception of overall tone. For example, pore size and distribution, and skin texture may also be considered attributes of overall skin tone.

“Software” and “software application” mean one or more computer readable and/or executable instructions that cause a computing device or other electronic device to perform functions, actions, and/or behave in a desired manner. The instructions may be embodied in one or more various forms like routines, algorithms, modules, libraries, methods, and/or programs. Software may be implemented in a variety of executable and/or loadable forms and can be located in one computer component and/or distributed between two or more communicating, co-operating, and/or parallel processing computer components and thus can be loaded and/or executed in serial, parallel, and other manners. Software can be stored on one or more computer readable medium and may implement, in whole or part, the methods and functionalities of the present invention.

“Topical application” means to apply or spread the compositions of the present invention onto the surface of the keratinous tissue.

Before now, the underlying causes of periorbital dyschromia were not particularly well elucidated. However, it has unexpectedly been found that there are common themes associated with periorbital dyschromia that can lend themselves to differentiation based on a variety of relatively straightforward evaluation techniques. Previous attempts to classify periorbital dyschromia did not appreciate that periorbital dyschromia can be grouped into distinct categories based on the visual evaluation, imaging, biomarker, histology, and/or genetic analysis techniques disclosed herein. Based on these newly discovered distinctions, it is believed that the methods and systems described herein, individually and/or collectively, may enable the development and/or marketing of improved cosmetic products and/or treatment regimens particularly suited for treating different types of periorbital dyschromia.

Visual Evaluation

Periorbital dyschromia may be classified into three different types as well as a “No Dyschromia” condition using visual evaluation techniques. In particular, the location and/or tone(s) of a dyschromic portion of periorbital skin may be analyzed visually to determine whether perirorbital dyschromia is present and, if present, which type is present. For example, a No Dyschromia condition may be visually characterized by the lack of an uneven or discontinuous skin tone in the periorbital region. Visual evaluation may be done by an expert grader (i.e., someone trained to visually classify periorbital dyschromia), for example, as described in more detail in the Methods section below, or the visual classification may be done by a non-expert (e.g., a consumer who self-diagnoses) based on, for example, a set of instructions or a visual cue.

FIG. 1 illustrates the periorbital region 10 of a human face 5 divided into three zones. Zone 1 11 is disposed generally under the eye in the longitudinal direction (represented by the arrow Y) and extends under the eye in the lateral direction (represented by the arrow X) from the inner canthus 4 (i.e., the corner of the eye proximate the nose 20) to an area under the eye that is less than the complete distance to the outer canthus 6 (i.e., the corner of the eye spaced furthest from the nose). For example, as illustrated in FIG. 1, Zone 1 11 may extend from the inner canthus 4 to about the middle of the undereye portion of the periorbital region 10. But it is to be appreciated that, in some individuals, Zone 1 may extend more than halfway or less than halfway across the under-eye region, but typically not more than 90% of the distance from the inner canthus 4 to the outer canthus 6. Zone 2 12 extends from the distal edge of Zone 1 11 (i.e., the portion of Zone 1 furthest from the nose 20 in the lateral direction) to the outer canthus 6 of the eye. Zone 3 is disposed above the eye and extends laterally from the inner canthus 4 to the outer canthus 6. Zone 3 13 also extends generally in the longitudinal direction Y from the upper eyelid to the bottom of the eyebrow. In some embodiments, it may be desirable to use a target portion of skin disposed on the cheek 7 as a reference or control when evaluating the location and/or tones of periorbital dyschromia.

“Type I” periorbital dyschromia may be visually characterized by continuous discoloration of both the upper and lower eyelid skin. The dyschromic periorbital skin associated with Type I periorbital dyschromia typically includes substantially uniform brown, yellow and/or orange tones, which may resemble the color of tanned skin or an age spot. Additionally or alternatively, Type I periorbital dyschromia may be visually characterized by being generally present in Zones 1, 2 and 3 of the periorbital region of a person.

“Type II” may be visually characterized by continuous discoloration of the lower eyelid skin. The discolored periorbital skin associated with Type II periorbital dyschromia typically includes substantially uniform purple, pink and/or bluish tones, which may resemble bruised skin. Additionally or alternatively, Type II periorbital dyschromia may be visually characterized by being generally present in Zone 1 of the periorbital region and generally absent from Zone 2 and Zone 3.

“Type III periorbital dyschromia” typically includes a combination of characteristics of Types I and II, such as color and location in the periorbital region. In some instances, Type III perioribital dyschromia may be characterized by discontinuous discoloration of the undereye portion of the periorbital region, which is different from the more uniform discoloration associated with Types I and II. The patches of discolored periorbital skin associated with Type III periorbital dyschromia are generally present in Zone 1 and Zone 2 and may also be present in the inner portion of Zone 3 (i.e., the portion of Zone 3 that is closest to the nose).

FIGS. 2A and 2B illustrate examples of Type I periorbital dyschromia, which is represented by the shaded portions 200 and 201, respectively, of the periorbital region. FIGS. 3A and 3B illustrate examples of Type II periorbital dyschromia (i.e., the shaded portions 300 and 301, respectively, of the periorbital region). FIGS. 4A and 4B illustrate examples of Type III periorbital dyschromia (i.e., the shaded portions 400 and 401, respectively, of the periorbital region).

Imaging Classification—RGB

Type I, Type II and Type III periorbital dyschromia may be distinguished from one another using known imaging technique such as RGB and/or RBX® color imaging and/or gray scale imaging. An image of the region of interest (“ROI”) (e.g., periorbital region of a person) is captured by an image capture device, and at least a portion of the image is analyzed (e.g., by a computer) and assigned an imaging value based on the analysis. This determined imaging value may then be compared to a predetermined imaging value, which can be a single value or a range of values (e.g., one or more of the RGB values disclosed herein). The predetermined imaging value defines a particular type of periorbital dyschromia, and the comparison enables a user to identify which type of periorbital dyschromia, if any, is exhibited by the person. For example, RGB color imaging uses an additive color model wherein red, green, and blue light are added together in various ways to reproduce a broad array of colors. The RGB color model is particularly suited for sensing, representing, and displaying images in electronic systems such as televisions and computers. RGB is a device-dependent color model, which means that different devices may detect or reproduce a given RGB value differently, since the color elements (such as phosphors or dyes) and their response to the individual R, G, and B levels may vary from manufacturer to manufacturer, or even in the same device over time. Thus, it can be important to use color correction to ensure that an RGB value defines the same color across devices or in the same device over time. Color correction can be readily accomplished by one skilled in the art using commercially available software and techniques.

Classifying periorbital dyschromia according to the imaging classification methods and systems described herein depends on, among other things, the skin tone of an individual. For example, people who are Fitzpatrick I, II and III skin types according to the commonly known Fitzpatrick Scale, may have different color values associated with the different types of periorbital dyschromia as compared to people who are Fitzpatrick skin type IV, V or VI. In some of the examples and descriptions below, the different types of periorbital dyschromia are in relation to people who are Fitzpatrick skin type I, II and/or III (e.g., the imaging values and ratios). However, it is believed, without being limited by theory, that the classification methods and systems herein can be reapplied to people with Fitzpatrick IV, V and VI skin types in the substantially the same manner. In some instances, it may be desirable to normalize the imaging values of one or more zones in the periorbital region to a reference or control value such as an imaging value associated with the cheek. The normalized value may then be used to determine whether periorbital dyschromia is present and, if so, which type.

Type I periorbital dyschromia may be characterized by generally having lower RGB values relative to Types II and III as well as a different ratio of B value to G value (“B/G”). Type II periorbital dyschromia may be characterized by generally having higher RGB values compared to Types I and III. Type III periorbital dyschromia may include characteristics of both Type I and Type II. Tables 1, 2 and 3 below show ranges of color corrected RGB values, B/G ratios, L*a*b* values, chroma values and hue values that may be used to characterize Type I, Type II and Type III periorbital dyschromia, respectively, exhibited by a person having a Fitzpatrick skin type of I, II or III. The values provided in Tables 1, 2 and 3 correspond to a particular portion of the periorbital region referred to as a “mask.” Masks, and in particular Mask A, Mask B and Mask C are described in more detail below in the Imaging Method, which provides a suitable method of determining imaging values.

TABLE 1
Type I

	Imaging Value	Mask A	Mask B	Mask C
	R	118-166	135-187	128-178
	G	83-119	94-136	89-129
	B	76-108	81-112	79-112
	B/G	0.75-0.92	0.73-0.86	0.74-0.89
	L	48-54	43-61	41-59
	A	13-18	9-17	12-18
	b	9-23	14-25	12-23
	Hue (h)	35-53	42-60	39-56
	Chroma (C)	16-28	17-28	17-28

TABLE 2
Type II

	Imaging Value	Mask A	Mask B	Mask C
	R	148-176	165-201	159-186
	G	102-135	128-160	115-148
	B	96-128	108-145	103-136
	B/G	0.86-0.98	0.82-0.93	0.84-0.94
	L	48-60	57-69	52-64
	a	11-20	9-19	10-19
	b	7-16	10-20	9-17
	Hue (h)	24-54	33-61	32-57
	Chroma (C)	15-23	15-22	15-22

TABLE 3
Type III

	Imaging Value	Mask A	Mask B	Mask C
	R	142-172	160-188	153-177
	G	97-129	110-148	105-137
	B	88-114	92-129	90-119
	B/G	0.81-0.95	0.79-0.89	0.80-0.92
	L	46-57	51-64	49-60
	a	11-20	10-17	11-18
	b	9-19	13-21	11-19
	Hue (h)	29-54	42-62	36-57
	Chroma (C)	17-24	18-24	18-24

Imaging Classification—RBX

Attempts have been made in the past to classify periorbital dyschromia based on melanin and/or hemoglobin content, which are believed to be the chromophores primarily responsible for skin tone. For example, some previous attempts used conventional instruments (e.g., Mexameter MX-18) to measure the amount of melanin and hemoglobin in the skin. The measured values are then compared to the different types of periorbital dyschromia observed in test subjects to identify any correlations that might be used in classifying the different types of periorbital dyschromia. However, these past attempts concluded that measuring melanin and hemoglobin in this manner does not provide a useful tool for differentiating periorbital dyschromia.

In contrast with previous findings, it has been found that certain imaging technology such as RBX® brand imaging technology, available from Canfield Scientific, Inc., New Jersey, may provide a suitable distinction between Type I, Type II and Type III periorbital dyschromia, based on differences in the Red Channel and Brown channel images, which can correspond to the melanin and hemoglobin present in the skin. This is an unexpected finding, since previous studies have concluded that using imaging systems to measure colorants or chomophores in the skin does not provide a suitable means for classifying periorbital dyschromia.

RBX® brand imaging technology is based on the premise that skin color is characterized by a limited number of colorants, or chromophores, within the layers of skin. In normal, healthy skin, melanin particles, which are primarily responsible for the overall skin color, are small and uniformly distributed resulting in a smooth, even skin tone. Hemoglobin occurs within the vascular structure at the papillary dermis, a sub-layer of skin, in oxygenated and deoxygenated forms and is responsible for red colorations of skin tone. However, it may not be desirable to quantify skin pigmentation by only measuring the total attenuation of broadband light because, apart from melanin, hemoglobin in skin also absorbs visible light in a wavelength dependent manner. Therefore, methods are required to measure light absorbance in more than one spectral band. RBX® brand imaging technology transforms a conventional RGB image (e.g., captured by a conventional digital camera) into a color space where the Red and Brown channels represent hemoglobin and melanin distribution, respectively.

In some instances, Type I periorbital dyschromia may be characterized by relatively high Brown and Red channel contrast in the periorbital region as compared to other portions of the face (e.g., cheek, chin, nose or forehead). FIGS. 5A to 5E illustrate an example of Type I periorbital dyschromia observed in an RBX® image. FIG. 5A is a full color image of a test subject captured with a digital camera. As can be seen in FIG. 5A, periorbital dyschromia appears in Zones I, II and III of the periorbital region of the test subject. FIG. 5B shows the Brown Channel image that corresponds to the digital image of FIG. 5A. FIG. 5C shows the Red Channel image that corresponds to the digital image from FIG. 5A. FIG. 5D provides an illustration of the location of the periorbital dyschromia provided in FIG. 5B (i.e., in the Brown channel), and FIG. 5E provides an illustration of the location of the periorbital dyschromia provided in FIG. 5C (i.e., the Red Channel). As can be seen in FIG. 5C, and as illustrated in FIG. 5E, periorbital dyschromia is present in Zones 1 and 2 and in a portion of Zone 3. However, the periorbital dyschromia appearing in Zone 3 of FIG. 5C is not present in as large an area as the periorbital dyschromia in Zone 3 of FIG. 5B. This may suggest that melanin and hemoglobin both influence the appearance of Type I periorbital dyschromia, but melanin is the more abundant chromophore. FIG. 5E provides an illustration of the periorbital dyschromia that appears in FIG. 5C (i.e., in the Red Channel).

Type II periorbital dyschromia may be characterized by relatively low Brown Channel intensity values in the periorbital skin relative to the surrounding areas of face (e.g., cheek and forehead) and high Red Channel contrast in the periorbital region as compared to other portions of the face. FIGS. 6A to 6E illustrate an example of Type II periorbital dyschromia observed in an RBX®. FIG. 6A is an image of a subject captured with a digital camera. As can be seen in FIG. 6A, periorbital dyschromia appears in Zone 1, but appears to be substantially absent from Zones 2 and 3. FIG. 6B shows the Brown channel image that corresponds to the digital image of FIG. 6A. FIG. 6C shows the Red Channel image that corresponds to the digital image of FIG. 6A. FIG. 6D provides an illustration of the location of the periorbital dyschromia provided in FIG. 6B (i.e., in the Brown channel), and FIG. 6E provides an illustration of the location of the periorbital dyschromia provided in FIG. 6C (i.e., the Red Channel). As can be seen in FIG. 6C, and as illustrated in FIG. 6E, periorbital dyschromia is visible in Zone 1, but appears to be substantially absent from Zones 2 and 3. This may suggest that melanin does not play as significant a role as hemoglobin in Type II periorbital dyschromia.

Type III periorbital dyschromia may be characterized by discontinuous patches of Brown Channel and Red channel intensity in the periorbital region. FIGS. 7A to 7E illustrate an example of Type III periorbital dyschromia observed in an RBX® image. FIG. 7A is an image of a test subject captured with a digital camera. As can be seen in FIG. 7A, periorbital dyschromia appears in Zones 1 and 3, but appears to be substantially absent from Zone 2. FIG. 7B shows the Brown channel image that corresponds to the digital image from FIG. 7A. FIG. 7C shows the Red channel image that corresponds to the digital image from FIG. 7A. FIG. 7D provides an illustration of the location of the periorbital dyschromia provided in FIG. 7B (i.e., in the Brown channel), and FIG. 7E provides an illustration of the location of the periorbital dyschromia provided in FIG. 7C (i.e., the Red Channel). As can be seen in FIG. 7B, and as illustrated in FIG. 7D, periorbital dyschromia appears in Zones 1 and 3 of the periorbital region of the test subject. And as can be seen in FIG. 7C, and as illustrated in FIG. 7E, periorbital dyschromia appears in Zone 1, but appears to be substantially absent from Zones 2 and 3.

Histology

Type I, Type II and Type III periorbital dyschromia may be distinguished from one another using histological evaluation techniques that include, for example, sectioning and staining, followed by examination under a microscope (e.g., light or electron). In particular, it has been found that the abundance and/or location of certain cellular structures (e.g., melanin) within skin biopsy samples obtained from a discolored area of periorbital skin may be used to distinguish Type I, Type II and Type III periorbital dyschromia from one another. Skin tissue samples for use herein may be obtained, sectioned and/or stained according to any suitable method in the art. The Biopsy Method described in more detail below is an example of a suitable method of sample collection, sectioning and staining. Examples of conventional stains suitable for use herein include hematoxylin and eosin stain (“H&E stain”) and Fontana-Masson stain. H&E stain is a known for use in histology and involves the application of hemalum, which is a complex formed from aluminum ions and oxidized haematoxylin, to a tissue sample. The application of hemalum colors the nuclei of the cells in the sample dark blue or purple. The nuclear staining is followed by counterstaining with an aqueous or alcoholic solution of eosin Y, which colors eosinophilic structures such as cytoplasm in various shades of red, pink and orange. Fontana-Masson stain uses ammoniacal silver nitrate to detect cellular structures in a tissue sample that are capable of reducing the silver nitrate to metallic silver, which stains the structure black.

FIGS. 8 to 11 are micrograph images at 20× magnification of H&E-stained biopsy samples from skin disposed in the periorbital region of human test subjects. The samples were collected, sectioned and stained according to the Biopsy Method described in more detail below. Each test subject was classified as exhibiting Type I, Type II, Type III or No Dyschromia by an expert grader. The skin tissue sample shown in FIG. 8 is from a test subject classified as exhibiting No Dyschromia, and thus may serve as a suitable control. The dark (i.e., purple) bodies shown in FIG. 8 are nuclei of the various cells commonly disposed in the dermis and epidermis of an individual. The lighter (i.e., red/pink) stained areas between the nuclei corresponds to cytoplasm, connective tissue and glycoproteins.

The skin tissue sample shown in FIG. 9 is from a test subject classified as exhibiting Type I periorbital dyschromia. The white arrowheads shown in FIG. 9 point to deposits, which are brown in color when seen in a color micrograph, disposed around the nuclei of some of the cells in the sample. When the tissue samples are stained with Fontana-Masson stain, the deposits appear black (“Fontana-Masson positive deposits”), which indicates that they may be melanin. This is surprising because melanin is generally not associated with the dermis and is more commonly found in the epidermis. As can be seen in FIG. 9, the Fontana-Masson positive deposits are generally disposed around the nuclei of cells that appear to be clustered together underneath the epidermal-dermal junction. The clustered cells are believed to be fibroblasts, which account for the majority of cells typically found in a healthy dermis. Healthy fibroblasts generally appear as elongated, flat cells, but the clustered cells in FIG. 9 are round when viewed under a light microscope, which indicates that they may not be healthy fibroblasts. Thus, it is believed, without being limited by theory, that the presence of these melanin deposits in the dermis may be related to an underlying biological cause of Type I perioribital dyschromia. In particular, the round clustered appearance of the fibroblasts may be associated with an inflammation response. In view of this discovery, it may be desirable to provide a method and system of classifying periorbital dyschromia based, at least in part, on dermal melanin content. It may also be desirable to configure products and regimens suited for treating Type I periorbital dyschromia to address the presence of melanin in the dermis and/or the factors that may influence the presence of melanin in the dermis.

In addition to the discovery of unexpected amounts of Fontana-Masson positive deposits in the dermis, there also appeared to be an overabundance of melanin in the epidermis of periorbital skin tissue samples taken from Type I individuals. Thus, it may be desirable to tailor products for treating Type I periorbital dyschromia to include a cosmetic active that addresses the presence of excess melanin in the epidermis.

The skin tissue sample shown in FIG. 10 is a sample from a test subject classified as exhibiting Type II periorbital dyschromia. The Fontana-Masson positive deposits that can be seen in the dermis of the Type I sample of FIG. 9 are absent from the dermis of the Type II sample in FIG. 10. Thus, the underlying biological causes of Type I and Type II periorbital dyschromia may be different from one another, which is important since products and treatments suitable for one type of periorbital dyschromia may not suitable for another type. In particular, products and treatments for Type II periorbital dyschromia may not need to address the presence of melanin in the dermis.

Examination of the skin tissue samples taken from Type II individuals also showed a lack of melanin in the epidermis. Thus, it is also important to recognize that periorbital dyschromia may be influenced not only by hyperpigmentation (i.e., too much pigmentation), as suggested by some researchers, but surprisingly appears to be influenced by hypopigmentation (i.e., not enough pigmentation) as well.

The skin tissue sample shown in FIG. 11 is a sample obtained from a test subject classified as exhibiting Type III periorbital dyschromia. As indicated by the white arrowheads in FIG. 11, there are Fontana-Masson positive deposits present around the nuclei of some cells in the dermis, but not as many as seen in the Type I sample shown in FIG. 9. It is believed, without being limited by theory, that Type III periorbital dyschromia may occur as a result of one or more factors from Type I and Type II periorbital dyschromia acting to produce periorbital dyschromia that exhibits at least some of the characteristics of both of these types. For example, the unexpected presence of melanin in the dermis may indicate that Type III periorbital dyschromia shares a common underlying cause with Type I, but less severe as evidenced by a lower amount of dermal melanin relative to Type I. Thus, products and treatments suitable for treating Type III periorbital dyschromia may need to address the underlying causes of Type I and/or Type II periorbital dyschromia, but perhaps not to the same extent. For example, a product suitable for treating Type I periorbital dyschromia that includes an active for addressing the presence of melanin in the dermis may not need to include as much of the active.

Biomarker

Type I, Type II and Type III periorbital dyschromia may be distinguished from one another by collecting and analyzing the biomarkers present in periorbital skin. In particular, it has been found that the presence, absence and/or abundance of certain molecules in the epidermis of periorbital skin can be useful in distinguishing Type I, Type II and Type III periorbital dyschromia from one another. An example of such a molecule is pyrrole-2,3,5-tricarboxylic acid (“PTCA”), which is formed as a result oxidative degradation of eumelanin. It has been found that Type I and Type III periorbital dyschromia have higher PTCA levels than Type II, and that Type I may exhibit higher PTCA levels than Type III. FIG. 13 illustrates the comparison between PTCA levels of samples obtained from a subject classified as No Dyschromia 382, a subject who classified as Type I periorbital dyschromia 384, 2) a subject classified as Type II periorbital dyschromia 386, and 3) a test subject classified as Type III periorbital dyschromia 388. As illustrated in the chart 550 of FIG. 13, the PTCA levels of the Type I 384 and Type III 388 subjects was higher than the No Dyschromia 382 and the Type II subject 386 by a statistically significant amount. In contrast, the PTCA level of the Type II subject 386 was not higher than the No Dyschromia 382 by a statistically significant amount. PTCA levels herein are determined according to the Tape Stripping method described in more detail below.

Gene Expression

Type I, Type II and Type III periorbital dyschromia may be distinguished from one another by analyzing the expression of certain genes, individually or collectively, in the dermis and/or epidermis of periorbital skin. The gene expression signature of a periorbital skin sample may be obtained by any suitable means known in the art. For example, genetic material may be obtained from a tissue sample provide by a donor (e.g., full thickness skin biopsy that exhibits a condition of interest) and subsequently processed using any suitable technology such as, for example, microarray analysis or NextGen sequencing to provide a gene expression signature. The gene expression signatures of Type I, Type II and Type III periorbital dyschromia can then be compared to one another and/or a control to identify the differences in gene expression. Example 4 below provides an example of gene expression signatures associated with each of Type I, Type II and Type III periorbital dyschromia.

It may be desirable to distinguish the different types of periorbital dyschromia based on biological themes that correspond to the expression of certain genes, combinations of genes and/or gene families. That is, a technique sometimes referred to as theme analysis may be used to identify biological or phenotypic themes associated with the gene expression data that correspond to the different types of periorbital dyschromia. Theme analysis is a statistical analysis-based method for detecting biological patterns in gene expression data. The method uses an ontology of controlled vocabulary terms developed by the Gene Ontology (“GO”) Consortium [Ashburner, M. et al. (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet, 25, 25-29] that describe the biological processes, molecular functions and cellular components associated with gene products. Analysis involves statistical comparison of a regulated list of genes and a larger reference list of all the expressed genes, to determine if genes annotated to specific GO terms are significantly enriched in the regulated list. This analysis may reveal biological patterns when multiple genes associated with a given GO term occur on the regulated list at a frequency greater than expected by chance. Such analysis may be performed using Theme Extractor proprietary software and an algorithm that calculates a p-value of each ontology term. Data may be analyzed for statistical significance, for example, by the Fisher's Exact Test. Conventional approaches and statistical methods such as, for example, Gene Set Enrichment Analysis described by Subramanian, A., et al., in “Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles,” Proc. Natl. Acad Sci U.S.A, 102, 15545-155501 (2005) are suitable for conducting theme analysis herein.

Methods and Systems for Classifying Periorbital Discoloration

In some instances, the method herein includes indentifying a target portion of skin in the periorbital region of a person, evaluating the target skin portion based on the relevant characteristics described herein and classifying the person as having Type I, Type II or Type III periorbital dyschromia, if one or more characteristics associated with the relevant type of periorbital dyschromia are met. In some instances, the method may include classifying the type of periorbital dyschromia based solely on one of the foregoing distinguishing characteristics (i.e., visual characteristics such as RGB and/or RBX values, biomarkers, histology or gene expression). In some instances, the method includes classifying periorbital dyschromia based on a combination of two or more of the foregoing characteristics (e.g., visual and gene expression characteristics, visual and biomarker characteristics, or visual and histology characteristics).

Systems suitable for classifying periorbital discoloration herein may include an image capture device, an image analysis device, a means for communicating a type of periorbital dyschromia to a user of the system and, optionally, a set of instructions for using the system. The type of periorbital dyschromia may be selected from Type I, Type II and Type III as described herein. A user may also be classified as having No Dyschromia with the present system. The system may include a camera or similar device capable of capturing digital images of sufficient quality (e.g., greater than 8 megapixels per inch) for analysis by the image analysis device. The image capture device may be configured to store and/or transfer raw digital images and JPG digital image files. In some instances, the image analysis device may be a computer in electronic communication with the image capture device. The image analysis device should be capable of receiving and analyzing a raw digital image and/or a JPG image and converting the RGB color values of each pixel in the image to a more suitable color scale such as L*a*b* and, optionally, color and/or hue values (e.g., C* and h* values). Suitable image processing software (e.g., stored directly on the image analysis device or available for use or on the internal may be used by the image analysis device to process and/or analyze various aspects of the image. In some instances, it may be desirable to normalize the pixel colors of the image analysis system to reduce variation between images captured by different devices (e.g., using known color correction techniques and/or software). An exemplary method of normalizing an image analysis device is described in more detail below. Of course, it is to be appreciated that other suitable normalization techniques known in the art may be used.

The image analysis system may be configured to classify each pixel (or a predetermined number of pixels) into one of three groups (e.g., Type I, Type II and No Dyschromia) based on the color of the pixel. The image analysis system may then calculate the percent total number of pixels in each classification and determine which type of periorbital dyschromia is present or whether any periorbital dyschromia is present, based on the percentage of pixel types from each group. After determining the type of periorbital dyschromia present, if any, the system communicates the results of the analysis to the user, for example, visually via a monitor or television, audibly via a speaker or by any other suitable communication means known in the art.

In some embodiments, it may be desirable to place the system in a commercial environment such as a retail store to enable consumers to self-diagnose. In this way, a consumer would know which type of periorbital discoloration they might have and can select the appropriate cosmetic product to treat it.

Test Methods

Visual Classification Method

This method provides a suitable means to visually evaluate and classify periorbital dyschromia using expert graders. The visual evaluation can be done in-person as well as from images (e.g., cross-polarized images).

In-Person Grading

Prior to visual evaluation, the subjects are asked to wash their face and remove any make-up, especially eye make-up. The hair of the subject is covered with a hairnet and the head and shoulders of the subject are covered with black cloth. The subjects are asked to sit between two sets of lights that illuminate each side of their face without casting shadows or causing shine in the area of the eye. The expert grader assesses the subjects from a distance of approximately 60 cm, during which time subjects are asked to relax and refrain from making any facial expressions. The expert grader evaluates area, contrast and color of the periorbital region of the subject when classifying.

Image Grading

When visually evaluating and classify periorbital dyschromia from images, it may be desirable to capture an image of the region of interest of the test subject. To capture an image, prepare the subject by covering the hair of the subject with a hairnet and covering the head and shoulders of the subject with a black cloth. All jewelry that can be seen in an image is removed. The subject is seated on the adjustable stool and rotated towards the chin rest. The operator adjusts the stool such that the subject's chin rests comfortably on the chin rest. Front view images are captured using the Cross Polarized lighting modality. The images are evaluated in a dark room using professional color calibrated LCD monitors such as LACIE brand monitors. Graders are positioned approximately 60 cm from the monitor. Attributes such as area, intensity, contrast, color and continuity are evaluated for each subject.

Imaging Method

This method provides a suitable means for capturing a reproducible and analyzable image. Any suitable image capture device along with imaging software and other associated ancillary equipment (e.g., computer and lights) may be used. A particularly suitable imaging system is the Visia-CR® brand imaging system, available from Canfield Scientific, New Jersey. The Visia® brand imaging system incorporates a Canon® brand EOS-1Ds Mk III SLR camera, which includes a CMOS sensor and provides 21.1 Mega pixel resolution (14-bit A/D converter).

Images may be collected under different lighting modalities using standard light, UV, cross-polarization, parallel-polarization or a combination of these. For example, the values and ranges described herein are reported using a (D65/2) light source. One skilled in the art will appreciate that these values can be reported at a wide range of different illuminations (D50, D75, Illuminant A, F2, F7, F11, TL84, etc. or 2 or 10 degree observer) according to well known conversion methods, and when such conversions occur, the color values will typically change accordingly. In other words, even though the actual limits and/or ranges may change based on the conditions under which the image is captured, similar relationships among the values and ranges will still be seen. For example, if the camera has lower spectral sensitivity in the red channel than the camera described herein, the R channel response may be lower and the corresponding L*a*b*C*h* (“LabCh”) color values will be different, which in this case may result in lower a* values, higher b* values, and/or higher hues. Accordingly different camera sensitivities, lightings and relevant exposures are contemplated by the method herein, and the actual limits and/or ranges disclosed herein may vary according to the particular circumstances in which the image is captured without departing from the scope of the systems and/or methods described herein.

In preparation for image capture, test subjects are required to wash their faces and wait for at least 15 minutes to let their face dry. The hair of the subject is covered with a hairnet and the head and shoulders of the subject are covered with a black cloth. All jewelry that can be seen in an image area of interest is removed. The subject is positioned such that the subject's chin is resting comfortably on the chin rest of the imaging system, and a front image of the face (as opposed to a left-side or right-side image) can be suitably captured by the image capture device. After the subject is positioned, one or more images are captured (e.g., between 1 and 24, 2 and 20 or even between 3 and 15) with the subject's eyes open. It can be important to ensure that the subject's eyes are open when the image is captured, otherwise the closed upper eyelid may cause an inaccurate pigmentation reading. The captured image(s) are processed by converting the raw image to a .jpg file format.

Next, the .jpg format image is analyzed by a computer with suitable image analysis software. In some instances, it may be desirable to analyze only a portion of the image (e.g., Zone 1, 2 and/or 3 of the periorbital region). The portion of the image to be analyzed may be “masked,” for example, as shown in FIGS. 14 to 18, using image editing software such as Photoshop® or ImageJ®. The masked region can then be isolated and analyzed as a separate image. FIG. 14 illustrates an example of a masked region corresponding to Zone 1, which is referred to herein as “Mask A.” FIG. 15 illustrates an example of a masked region corresponding to Zone 2, which is referred to herein as “Mask B.” FIG. 16 illustrates an example of a masked region corresponding to Zones 1 and 2, which is referred to herein as “Mask C.” FIGS. 17 and 18 both illustrate an example of a masked region corresponding to the cheek. It is to be appreciated that the image need not necessarily be masked for suitable analysis, and in some instances the entire image may be analyzed. In some instances, it may be desirable to reduce the size of the image, mask and/or region of interest by several pixels (e.g., between 5 and 15 pixels) around the outer edge of the image where some shadowing may occur.

In some instances, it may be desirable to convert some or all of the RGB values in the image or a portion thereof to LabCh values. The LabCh values can be calculated using a suitable RGB conversion tool at D65 Illuminant and 2 degree observer (i.e., D65/2). This conversion can be performed by software installed on the computer or a suitable conversion tool may be found online. The conversion from RGB values to LabCh values can be performed on the entire image, a portion thereof or on one or more individual pixels. The resulting LabCh values may be averaged to provide average values for the image, mask or region of interest.

In some instances, the pixels may be analyzed individually and each pixel classified as corresponding to a particular type of periorbital dyschromia based on one or more of the LabCh values. When analyzed individually, the pixels may be analyzed according to their distribution across the different types of periorbital dyschromia. An example of classifying periorbital dyschromia based on individual pixel distributions is described below in Example 2. Since color may be perceived as being relative, depending on, for example, which instruments and/or imaging system is used, it can be important to color correct the masked region for each subject using a suitable color correction technique (e.g., according to International Color Consortium standards and practices), which helps make the color determination by the system less instrument specific. In some instances, it may be desirable to normalize the color in a region of interest (e.g., a masked region) to the basal skin tone of a nearby region (e.g., cheek). For example, the basal skin tone of the cheek may be obtained by masking a region of interest in the cheek (e.g., as illustrated in FIG. 20 or 21) and converting the RGB values in the masked region to L*a*b*C*h* values as described above. The resulting basal skin tone values for the cheek may then be subtracted from the corresponding values in the region of interest to provide normalized values. Color normalization may be performed on the entire region of interest (e.g., an average value for the ROI) or on a pixel by pixel basis for some or all of the pixels in the ROI, which may be 200,000 or more pixels. The following formula provides an illustration of color normalization.
DL1=Lpixel1−Lcheekave
DC1=Cpixel1−Ccheekave
Dh1=hpixel1−hcheek ave

• • Where DL, DC and Dh are the normalized L*, C*, and h* values, respectively, of a pixel in the mask region; Lpixel, Cpixel and hpixel are the respective L*, C* and h* values of the pixels as determined from the image analysis; and Lcheekave, Ccheekave and hcheekave are the respective average L*, C* and h* values determined for the cheek.
    Biopsy Method.

The biopsy method provides a suitable means for collecting, processing, storing and staining skin tissue samples. The biopsy also provides a suitable means for analyzing the skin samples for histological features associated with the different types of periorbital dyschromia. It is to be appreciated that certain portions of the method may refer to particular tools, equipment, or materials and the use thereof, but, unless indicated otherwise, one of ordinary skill in the art will recognize that equivalent tools, equipments and/or materials and the uses thereof may also be employed without departing from the scope of this method.

Sample Collection.

Skin tissue samples herein may be collected by means of a biopsy, which involves the physical removal of skin tissue from a subject. Biopsy samples collected for use herein may be removed according to any safe and aseptic biopsy method known in the art. For example, the biopsy samples may be collected from a living subject by a physician using conventional, aseptic techniques, and then flash frozen in liquid nitrogen and stored at −80° C. Eyelid biopsy sample collection involves the removal of skin tissue (down to the fatty layer) with, for example, a small elliptical surgical snip (e.g., Westcott™ brand scissors or equivalent). In at least some subjects, the elliptical shape of the incision allows for improved healing in the eyelid areas. Biopsy samples from other areas of skin on the body (e.g., cheek, forehead, arm or leg) may be obtained using, for example, a 2 mm sterile punch biopsy instrument. The size of the resulting punch biopsy sample is typically 2.0 mm in diameter and between 0.25 mm to 1.5 cm thick. In some instances, it may be desirable to suture the biopsy site.

Sample Storage

Biopsy samples should be frozen as soon as possible to minimize sample degradation Thus, it may be desirable to embed the biopsy samples in optimum cutting temperature (“OCT”) tissue freezing medium (e.g., Tissue-tek® brand OCT tissue freezing medium available from Sakura Finetek, Calif.) within 5 minutes of biopsy collection and store the samples in a suitable freezer at a temperature of −80° C. or less.

Sample Sectioning.

Frozen biopsy samples may be sectioned using a Microm HM500 brand cryostat or equivalent. The cryostat should include a microtome capable of producing multiple slices of sectioned tissue sample ranging from 5 to 300 μm in thickness. For example, 14 μm thick sectioned tissue samples are suitable for use herein. Sectioned tissue samples may be placed on slides or other support medium suitable for further analysis (e.g., viewing under a light microscope).

Sample Staining.

Hematoxylin and Eosin stain are commonly used in pathology to get an overall assessment of the tissue and determine if structural abnormalities are present. Commercially available kits such as the Shandon Rapid Chrome Frozen Section Kit available from Thermo Scientific may be used according to the manufacturer's protocol for H&E staining of the sectioned tissue samples. Other staining techniques suitable for identifying histological features in a skin tissue sample (e.g., commercially available Fontana-Masson staining kits) may also be used herein in accordance with a manufacturer's protocol and/or another suitable method known in the art.

Tape Stripping Method

This method provides a suitable means of obtaining PTCA and/or other biomarkers from biological samples collected from test subjects. It has been discovered that biological material collected in this way may be correlated to a type of periorbital dyschromia (i.e., Type I, Type II, Type III or No Dyschromia). Samples may be collected by contacting a suitable adhesive-containing substrate (“tape strip”) with a target skin surface such that biological material on and/or in the targeted skin portion adheres to the adhesive. Examples of suitable tape strips for use herein include D-Squame® brand polyacrylate ester adhesive tape (available from CuDerm; Dallas Tex.), Durapor, Sebutape™, and Tegaderm™ brand tape, duct tape (e.g., 333 Duct Tape, Nashua tape products), Scotch® brand tape (3M Scotch 810, St. Paul, Minn.), Diamond™ brand tape (The Sellotape Company; Eindhoven, the Netherlands), Sentega™ (polypropylene tape, Sentega Eiketten BV, Utrecht, The Netherlands).

The tape strips are digested with a suitable quantity and concentration of hydrogen peroxide to obtain PTCA from eumelanin. PTCA and its stable-isotope-labeled internal standard, PTCA-¹⁸O, are then isolated from the digest by a liquid-liquid extraction procedure. The extracted analyte is subjected to reverse-phase, high-performance liquid chromatographic (“HPLC”) analysis on a Waters Atlantis dC18 (3 μm 2.1×100 mm) or equivalent. Detection and quantitation of the PTCA is by tandem mass spectrometry (MS/MS) operating under multiple reaction monitoring conditions, as described in more detail below. Calibration standards are used to quantitate extracted Quality Control samples and unknown Study Specimens. The nominal range of quantitation is 0.15 to 100 ng of PTCA per sample. The concentration of PTCA is determined in the tape strip extract and then converted into total mass/tape strip by multiplying by the extraction volume. The squame scan total protein content found on the tape strips and extracts is determined and the final results are reported as total mass of analyte (ng or μg) per total weight of protein (μg) per sample. Specimen concentrations are determined by back-calculation using a weighted (1/x2) quadratic regression of a calibration curve generated from spiked matrix standards.

Sample Collection

A suitably sized tape strip (e.g., 14 mm diameter (circular) D-Squame® brand polyacrylate ester adhesive tape) is placed on a clean area of the target skin surface (e.g., periorbital region and/or cheek) and adequate pressure is applied to obtain the sample but not cause discomfort to the subject. The tape strip sample is then stored in a suitable storage container (e.g., storage tray or tube) until subjected to the digestion process.

PTCA Analysis

The tape strip sample is carefully removed from the storage container using tweezers. The tape strip sample is curled such that the adhesive-side faces inward and the non-adhesive side faces outward to reduce the possibility of contaminating the skin sample contained on the adhesive side of the tape. The curled tape strip sample is placed as deeply as possible into a 2 mL-polypropylene analysis tube in preparation for extraction of the biological material. The tape strip sample may be transferred to the analysis tube on the day of extraction or samples may be placed on storage plates and transferred to the 2 mL analysis tubes prior to extraction.

The tape strip sample is transferred from the 2 mL analysis tube to a 4 mL cryogenic Nalgene tube. A matrix blank is also prepared. The blank acts as a control and undergoes the sample process as the samples, but does not include a tape strip sample. 0.900 mL of 2 M ammonium hydroxide and 0.900 mL of 6% hydrogen peroxide are added to each of the Nalgene tubes, capped and vortexed. The tubes are placed on a rocker to incubate for three hours at 200 Mot/minute. The tubes are removed from the rocker and carefully uncapped to release any pressure that may build up during incubation. The liquid contents of each 4 mL Nalgene tube are transferred to separate 15 mL conical tubes. The tape strip is discarded and not transferred to the 15 mL conical tube. 32 μL of 10% sodium bisulfite is added to each 15 mL conical tube, capped and vortexed. Add 50 μL internal standard solution, cap and vortex. Internal standard solution is prepared as follows:

• • Using the appropriate Internal Standard Reference Standard (i.e., stable, isotope-labeled PTCA ¹⁸O) weigh approximately 5 mg of Internal Standard into a glass scintillation vial and record the weight to at least the nearest 0.01 mg. Add of the exact amount of 10 mM ammonium acetate solution to give exactly a 1.00 mg/mL solution of the compound according to the following equation:

Volume ⁢ ⁢ ( mL ) = Mass ⁢ ⁢ of ⁢ ⁢ material ⁢ ⁢ ( mg ) 1.0 ⁢ ⁢ mg / mL × Purity × SCF

• •  Where:
    • Purity=Decimal % purity assigned to the Analytical Reference Standard; and
    • SCF=salt correction factor.
  • Cap with a polytetraflouroethylene-lined cap and mix thoroughly and sonicate to dissolve the compound. Store the resulting solutions at −70 C.
    2.00 mL of methyl-tert-butyl ether, 1.00 mL of 37% HCL, and 1.00 mL of saturated ammonium sulfate are added to each tube. The tubes are capped and vortexed. Centrifuge the samples at 3,000 RPM for 15 minutes and then transfer 1.00 mL of the organic layer of each tube to separate liquid chromatography vials. Dry the vials down under nitrogen as is known in the art. Reconstitute the vials with 0.250 mL of ammonium acetate, cap and vortex. Analyze the samples by high-performance liquid chromatography (HPLC)/mass spectrometry (MS)/mass spectrometry (MS).

EXAMPLES

Example 1

This example illustrates how different types of periorbital dyschromia can be distinguished using the Visual Classification Method. The Munsell Book of Color, Matte Collection (Munsell Color, Inc.) nomenclature is used to describe the color appearance of the different types of periorbital dyschromia or the lack thereof. The basal skin tone in this example refers to overall tone of the skin on the cheek.

1. No Dyschromia: occurs when there is no discoloration present in the periorbital region, discoloration is present but the intensity is very low (“non-severe”), or the discoloration does not extend beyond the inner corner of the eye (e.g., into Zone 1).

2. Type 1 Periorbital Dyschromia: occurs when Zone 1, Zone 2 and Zone 3 of the periorbital skin region are affected with a “tanned-like” skin tone. The tanned-like appearance found on Type I periorbital dyschromia may result from a darkening of the periorbital skin and an increase of the chroma relative to the basal skin tone. In this scenario, the hue in the periorbital skin is similar to basal skin hue. The Munsell Book of Color, Matte Collection (Munsell Color, Inc.) nomenclature can be used to describe this visual classification. For example, a Caucasian female (i.e., Fitzpatrick skin type I to III) who has basal skin tone of 10R 7/4 according to the Munsell Color nomenclature (H V/C—which corresponds to “hue”, “value” (i.e., darkness) and “chroma” respectively), will be classified as Type 1 when the periorbital skin V value is 6 or lower and C value is 5 or higher (e.g., 10R 6/5 10R6/6, 10R 5/5, 10R 5/6). In another example, a Caucasian female with basal skin tone 10R 7/4 will be classified as Type I when the periorbital skin value 2.5YR 5/5 or 2.5YR 5/6.
3. Type II Periorbital Dyschromia: occurs when Zone 1 of the periorbital skin is affected with a “bruised-liked” tone relative to the basal skin. Bruised appearance of the periorbital skin can be a result of a darkening of the skin accompanied by a decrease in chroma relative to the basal skin tone. In this case, the periorbital skin hue may be similar to basal skin hue. For example, using the Munsell Matte Color collection, a Caucasian female with a basal skin tone of 10R 7/4 may manifest a bruised appearance characteristic of Type II periorbital dyschromia when the V value for Zone I and/or II drops to 6 or below and the chroma value drops to 4 or below (e.g., 10R 6/3, 10R6/2, 10R 5/3, 10R 5/2). The bruised appearance characteristic of Type II periorbital dyschromia can also result when the periorbital skin gets darker, chroma decreases and red hues are present. A Caucasian female with a basal skin tone of 10R 7/4 will manifest bruised appearance of Type II periorbital dyschromia when the periorbital skin hue is 7.5R, V is less than 7 and Chroma is less than 4 (e.g., 7.5R 6/2, 7.5R 5/2 7.5R 6/3, or 7.5R5/3).
4. Type III Periorbital Dyschromia: may occur when elements of both Type I and Type II periorbital dyschromia are present. Type III is typically observed in Zone I and Zone 2 of the periorbital region, and may a display “bruised-like” and “tanned-like” appearance. The “bruised-like” and “tanned-like” appearances may be observed in the same or different periorbital Zones simultaneously. For example, a Caucasian female may exhibit Type III periorbital dyschromia when Zone I displays a bruised appearance and Zone II displays tanned appearance. Type III periorbital dyschromia can also occur when bruised and tanned appearance occur simultaneously in Zone I and Type III can also occur when Zone 1 and/or Zone 2 of the periorbital region are affected with “bruised-like” and “tanned like” appearance and Zone 3 is effected by either “bruised-like” or “tanned-like” appearance. Type III can also occur when there is a darkening in the periorbital skin when compared to basal skin such as the cheek with no change in chroma value. For a Caucasian female with basal skin tone 10R 7/4, Type III periorbital dyschromia may occur from a darkening in the skin with no change in chroma, can be represented, for example, by 10R 6/4, 7.5R 6/4.

Example 2

This example illustrates the distinctions between Type I, Type II and Type III periorbital dyschromia using imaging methods. Using the methods described herein, images were obtained from test subjects identified as having Type I, Type II, or Type III periorbital dyschromia, and the RGB values and B/G ratios from each of zones 1, 2 and 4 were determined for each subject. Zone 4 refers to the combination of Zones 1 and 2. The zones were masked as described in the imaging analysis method above. Zone 4 was masked as illustrated in FIG. 16. Side-by-side plots of the various RGB values and B/G ratios are illustrated in FIGS. 19 to 30. The percentile shown on the y-axis of the charts in FIGS. 19 to 30 represents the percentile ranking of each individual in the distribution. The data point at the 50^th percentile represents the median of the data set (i.e., the individual who was in the middle of the rank ordered population). The X-axis shows the average imaging value for the region analyzed. As can be seen in FIGS. 19-30, those individuals who fall generally in the middle of the population distribution (e.g., between the 25^th and 75^th percentile; the 33^rd and 67^th percentile; or the 40^th and 60^th percentile) exhibit color imaging values that can be used to distinguish the different types of periorbital dyschromia from one another.

FIGS. 19-30 are side-by-side comparisons of graphical plots representing imaging values corresponding to Type I, Type II and Type III test subjects. FIG. 19 shows a side-by-side comparison of Zone 1 R values. FIG. 20 shows a side-by-side comparison of the Zone 1 B values. FIG. 21 shows a side-by-side comparison of the Zone 1 G values. FIG. 22 shows a side-by-side comparison of the Zone 1 B/G ratios. FIG. 23 shows a side-by-side comparison of the Zone 2 R values. FIG. 24 shows a side-by-side comparison of the Zone 2 G values. FIG. 25 shows a side-by-side comparison of the Zone 2 B values. FIG. 26 shows a side-by-side comparison of the Zone 2 B/G ratios. FIG. 27 shows a side-by-side comparison of the R values from Zone 4. FIG. 28 shows a side-by-side comparison of the B values from Zone 4. FIG. 29 shows a side-by-side comparison of the plots of the G values from Zone 4. FIG. 30 shows a side-by-side comparison of the plots of the B/G ratios from Zone 4.

Because skin is complex, there can be many different colors in a particular region of interest. Different people may appear to have some or all of the same colors present in particular area of skin, but the colors may be present at different percentages. And it is the distribution and/or preponderance of the different colors in the region of interest that drives how periorbital dyschromia is perceived. Thus, the images described in this Example were also analyzed on a pixel by pixel basis to determine if differences between different types of periorbital dyschromia could be observed. The RGB values for each pixel were converted to LabCh values as described in the imaging method above, and the L, C and h values were normalized to the cheek basal skin tone. The DL, Dc and Dh values of each pixel are classified as follows:

DL>−5: the pixel is not meaningfully darker than the nearby cheek skin (or it could even be lighter), these pixels were classified as No Dyschromia

DL<−5 and DC>2: the pixel is both darker and more chromatic than the nearby skin. These pixels are classified as Type I.

DL<−5 and DC<2: the pixel is darker, but without a meaningful increase in chroma. These pixels are classified as Type II periorbital dyschromia.

After each pixel was classified, the distribution of the pixels in the masked region was determined by counting the number of pixels classified as each type of periorbital dyschromia (i.e., No Dyschromia, Type I and Type II) and dividing by the total number pixels in each mask to obtain percentages, (e.g., % Type I=# pixels classified as Type I divided by Total # pixels) Table 1 illustrates how the different types of periorbital dyschromia may be classified based on the observations from the pixel by pixel analysis of the images.

	TABLE 4
		Subject
	Pixel Distribution	Classified as:
	>36.4% classified as Type I	Type I
	<9.6% classified as Type I; AND	Type II
	>21.2% classified as Type II
	>9.6% but less than 36.4%	Type III
	classified as Type I; AND >20%
	classified as Type II.
	<9.6% classified as Type I AND	No
	<21.2% classified as Type II.	Dyschromia

Example 3

This example further illustrates how imaging values can be used to distinguish Type I, Type II and Type III periorbital dyschromia. Using the methods described herein, images were obtained from test subjects identified as having Type I, Type II, or Type III periorbital dyschromia, and the color corrected imaging values for each of Mask A, Mask B and Mask C were determined for each image. Table 5 shows the resulting values.

TABLE 5
Type I

	Imaging Value	Mask A	Mask B	Mask C

	R	153	167	161
	G	108	123	116
	B	95	101	98
	B/G	0.87	0.82	0.84
	L	50	55	53
	a*	16	14	15
	b*	15	19	17
	Hue (h)	43	53	49
	Chroma (C)	22	23	23

TABLE 6
Type II

	Imaging Value	Mask A	Mask B	Mask C

	R	161	176	169
	G	119	135	128
	B	108	116	112
	B/G	0.91	0.86	0.88
	L	54	60	57
	a*	15	13	14
	b*	12	17	15
	Hue (h)	39	52	46
	Chroma (C)	20	21	20

TABLE 7
Type III

	Imaging Value	Mask A	Mask B	Mask C

	R	157	176	167
	G	113	133	124
	B	101	111	107
	B/G	0.89	0.84	0.86
	L	52	59	56
	a*	16	13	14
	b*	14	18	16
	Hue (h)	41	54	48
	Chroma (C)	21	23	22

This example illustrates the histological differences between No Dyschromia, Type I, Type II and Type III periorbital dyschromia. Biopsy samples were collected from upper eyelid, lower eyelid and the area of the face near the temple of fifty-five test subjects. The biopsy samples were collected, stored, sectioned and stained with H&E stain according to the Biopsy method above. An analysis of the sectioned and stained samples revealed the presence of deposits disposed around the nuclei of cells clustered together in the dermal region of the tissue sample. The deposits appeared brown in a color micrograph, and it is believed that the deposits are melanin. The samples were stained with Fontana-Masson stain and turned black (i.e., “Fontana-Masson positive deposits”), which indicates that the deposits may be melanin.

Thirty biopsy samples representative of the four different classifications were selected at random for further analysis (6 non-dyschromia samples, 9 Type I sample, 9 Type II samples, and 6 Type III samples). The thirty samples were analyzed at 20× magnification under an Olympus® Model BX51TRF brand light microscope. For the analysis, a minimum of two tissue sections and 8 fields of view (“FOV”), which is defined as the area of tissue that can be observed under 20× magnification, are analyzed per subject. The analysis revealed that Type I and Type III periorbital dyschromia exhibited higher amounts of the Fontana-Masson positive deposits on the dermis than Type II and those subjects identified as not having severe periorbital dyschromia. The average number of Fontana-Masson positive deposits per field of view is provided in Table 2 below. FIG. 12 graphically depicts the results illustrated in Table 2.

TABLE 8
	No
	Dyschromia	Type I	Type II	Type III

Subject 1	2.88	15.00	0.87	13.6
Subject 2	4.67	11.50	0.10	4.19
Subject 3	1.69	22.45	0.00	2.35
Subject 4	1.94	12.96	4.00	3.81
Subject 5	2.58	11.50	0.38	6.33
Subject 6	2.33	6.95	0.56	14.25
Subject 7		10.58	0.07
Subject 8		12.33	0.00
Subject 9		21.78	0.50
Average	2.68	13.89	0.75	7.42
STD DEV	0.43	1.49	0.45	2.12

As can be seen in Table 8 and FIG. 12, the Fontana-Masson positive deposits distinguish the different types of periorbital dyschromia from each other and from the control. The chart in FIG. 12 illustrates this distinction based on the difference in the average number of Fontana-Masson positive deposits observed per FOV under 20× magnification.

Example 4

This example illustrates the differences in gene expression between No Dyschromia, Type I, Type II and Type III periorbital dyschromia. In this example, gene expression profiles and phenotype themes were determined from biopsy samples of female test subjects aged 18 to 45 who were classified as exhibiting Type I, Type II or Type III periorbital dyschromia by an expert grader. Thirteen subjects were classified as Type I periorbital dyschromia, fourteen subjects were classified as Type II periorbital dyschromia, seven subjects were classified as Type III periorbital dyschromia, and 8 test subjects were classified as No Dyschromia. The biopsy samples were collected, stored and sectioned according to the Biopsy method described above. The epidermis and dermis layers of the section biopsy samples were separated with a PALM Microbeam IV™ brand Laser-capture Micro dissection (“LCM”) system (available from Carl Zeiss MicroImaging GmbH, Germany) in accordance with the manufacturer's instructions.

After separating the epidermal and dermal layers of the sectioned biopsy samples, each layer was subjected to RNA extraction. In this example, RNA was extracted from each of the epidermis and dermis layers by utilizing the Arcturs picopure kit according to the manufacturer's instructions. RNA quantification and quality assurance was performed using Agilence 2100 bioanalyzer. Of course it is to be appreciated that any suitable means of extracting RNA from a tissue sample known in the art may be used. The extracted RNA was then run on a GeneTitan U129 brand microarray to identify how certain genes were expressed in each sample. A statistical analysis of the microarray data was performed to derive the gene expression signatures. A general description of the statistical analysis is provided below. It is to be appreciated that while the statistical analysis below provides a suitable means of generating a gene signature from the microarray data, other statistical methods known in the art may also be suitable for use herein.

Filtering based on Present Calls

Filtering creates a list of potential genes for inclusion in the gene expression signature. For example, as a first filter step, at least 50% of the samples in one treatment group must have a “Present call” for each probe set. Present calls are derived from processing the raw microarray data and provide evidence that the gene transcript complementary to a probe set is actually expressed in the biological sample. The probes that are absent from all samples are likely to be just noisy measurements. It is important to filter out probe sets that do not contribute meaningful data to the signature. For all gene expression signatures in this example, the data was filtered for probe sets with at least 10% Present calls provided by the Affymetrix MAS 5 software.

Filtering According to a Statistical Measure

As a second filtering step, it may be desirable to use a suitable statistical measure such as, for example, p-values from a t-test, ANOVA, correlation coefficient, or other suitable model-based analysis. Limiting the gene signature list to genes that meet some reasonable cutoff (e.g., p ≤0.05, 0.01, 0.001, or even ≤0.0001 or less) for statistical significance compared to an appropriate control is important to allow selection of genes that are characteristic of the biological state of interest. This is preferable to using a fold change value, which does not take into account the noise around the measurements. For example, p-values may be chosen as the statistical measure and a cutoff value of p≤0.05 may be chosen. The t-statistic was used in this example to select the probe sets in the signatures because it provides an indication of the directionality of the gene expression changes (i.e. up- or down-regulated) as well as statistical significance.

Sorting the Probe Sets

All the probe sets are sorted into sets of up-regulated and down-regulated sets using the statistical measure. In this example, a t-test was used to compute p-values, the values (positive and negative) of the t-statistic are used to sort the list since p-values are always positive. The sorted t-statistics will place the sets with the most significant p-values at the top and bottom of the list with the less-significant p-values being placed towards the middle.

Creation of the Gene Expression Signature

Using the filtered and sorted list created, a suitable number of probe sets from the top and bottom are selected to create a gene expression signature that preferably has approximately the same number of sets chosen from the top as chosen from the bottom. For example, the gene expression signature created may have at least 10, 50, 100, 200, or 300 and/or less than 800, 600, or about 400 genes corresponding to a probe set on the chip. The number of probe sets approximately corresponds to the number of genes, but a single gene may be represented by more than one probe set. It is understood that the phrase “number of genes” as used herein, corresponds generally with the phrase “number of probe sets.”

U.S. Publication No. 2012/0283112 titled “Systems and Methods For Identifying Cosmetic Agents For Skin Care Compositions” filed by Binder, et al., on Feb. 22, 2012 and U.S. Publication No. 2013/0261007 titled “Systems, Models and Methods for Identifying and Evaluating Skin-Active Agents Effective for Treating Conditions and Disorders of Skin Pigmentation,” filed by Hakozaki, et al., on Mar. 27, 2012 disclose suitable nonlimiting examples of methods of generating a gene expression profile.

Tables 9 through 20 below show gene expression signatures associated with Type I, Type II or Type III periorbital dyschromia, as compared to the gene expression signature for No Dyschromia. The gene expression data was obtained by extracting RNA from lower eyelid biopsy samples obtained according to the biopsy method. Only genes that showed up-regulation or down-regulation with a p-value of 0.05 or less and fold change of 1.1 or more are shown. Table 9 shows the top 100 up-regulated genes expressed in the epidermis of subjects identified as having Type I periorbital dyschromia. Table 10 shows the top 100 down-regulated genes expressed in the epidermis of subjects identified as having Type I periorbital dyschromia. Table 11 shows the top 100 up-regulated genes expressed in the dermis of subjects identified as having Type I periorbital dyschromia. Table 12 shows the top 100 down-regulated genes expressed in the dermis of subjects identified as having Type I periorbital dyschromia. Table 13 shows the top 100 up-regulated genes expressed in the epidermis of subjects identified as having Type II periorbital dyschromia. Table 14 shows the top 100 down-regulated genes expressed in the dermis of subjects identified as having Type II periorbital dyschromia. Table 15 shows the top 71 up-regulated genes expressed in the dermis of subjects identified as having Type II periorbital dyschromia. Table 16 shows the top 100 down-regulated genes expressed in the dermis of subjects identified as having Type II periorbital dyschromia. Table 17 shows the top 100 up-regulated genes expressed in the epidermis of subjects identified as having Type III periorbital dyschromia. Table 18 shows the top 100 down-regulated genes expressed in the epidermis of subjects identified as having Type III periorbital dyschromia. Table 19 shows the top 100 up-regulated genes expressed in the dermis of subjects identified as having Type III periorbital dyschromia. Table 20 show the top 100 down-regulated genes expressed in the dermis of subjects identified as having Type III periorbital dyschromia.

TABLE 9
Type I Epidermis; Up-regulated

GeneTitan_ID	Gene	Title	Public ID	p
11719428_a_at	BTBD7	BTB (POZ) domain containing 7	AI580162	0.000259
11724297_a_at	BMP7	bone morphogenetic protein 7	NM_001719.2	0.000396
11715192_s_at	C7orf46	chromosome 7 open reading frame 46	g188219621	0.000446
11724759_s_at	CALM1	calmodulin 1 (phosphorylase kinase,	NM_006888.3	0.000486
		delta)
11735610_a_at	RPS6KA5	ribosomal protein S6 kinase, 90 kDa,	AF074393.1	0.000746
		polypeptide 5
11758022_s_at	TNNI2	troponin I type 2 (skeletal, fast)	AA728828	0.00151
11721260_a_at	WDR47	WD repeat domain 47	NM_001142550.1	0.001528
11727979_a_at	MAN2B2	mannosidase, alpha, class 2B,	BC094773.1	0.002024
		member 2
11753967_a_at	SLC6A2	solute carrier family 6	AK301811.1	0.002393
		(neurotransmitter transporter,
		noradrenalin), member 2
11722090_a_at	EFNA4	ephrin-A4	NM_005227.2	0.002687
11758092_s_at	EFNA5	ephrin-A5	BE464799	0.002776
11717146_at	PTPN1	protein tyrosine phosphatase, non-	NM_002827.2	0.002876
		receptor type 1
11716283_at	PAPD7	PAP associated domain containing 7	NM_006999.3	0.003497
11746140_a_at	ARHGEF26	Rho guanine nucleotide exchange	AF415176.1	0.003751
		factor (GEF) 26
11724038_a_at	PTGS2	prostaglandin-endoperoxide	BC013734.1	0.003867
		synthase 2 (prostaglandin G/H
		synthase and cyclooxygenase)
11723156_a_at	LSP1	lymphocyte-specific protein 1	NM_001013254.1	0.004011
11729840_s_at	ZCCHC2	zinc finger, CCHC domain containing 2	NM_017742.4	0.004086
11754302_a_at	ATP2A2	ATPase, Ca++ transporting, cardiac	BM676899	0.004156
		muscle, slow twitch 2
11754447_a_at	RPS6KA5	ribosomal protein S6 kinase, 90 kDa,	BM968829	0.00436
		polypeptide 5
11739724_a_at	ATP2B2	ATPase, Ca++ transporting, plasma	AL138283	0.004438
		membrane 2
11723075_a_at	BCL9L	B-cell CLL/lymphoma 9-like	AY296059.1	0.00493
11717385_a_at	MT1G	metallothionein 1G	NM_005950.1	0.005447
11758557_s_at	ZFP36L1	zinc finger protein 36, C3H type-like 1	AI758505	0.005544
11724628_a_at	MAT1A	methionine adenosyltransferase I,	NM_000429.2	0.005576
		alpha
11744955_a_at	ANXA1	annexin A1	AK296808.1	0.005629
11718966_at	NUFIP2	nuclear fragile X mental retardation	BU533767	0.006124
		protein interacting protein 2
11744953_a_at	ANXA1	annexin A1	BC034157.1	0.007553
11717387_x_at	MT1G	metallothionein 1G	NM_005950.1	0.007682
11727642_a_at	TRERF1	transcriptional regulating factor 1	AF111801.1	0.0078
11745806_a_at	AMMECR1L	AMME chromosomal region gene 1-like	AK095871.1	0.008163
11717514_a_at	ANXA1	annexin A1	NM_000700.1	0.008725
11744954_x_at	ANXA1	annexin A1	BC034157.1	0.009223
11743864_a_at	ATP2B1	ATPase, Ca++ transporting, plasma	S49852.1	0.009249
		membrane 1
11717927_at	FOXK2	forkhead box K2	NM_004514.3	0.009268
11717386_s_at	MT1G	metallothionein 1G	NM_005950.1	0.009421
11730080_x_at	IL28RA	interleukin 28 receptor, alpha	NM_170743.2	0.009429
		(interferon, lambda receptor)
11763297_x_at	CCDC76	coiled-coil domain containing 76	BQ614335	0.010042
11726119_at	RPGR	retinitis pigmentosa GTPase regulator	AK291832.1	0.01012
11739805_a_at	RASAL2	RAS protein activator like 2	AK075169.1	0.010243
11715190_s_at	C7orf46	chromosome 7 open reading frame 46	g188219617	0.010448
11726351_at	EFNA5	ephrin-A5	CB240929	0.010459
11738035_s_at	RTN4	reticulon 4	AK302741.1	0.010618
11724104_s_at	SGK3	serum/glucocorticoid regulated	NM_001033578.1	0.010735
		kinase family, member 3
11729396_a_at	NEK1	NIMA (never in mitosis gene a)-	Z25431.1	0.010781
		related kinase 1
11723592_at	LRRC8C	leucine rich repeat containing 8	NM_032270.4	0.011015
		family, member C
11757982_s_at	KIF21A	kinesin family member 21A	N39407	0.011191
11731899_s_at	PPAT	phosphoribosyl pyrophosphate	D13757.1	0.01137
		amidotransferase
11726633_s_at	TRIM8	tripartite motif-containing 8	BC021925.1	0.011932
11725675_a_at	RORA	RAR-related orphan receptor A	AA034012	0.012081
11745021_a_at	MYC	v-myc myelocytomatosis viral	K02276.1	0.012276
		oncogene homolog (avian)
11758246_s_at	ARL4D	ADP-ribosylation factor-like 4D	BM719529	0.012438
11726634_a_at	MYST3	MYST histone acetyltransferase	NM_001099412.1	0.012468
		(monocytic leukemia) 3
11735421_a_at	NKD2	naked cuticle homolog 2	AF358137.1	0.013343
		(Drosophila)
11723821_a_at	SMURF2	SMAD specific E3 ubiquitin protein	AY014180.1	0.013348
		ligase 2
11733165_s_at	YIPF5	Yip1 domain family, member 5	NM_001024947.2	0.013814
11723169_s_at	FOXN2	forkhead box N2	NM_002158.3	0.014398
11728958_x_at	E2F8	E2F transcription factor 8	NM_024680.2	0.014717
11762525_s_at			AF339086.1	0.015079
11731645_a_at	CAMKK2	calcium/calmodulin-dependent	BC026060.2	0.016269
		protein kinase kinase 2, beta
11730893_a_at	UBA6	ubiquitin-like modifier activating	EF623993.1	0.016784
		enzyme 6
11730360_at	CCDC126	coiled-coil domain containing 126	NM_138771.3	0.016798
11736426_s_at	CLIP4	CAP-GLY domain containing linker	BM994685	0.017149
		protein family, member 4
11725820_s_at	PAQR3	progestin and adipoQ receptor	NM_001040202.1	0.01721
		family member III
11743411_a_at	RBM25	RNA binding motif protein 25	BG251218	0.017641
11718873_a_at	ATP2A2	ATPase, Ca++ transporting, cardiac	NM_170665.3	0.018009
		muscle, slow twitch 2
11739797_a_at	RFX2	regulatory factor X, 2 (influences	NM_134433.2	0.018119
		HLA class II expression)
11739408_at	MLL3	myeloid/lymphoid or mixed-lineage	DN917896	0.018481
		leukemia 3
11734164_a_at	ARHGEF26	Rho guanine nucleotide exchange	NM_015595.3	0.018897
		factor (GEF) 26
11721039_a_at	SOLH	small optic lobes homolog	NM_005632.2	0.019352
		(Drosophila)
11721053_s_at	KLHDC5	kelch domain containing 5	NM_020782.1	0.01948
11753735_x_at	TMSB4X	thymosin beta 4, X-linked	BC101792.1	0.019698
11748149_a_at	FNBP1	formin binding protein 1	AK293743.1	0.019714
11728706_x_at	EMP2	epithelial membrane protein 2	DB374012	0.020127
11717989_a_at	SUN1	Sad1 and UNC84 domain containing 1	NM_001130965.1	0.020293
11722448_at	KCNMB4	potassium large conductance	AF160967.1	0.020548
		calcium-activated channel,
		subfamily M, beta member 4
11727512_at	UBN2	ubinuclein 2	CA775887	0.020981
11759962_at	TPRKB	TP53RK binding protein	AY643713.1	0.021007
11728603_a_at	CLDN23	claudin 23	NM_194284.2	0.0211
11743497_at	BMP2	bone morphogenetic protein 2	BX101090	0.021788
11718874_s_at	ATP2A2	ATPase, Ca++ transporting, cardiac	NM_170665.3	0.0218
		muscle, slow twitch 2
11721216_s_at	TMEM106B	transmembrane protein 106B	AA789109	0.021968
11718006_a_at	MYLIP	myosin regulatory light chain	BC002860.2	0.02198
		interacting protein
11719104_s_at	CPNE3	copine III	BC066597.1	0.022194
11723130_a_at	ARHGEF7	Rho guanine nucleotide exchange	NM_003899.3	0.022803
		factor (GEF) 7
11757700_a_at	NDFIP2	Nedd4 family interacting protein 2	AA521251	0.022979
11718081_a_at	ATP2B4	ATPase, Ca++ transporting, plasma	NM_001001396.1	0.023666
		membrane 4
11748034_a_at	CMAH	cytidine monophosphate-N-	D86324.1	0.02381
		acetylneuraminic acid hydroxylase
		(CMP-N-acetylneuraminate
		monooxygenase) pseudogene
11740148_x_at	ZNF429	zinc finger protein 429	NM_001001415.2	0.023983
11716408_a_at	MET	met proto-oncogene (hepatocyte	NM_001127500.1	0.024171
		growth factor receptor)
11720082_at	CBX6	chromobox homolog 6	NM_014292.3	0.024178
11733076_x_at	PPP1R12A	protein phosphatase 1, regulatory	AK314193.1	0.024224
		(inhibitor) subunit 12A
11743280_a_at	WNK1	WNK lysine deficient protein kinase 1	BC013629.2	0.024246
11719028_a_at	PSD3	pleckstrin and Sec7 domain	DB314358	0.024644
		containing 3
11757869_s_at	AKAP13	A kinase (PRKA) anchor protein 13	BE504033	0.024753
11722290_a_at	ZBTB43	zinc finger and BTB domain	AI745225	0.024875
		containing 43
11743865_s_at	ATP2B1	ATPase, Ca++ transporting, plasma	AI337321	0.025057
		membrane 1
11734994_s_at	SKI	v-ski sarcoma viral oncogene	NM_003036.3	0.025378
		homolog (avian)
11731857_x_at	MT1H	metallothionein 1H	NM_005951.2	0.026268
11758247_x_at	ARL4D	ADP-ribosylation factor-like 4D	BM719529	0.026757
11731787_x_at	ERC1	ELKS/RAB6-interacting/CAST family	NM_178037.1	0.026811
		member 1

TABLE 10
Type I Epidermis; Down-regulated

GeneTitan_ID	Gene	Title	Public ID	p
11763233_x_at	TRAC	T cell receptor alpha constant	EU427374.1	0.000086
11750712_a_at	SEMA4A	sema domain, immunoglobulin	AK296693.1	0.000205
		domain (Ig), transmembrane
		domain (TM) and short
		cytoplasmic domain,
		(semaphorin) 4A
11743350_a_at	C15orf48	chromosome 15 open reading	CA309087	0.000277
		frame 48
11723817_at	ARHGAP29	Rho GTPase activating protein 29	BU620659	0.000376
11723854_at	SAMD9	sterile alpha motif domain	NM_017654.2	0.000398
		containing 9
11754862_a_at	RARRES2	retinoic acid receptor	AK092804.1	0.000534
		responder (tazarotene induced) 2
11729515_a_at	SLC26A9	solute carrier family 26,	NM_052934.3	0.001204
		member 9
11748896_s_at	CCRL1	chemokine (C-C motif)	AK304461.1	0.001209
		receptor-like 1
11761960_x_at	TRAV20	T cell receptor alpha variable 20	AY532913.1	0.001367
11741285_a_at	CCRL1	chemokine (C-C motif)	BC069438.1	0.00144
		receptor-like 1
11754482_a_at	PSMB1	proteasome (prosome,	BQ006450	0.001693
		macropain) subunit, beta type, 1
11754184_a_at	ALDH1A3	aldehyde dehydrogenase 1	BX538027.1	0.001883
		family, member A3
11726829_at	TYW1B	tRNA-yW synthesizing protein 1	NM_001145440.1	0.001956
		homolog B (S. cerevisiae)
11725368_at	LRG1	leucine-rich alpha-2-	NM_052972.2	0.001997
		glycoprotein 1
11723561_x_at	C11orf75	chromosome 11 open reading	NM_020179.2	0.002048
		frame 75
11734507_s_at	MECOM	MDS1 and EVI1 complex locus	AK292865.1	0.002142
11716805_s_at	PLEKHA2	pleckstrin homology domain	NM_021623.1	0.002256
		containing, family A
		(phosphoinositide binding
		specific) member 2
11754057_x_at	CRABP2	cellular retinoic acid binding	BT019827.1	0.00239
		protein 2
11737108_a_at	CCRL1	chemokine (C-C motif)	NM_178445.1	0.002438
		receptor-like 1
11720080_at	NTRK2	neurotrophic tyrosine kinase,	NM_001007097.1	0.002467
		receptor, type 2
11715767_s_at	ACAA2	acetyl-CoA acyltransferase 2	NM_006111.2	0.002477
11715670_a_at	IFITM1	interferon induced	NM_003641.3	0.002619
		transmembrane protein 1 (9-27)
11735937_a_at	CD48	CD48 molecule	NM_001778.2	0.002662
11746503_a_at	EHF	ets homologous factor	AF203977.1	0.00321
11736806_at	GABRA4	gamma-aminobutyric acid	NM_000809.2	0.003627
		(GABA) A receptor, alpha 4
11720157_at	GDA	guanine deaminase	AK295716.1	0.003854
11720132_a_at	SPIRE1	spire homolog 1 (Drosophila)	BC125206.1	0.003917
11725832_s_at	OTUB2	OTU domain, ubiquitin	NM_023112.3	0.004105
		aldehyde binding 2
11717763_a_at	MGLL	monoglyceride lipase	BC006230.2	0.004157
11756683_a_at	CD1E	CD1e molecule	AK311643.1	0.004158
11728008_x_at	FUT3	fucosyltransferase 3	NM_000149.3	0.004308
		(galactoside 3(4)-L-
		fucosyltransferase, Lewis blood
		group)
11750244_a_at	MGLL	monoglyceride lipase	AK304844.1	0.004332
11724346_a_at	IFIH1	interferon induced with	NM_022168.2	0.004365
		helicase C domain 1
11750245_x_at	MGLL	monoglyceride lipase	AK304844.1	0.004459
11758377_s_at	TLR1	toll-like receptor 1	BU623316	0.004771
11740897_a_at	TREX2	three prime repair exonuclease 2	NM_080701.3	0.004847
11718077_s_at	MAPKAPK3	mitogen-activated protein	NM_004635.3	0.004908
		kinase-activated protein kinase 3
11763697_s_at	SNHG9	small nucleolar RNA host gene	AW958849	0.004956
		9 (non-protein coding)
11719591_s_at	GLTP	glycolipid transfer protein	NM_016433.3	0.005188
11715671_x_at	IFITM1	interferon induced	NM_003641.3	0.005216
		transmembrane protein 1 (9- 27)
11725641_at	EFHD2	EF-hand domain family,	CB240768	0.005381
		member D2
11727633_at	SLC16A10	solute carrier family 16,	BC066985.1	0.005429
		member 10 (aromatic amino
		acid transporter)
11717764_x_at	MGLL	monoglyceride lipase	BC006230.2	0.005967
11750324_a_at	GAS7	growth arrest-specific 7	AK293755.1	0.006052
11735833_a_at	KIAA1199	KIAA1199	NM_018689.1	0.006555
11757367_s_at	HSPA7	heat shock 70 kDa protein 7	BM677874	0.006575
		(HSP70B)
11741263_s_at	LTBP1	latent transforming growth	M34057.1	0.006584
		factor beta binding protein 1
11723235_a_at	IFI44L	interferon-induced protein 44-like	AB000115.1	0.006657
11729692_a_at	SERPINB3	serpin peptidase inhibitor,	EU852041.1	0.006806
		clade B (ovalbumin), member 3
11727385_a_at	PCCA	propionyl CoA carboxylase,	NM_000282.2	0.006811
		alpha polypeptide
11729742_x_at	IFI27L2	interferon, alpha-inducible	NM_032036.2	0.006823
		protein 27-like 2
11731973_at	SCNN1G	sodium channel, nonvoltage-	NM_001039.3	0.00716
		gated 1, gamma
11743404_at	ZMAT2	zinc finger, matrin-type 2	BM450158	0.007256
11736058_s_at	C10orf32	chromosome 10 open reading	NM_001136200.1	0.007371
		frame 32
11715239_x_at	IFITM3	interferon induced	g148612841	0.007374
		transmembrane protein 3 (1-8U)
11726154_at	CA6	carbonic anhydrase VI	NM_001215.2	0.007409
11718850_a_at	SRPK1	SRSF protein kinase 1	AK299591.1	0.007419
11729693_at	SERPINB3	serpin peptidase inhibitor,	EU852041.1	0.007514
		clade B (ovalbumin), member 3
11755950_a_at		coiled-coil domain containing 71	AK098658.1	0.007621
11740349_at	RNASE7	ribonuclease, RNase A family, 7	BC112334.1	0.007692
11757300_s_at	ELOVL5	ELOVL family member 5,	AL576414	0.007702
		elongation of long chain fatty
		acids (FEN1/Elo2, SUR4/Elo3-
		like, yeast)
11725310_at	CRISP3	cysteine-rich secretory protein 3	NM_006061.1	0.007915
11723490_at	GCLM	glutamate-cysteine ligase,	BC041809.1	0.008288
11757595_x_at	CRABP2	cellular retinoic acid binding	BU631189	0.008352
		protein 2
11752101_s_at	EIF2S1	eukaryotic translation initiation	BC002513.2	0.008373
		factor 2, subunit 1 alpha, 35 kDa
11737496_a_at	CD200R1	CD200 receptor 1	NM_170780.2	0.008378
11749745_a_at	SRP68	signal recognition particle	AK301100.1	0.008462
		68 kDa
11718142_a_at	TTC27	tetratripeptide repeat	NM_017735.3	0.00876
		domain 27
11737432_a_at	PAPL	iron/zinc purple acid	BC136722.1	0.008796
		phosphatase-like-protein
11753762_x_at	KLK6	kallikrein-related peptidase 6	AY457039.1	0.008902
11725875_at	WDR66	WD repeat domain 66	NM_144668.4	0.008916
11729694_s_at	SERPINB4	serpin peptidase inhibitor,	EU852041.1	0.009199
		clade B (ovalbumin), member 4
11763184_at	IDE	insulin-degrading enzyme	BQ006777	0.009364
11737743_a_at	ARSF	arylsulfatase F	NM_004042.3	0.009395
11724785_x_at	MRPS18C	mitochondrial ribosomal	BC005186.1	0.009553
		protein S18C
11723899_a_at	DHRS9	dehydrgenase/reductase (SDR	NM_005771.4	0.009689
		family) member 9
11743805_s_at	MRPL42	mitochondrial ribosomal	DB379276	0.009847
		protein L42
11758083_s_at	HPGD	hydroxyprostaglandin	AI743714	0.009851
		dehydrogenase 15-(NAD)
11727995_a_at	SPINKS	serine peptidase inhibitor	DQ149928.1	0.010277
		Kazal type 5
11727208_x_at	DDHD1	DDHD domain containing 1	NM_030637.1	0.010297
11737431_x_at	PAPL	iron/zinc purple acid	NM_001004318.2	0.010375
		phosphatase-like protein
11720510_a_at	APOBEC3G	apolopoprotein B mRNA editing	NM_021822.2	0.010471
		enzyme, catalytic polypeptide-
		like 3G
11719503_a_at	DHX36	DEAH (Asp-Glu-Ala-His) box	NM_020865.2	0.010702
		polypeptide 36
11753152_x_at	CFLAR	CASP8 and FADD-like apoptosis	AK297387.1	0.010705
		regulator
11726289_at	GRAMD3	GRAM domain containing 3	BC008590.1	0.010722
11722661_at	NFE2L3	nuclear factor (erythroid-	NM_004289.6	0.010893
		derived 2)-like 3
11716743_s_at	TJP2	tight junction protein 2 (zona	NM_004817.2	0.011228
		occludens 2)
11726894_a_at	IRAK3	interleukin-1 receptor-	BG929347	0.011364
		associated kinase 3
11753202_s_at	SERPINB4	serpin peptidase inhibitor,	AB046400.1	0.011604
		clade B (ovalbumin), member 4
11739292_at	EHF	ets homologous factor	NM_012153.3	0.012013
11748253_a_at	SLC5A1	solute carrier family 5	AK297665.1	0.01209
		(sodium/glucose
		cotransporter), member 1
11723953_a_at	CLINT1	clathrin interactor 1	NM_014666.2	0.01254
11736117_a_at	ZFAND5	zinc finger, AN1-type domain 5	AF062346.1	0.012593
11724795_at	ZG16B	zymogen granule protein 16	NM_145252.2	0.013029
		homolog B (rat)
11717765_a_at	MGLL	monoglyceride lipase	NM_007283.5	0.01317
11744194_a_at	ABCC3	ATP-binding cassette, sub-	CB055248	0.013406
		family C (CFTR/MRP), member 3
11746088_a_at	IFI44	interferon-induced protein 44	DB350079	0.013466
11733533_at	CYP4F22	cytochrome P450, family 4,	NM_173483.3	0.013708
		subfamily F, polypeptide 22
11746581_a_at	PCCA	propionyl CoA carboxylase,	AK298318.1	0.013745
		alpha polypeptide
11717981_a_at	ACP5	acid phosphatase 5, tartrate	NM_001611.3	0.014935
		resistant

TABLE 11
Type I Dermis; Up-regulated

GeneTitan_ID	Gene	Title	Public ID	p
11733167_at	LRRN4CL	LRRN4 C-terminal like	BC053902.1	0.000112
11720616_a_at	DNM1	dynamin 1	NM_001005336.1	0.000113
11758194_s_at	DPP4	dipeptidyl-peptidase 4	AI768728	0.000125
11759481_at	COPB1	Coatomer protein complex,	AU143964	0.000148
		subunit beta 1
11718627_at	TRAK1	trafficking protein, kinesin	CA415544	0.000173
		binding 1
11739544_a_at	C19orf12	chromosome 19 open reading	BX328123	0.000234
		frame 12
11743191_a_at	NTM	neurotrimin	AI343272	0.000278
11731649_x_at	NTM	neurotrimin	AY358331.1	0.000343
11723111_a_at	EMILIN2	elastin microfibril interfacer 2	NM_032048.2	0.000384
11719422_s_at	ABCC1	ATP-binding cassette, sub-	NM_004996.3	0.000385
		family C (CFTR/MRP),
		member 1
11739527_a_at	SECTM1	secreted and transmembrane 1	CR614987.1	0.000402
11758810_at	COL14A1	collagen, type XIV, alpha 1	NM_021110.1	0.000451
11724441_x_at	PTGIS	prostaglandin I2	NM_000961.3	0.000458
		(prostacyclin) synthase
11747944_a_at	PPFIA2	protein tyrosine phosphatase,	AK296380.1	0.000483
		receptor type, f polypeptide
		(PTPRF), interacting protein
		(liprin), alpha 2
11728451_a_at	PCOLCE2	procollagen C-endopeptidase	NM_013363.2	0.000493
		enhancer 2
11736086_a_at	HHIP	hedgehog interacting protein	NM_022475.1	0.000511
11758252_s_at	HSD3B7	hydroxy-delta-5-steroid	CB115219	0.000562
		dehydrogenase, 3 beta- and
		steroid delta-isomerase 7
11756706_a_at	DPP4	dipeptidyl-peptidase 4	AK314798.1	0.000563
11720690_a_at	C2orf18	chromosome 2 open reading	NM_017877.3	0.000604
		frame 18
11724619_at	RSPO3	R-spondin 3 homolog	NM_032784.3	0.000676
		(Xenopus laevis)
11743447_a_at	BICD2	bicaudal D homolog 2	AW409827	0.000721
		(Drosophila)
11725773_a_at	TBC1D24	TBC1 domain family, member 24	NM_020705.1	0.000726
11715704_x_at	ITGA5	integrin, alpha 5 (fibronectin	NM_002205.2	0.000766
		receptor, alpha polypeptide)
11756007_a_at	HHIP	hedgehog interacting protein	AK024645.1	0.000889
11741377_a_at	MMP2	matrix metallopeptidase 2	NM_001127891.1	0.000928
		(gelatinase A, 72 kDa
		gelatinase, 72 kDa type IV
		collagenase)
11734550_x_at	TGFBI	transforming growth factor,	NM_000358.2	0.000963
		beta-induced, 68 kDa
11730405_at	MEX3B	mex-3 homolog B (C. elegans)	BC111545.1	0.000968
11731648_a_at	NTM	neurotrimin	AY358331.1	0.000985
11740103_a_at	MAFG	v-maf musculoaponeurotic	BX427058	0.001077
		fibrosarcoma oncogene
		homolog G (avian)
11727783_s_at	TPM4	tropomyosin 4	NM_003290.2	0.001163
11718269_x_at	ANGPTL2	angiopoietin-like 2	AY358274.1	0.001231
11725897_at	TUBB1	tubulin, beta 1	BC033679.1	0.001234
11717803_a_at	NTN4	netrin 4	NM_021229.3	0.001243
11754476_x_at	DNM1	dynamin 1	BQ183716	0.00125
11746893_a_at	MPP1	membrane protein,	AK304538.1	0.001254
		palmitoylated 1, 55 kDa
11753088_a_at	MCTP1	multiple C2 domains,	AK297325.1	0.001305
		transmembrane 1
11717568_s_at	NQ01	NAD(P)H dehydrogenase,	NM_000903.2	0.001408
		quinone 1
11720051_at	SPOCK1	sparc/osteonectin, cwcv and	NM_004598.3	0.001423
		kazal-like domains
		proteoglycan (testican) 1
11757921_s_at	COL14A1	collagen, type XIV, alpha 1	AI248460	0.001424
11725923_s_at	ASAP2	ArfGAP with SH3 domain,	NM_001135191.1	0.001457
		ankyrin repeat and PH
		domain 2
11723225_a_at	CLDN11	claudin 11	BC013577.1	0.001495
11754368_a_at	FBN1	fibrillin 1	AB208840.1	0.001626
11758062_s_at	STK32B	serine/threonine kinase 32B	AI401203	0.001735
11740358_a_at	LILRB5	leukocyte immunoglobulin-	NM_001081443.1	0.001775
		like receptor, subfamily B
		(with TM and ITIM domains),
		member 5
11746200_s_at	EHD2	EH-domain containing 2	AK097126.1	0.001844
11747945_x_at	PPFIA2	protein tyrosine phosphatase,	AK296380.1	0.002036
		receptor type, f polypeptide
		(PTPRF), interacting protein
		(liprin), alpha 2
11720811_a_at	PAMR1	peptidase domain containing	NM_015430.2	0.002139
		associated with muscle
		regeneration 1
11731716_at	CCBP2	chemokine binding protein 2	NM_001296.4	0.002156
11754706_a_at	HHIP	hedgehog interacting protein	AK098525.1	0.002166
11722940_a_at	SRGAP2	SLIT-ROBO Rho GTPase	NM_001042758.1	0.00222
		activating protein 2
11724848_a_at	DIXDC1	DIX domain containing 1	DB358954	0.002285
11718842_a_at	C16orf62	chromosome 16 open reading	BC058845.1	0.002303
		frame 62
11734549_s_at	TGFBI	transforming growth factor,	NM_000358.2	0.002382
		beta-induced, 68 kDa
11734548_a_at	TGFBI	transforming growth factor,	NM_000358.2	0.002425
		beta-induced, 68 kDa
11731650_a_at	NTM	neurotrimin	NM_001048209.1	0.002477
11738845_x_at	NTM	neurotrimin	NM_001144059.1	0.002642
11726905_a_at	ARHGAP20	Rho GTPase activating protein 20	NM_020809.2	0.002644
11724735_a_at	PDPN	podoplanin	BC014668.1	0.002735
11755796_a_at	ADAM9	ADAM metallopeptidase	BC143924.1	0.002822
		domain 9
11726017_a_at	C17orf63	chromosome 17 open reading	AU253346	0.002907
		frame 63
11741286_a_at	CCRL1	chemokine (C-C motif)	AF110640.1	0.002908
		receptor-like 1
11743910_at	FAM69A	family with sequence	BQ015316	0.002927
		similarity 69, member A
11756911_a_at	C1QTNF3	C1q and tumor necrosis factor	BX640995.1	0.002969
		related protein 3
11746361_a_at	C7orf58	chromosome 7 open reading	BC030538.2	0.002971
		frame 58
11715703_s_at	ITGA5	integrin, alpha 5 (fibronectin	NM_002205.2	0.002995
		receptor, alpha polypeptide)
11735913_s_at	TNXB	tenascin XB	BC125114.1	0.003064
11730236_s_at	MYADM	myeloid-associated	AY358582.1	0.003084
		differentiation marker
11718267_a_at	ANGPTL2	angiopoietin-like 2	NM_012098.2	0.003114
11723217_x_at	SFXN3	sideroflexin 3	NM_030971.3	0.003152
11720286_a_at	TRAK1	trafficking protein, kinesin	BC015922.1	0.003236
		binding 1
11717133_a_at	MAFG	v-maf musculoaponeurotic	BF340448	0.003272
		fibrosarcoma oncogene
		homolog G (avian)
11717340_at	PTGFRN	prostaglandin F2 receptor	NM_020440.2	0.003311
		negative regulator
11729541_a_at	CAMKK2	calcium/calmodulin-	AB081337.1	0.003359
		dependent protein kinase
		kinase 2, beta
11718268_a_at	ANGPTL2	angiopoietin-like 2	AY358274.1	0.003373
11717413_a_at	WIPI1	WD repeat domain,	NM_017983.5	0.003406
		phosphoinositide interacting 1
11716226_a_at	LIMA1	LIM domain and actin binding 1	BC136763.1	0.003456
11740588_at	BDKRB2	bradykinin receptor B2	NM_000623.3	0.003464
11741128_a_at	CAPN2	calpain 2, (m/II) large subunit	NM_001146068.1	0.003473
11717891_a_at	ECM1	extracellular matrix protein 1	BC023505.2	0.003509
11730385_at	GREM2	gremlin 2	BG150451	0.003541
11756245_s_at	ANXA5	annexin A5	CR607543.1	0.003586
11721499_x_at	CTSA	cathepsin A	NM_001127695.1	0.003681
11717757_s_at	RALA	v-ral simian leukemia viral	AA548928	0.003773
		oncogene homolog A (ras
		related)
11723075_a_at	BCL9L	B-cell CLL/lymphoma 9-like	AY296059.1	0.003835
11748650_a_at	ADAM33	ADAM metallopeptidase	BC125113.1	0.003846
		domain 33
11758676_s_at	RHOQ	ras homolog gene family,	R23125	0.003853
		member Q
11724260_a_at	TRIO	triple functional domain	AF091395.1	0.004049
		(PTPRF interacting)
11724541_s_at	VWF	von Willebrand factor	NM_000552.3	0.004078
11716549_s_at	ISLR	immunoglobulin superfamily	NM_005545.3	0.0042
		containing leucine-rich repeat
11724228_at	RBMS1	RNA binding motif, single	BC080620.1	0.004204
		stranded interacting protein 1
11752423_a_at	F13A1	coagulation factor XIII, A1	AK304335.1	0.004293
		polypeptide
11757340_s_at	RHOQ	ras homolog gene family,	BM677515	0.004317
		member Q
11750650_a_at	PAMR1	peptidase domain containing	AK297092.1	0.004367
		associated with muscle
		regeneration 1
11735263_s_at	SCN2A	sodium channel, voltage-	NM_001040142.1	0.004453
		gated, type II, alpha subunit
11731682_at	CD70	CD70 molecule	NM_001252.3	0.004492
11737108_a_at	CCRL1	chemokine (C-C motif)	NM_178445.1	0.004501
		receptor-like 1
11743251_s_at	MMP2	matrix metallopeptidase 2	BX357054	0.004507
		(gelatinase A, 72 kDa
		gelatinase, 72 kDa type IV
		collagenase)
11727782_a_at	TPM4	tropomyosin 4	NM_003290.2	0.004515
11755955_a_at	FAP	fibroblast activation protein,	AL832166.1	0.004528
		alpha
11725868_at	SSC5D	scavenger receptor cysteine-	NM_001144950.1	0.004768
		rich glycoprotein

TABLE 12
Type I Dermis; Down-regulated

GeneTitan_ID	Gene	Title	Public ID	p
11718273_a_at	EIF3L	eukaryotic translation	NM_016091.2	0.000001
		initiation factor 3, subunit L
11729152_a_at	EIF3M	eukaryotic translation	NM_006360.3	0.000006
		initiation factor 3, subunit M
11755203_x_at	RPL21	ribosomal protein L21	BX647669.1	0.000006
11757356_x_at	RPL30	ribosomal protein L30	BM855760	0.000008
11717236_x_at	RPS7	ribosomal protein S7	NM_001011.3	0.000009
11745362_x_at	RPS11	ribosomal protein S11	BC100025.1	0.000009
11757363_x_at	RPS15A	ribosomal protein S15a	DB313157	0.000009
200062_PM_s_at	RPL30	ribosomal protein L30	L05095.1	0.000009
11716092_x_at	CKS1B	CDC28 protein kinase	NM_001826.2	0.00001
		regulatory subunit 1B
11743094_at	SPRR4	small proline-rich protein 4	BC069445.1	0.000011
11757421_x_at	RPL31	ribosomal protein L31	CD687230	0.000011
11718274_s_at	EIF3L	eukaryotic translation	NM_016091.2	0.000012
		initiation factor 3, subunit L
11715376_a_at	RPS11	ribosomal protein S11	NM_001015.3	0.000015
11757773_x_at	NCRNA00275	non-protein coding RNA 275	BF185165	0.000015
11753659_x_at	RPL30	ribosomal protein L30	BC095426.1	0.000016
11753694_x_at	RPS15A	ribosomal protein S15a	AB062400.1	0.000017
11755956_x_at	POLE3	polymerase (DNA directed),	AF070640.1	0.000017
		epsilon 3 (p17 subunit)
200063_PM_s_at	NPM1	nucleophosmin (nucleolar	BC002398.1	0.000017
		phosphoprotein B23,
		numatrin)
11740643_a_at	CYP4F8	cytochrome P450, family 4,	AF133298.1	0.00002
		subfamily F, polypeptide 8
11757305_x_at	RPSAP58	ribosomal protein SA	BI762726	0.000021
		pseudogene 58
11715958_s_at	RPL7	ribosomal protein L7	NM_000971.3	0.000023
11719783_at	RPS23	ribosomal protein S23	D14530.1	0.000027
11745154_a_at	NCL	nucleolin	BC006516.2	0.000027
11720183_s_at	EEF1B2	eukaryotic translation	NM_001959.3	0.000029
		elongation factor 1 beta 2
11753691_x_at	RPL24	ribosomal protein L24	CR456729.1	0.000031
200013_PM_at	RPL24	ribosomal protein L24	NM_000986.1	0.000034
11718275_x_at	EIF3L	eukaryotic translation	NM_016091.2	0.000037
		initiation factor 3, subunit L
11744326_s_at	RPL37	ribosomal protein L37	BC079477.1	0.000037
11757264_s_at	RPS3	ribosomal protein S3	BU588459	0.000038
200010_PM_at	RPL11	ribosomal protein L11	NM_000975.1	0.000039
11757027_x_at	RPL31	ribosomal protein L31	CR600452.1	0.000042
200018_PM_at	RPS13	ribosomal protein S13	NM_001017.1	0.000046
11757375_x_at	RPS15	ribosomal protein S15	AI625563	0.000047
11754031_s_at	CKS1B	CDC28 protein kinase	BT007196.1	0.000051
		regulatory subunit 1B
11715733_a_at	NIPSNAP1	nipsnap homolog 1 (C.	NM_003634.2	0.000054
		elegans)
11740644_x_at	CYP4F8	cytochrome P450, family 4,	AF133298.1	0.000061
		subfamily F, polypeptide 8
11736188_a_at	ORMDL3	ORM1-like 3 (S. cerevisiae)	NM_139280.1	0.000071
11730527_a_at	DAPK2	death-associated protein	AF052941.1	0.000088
		kinase 2
		peroxisomal membrane
11723312_a_at	PXMP2	protein 2, 22kDa	NM_018663.1	0.000092
11734833_s_at	TAF9B	TAF9B RNA polymerase II,	NM_015975.4	0.000093
		TATA box binding protein
		(TBP)-associated factor,
		31kDa
11732205_x_at	NAP1L1	nucleosome assembly	BX413854	0.000099
		protein 1-like 1
11752912_x_at	EIF3M	eukaryotic translation	AK292139.1	0.000099
		initiation factor 3, subunit M
11756437_x_at	RPS18	ribosomal protein S18	BQ057441	0.0001
11729011_at	CDH22	cadherin 22, type 2	NM_021248.1	0.000107
11734329_at	TNN	tenascin N	NM_022093.1	0.000107
11749558_a_at	CYP4F8	cytochrome P450, family 4,	AK300530.1	0.000119
		subfamily F, polypeptide 8
200029_PM_at	RPL19	ribosomal protein L19	NM_000981.1	0.000121
11757386_x_at	NPM1	nucleophosmin (nucleolar	AL563600	0.000122
		phosphoprotein B23,
		numatrin)
11733774_a_at	RPL37	ribosomal protein L37	NM_000997.4	0.000123
11729427_a_at	GLI1	GLI family zinc finger 1	NM_005269.2	0.000126
11754066_x_at	NPM1	nucleophosmin (nucleolar	BT007011.1	0.000128
		phosphoprotein B23,
		numatrin)
11715626_a_at	RPL11	ribosomal protein L11	NM_000975.2	0.00013
11757489_x_at	RPL22	ribosomal protein L22	AW268528	0.00013
11757355_x_at	RPL41	ribosomal protein L41	BU958994	0.000138
11752726_x_at	GNB2L1	guanine nucleotide binding	AY159316.1	0.000144
		protein (G protein), beta
		polypeptide 2-like 1
11728288_a_at	KRT15	keratin 15	NM_002275.3	0.000153
11756783_a_at	TF	transferrin	BC045772.1	0.000155
11757331_x_at	RPL13A	ribosomal protein L13a	BF688481	0.000157
11744365_a_at	NCRNA00275	non-protein coding RNA 275	AY513722.1	0.000159
11739727_x_at	NAP1L1	nucleosome assembly	BE965760	0.00016
		protein 1-like 1
200074_PM_s_at	RPL14	ribosomal protein L14	U16738.1	0.000161
200089_PM_s_at	RPL4	ribosomal protein L4	AI953886	0.000162
11734331_a_at	TNN	tenascin N	BC136619.1	0.000163
11757906_x_at	RPL10	ribosomal protein L10	AL558950	0.000167
11715645_s_at	C22orf28	chromosome 22 open	NM_014306.4	0.00018
		reading frame 28
11756875_x_at	COMMD6	COMM domain containing 6	CR603325.1	0.000184
11722318_a_at	EFNB3	ephrin-B3	NM_001406.3	0.000198
11756878_a_at	FBL	fibrillarin	CR593763.1	0.000198
11736721_x_at	RPL32	ribosomal protein L32	NM_001007073.1	0.000199
11720184_x_at	EEF1B2	eukaryotic translation	NM_001959.3	0.0002
		elongation factor 1 beta 2
11749786_x_at	HNRNPF	heterogeneous nuclear	AK296696.1	0.000201
		ribonucleoprotein F
11717058_x_at	RPL5	ribosomal protein L5	NM_000969.3	0.00021
11752911_a_at	EIF3M	eukaryotic translation	AK292139.1	0.000211
		initiation factor 3, subunit M
11730790_x_at	NPM1	nucleophosmin (nucleolar	AK290652.1	0.000213
		phosphoprotein B23,
		numatrin)
11753680_x_at	RPL21	ribosomal protein L21	CR457032.1	0.000213
200022_PM_at	RPL18	ribosomal protein L18	NM_000979.1	0.000213
200014_PM_s_at	HNRNPC	heterogeneous nuclear	NM_004500.1	0.000215
		ribonucleoprotein C (C1/C2)
11742667_x_at	RPS28	ribosomal protein S28	NM_001031.4	0.000242
200082_PM_s_at	RPS7	ribosomal protein S7	AI805587	0.00025
11728380_x_at	NACA2	nascent polypeptide-	NM_199290.2	0.000252
		associated complex alpha
		subunit 2
11756140_s_at	RPL4	ribosomal protein L4	BX447218	0.000254
11716304_a_at	ABHD14B	abhydrolase domain	NM_032750.2	0.000267
		containing 14B
11758357_x_at	RPL9	ribosomal protein L9	BF172613	0.000272
11715280_s_at	KRT17	keratin 17	g197383031	0.000274
11739813_a_at	FZD1	frizzled homolog 1	BF675672	0.000295
		(Drosophila)
11721885_s_at	CDC42	cell division cycle 42 (GTP	NM_001039802.1	0.000307
		binding protein, 25kDa)
11720954_s_at	RPL30	ribosomal protein L30	NM_000989.2	0.000309
11743688_at	GLI2	GLI family zinc finger 2	AB209354.1	0.000312
11720599_s_at	SUB1	SUB1 homolog	NM_006713.3	0.000315
		(S. cerevisiae)
11725875_at	WDR66	WD repeat domain 66	NM_144668.4	0.000318
11733496_x_at	COMMD6	COMM domain containing 6	AA535445	0.000323
11727795_x_at	EIF3E	eukaryotic translation	NM_001568.2	0.000327
		initiation factor 3, subunit E
11756215_x_at	UBA52	ubiquitin A-52 residue	BU619323	0.000331
		ribosomal protein fusion
		product 1
11757059_x_at	RPL36A	ribosomal protein L36a	CR617894.1	0.000331
200012_PM_x_at	RPL21	ribosomal protein L21	NM_000982.1	0.000335
11718344_a_at	CNOT7	CCR4-NOT transcription	NM_013354.5	0.00035
		complex, subunit 7
11717235_s_at	RPS7	ribosomal protein S7	NM_001011.3	0.000352
11757113_a_at	SNHG1	small nucleolar RNA host	6E836747	0.000365
		gene 1 (non-protein coding)
11743679_a_at	PTCH1	patched 1	DB299015	0.000374
11744366_a_at	NCRNA00275	non-protein coding RNA 275	CR936805.1	0.000378

TABLE 13
Type II Epidermis; Up-regulated

GeneTitan_ID	Gene	Title	Public ID	p
11729461_a_at	CTNS	cystinosis, nephropathic	NM_001031681.2	0.000105
11737824_a_at	STX16	syntaxin 16	NM_001134773.1	0.000753
11731828_at	GPC2	glypican 2	NM_152742.1	0.000819
11757259_x_at	SCARNA9L	small Cajal body-specific	NR_023358.1	0.000852
		RNA 9-like
		(retrotransposed)
11728498_a_at	SVIL	supervillin	NM_003174.3	0.001387
11733298_a_at	VIPR1	vasoactive intestinal	NM_004624.3	0.00166
		peptide receptor 1
11754972_s_at	BAZ2A	bromodomain adjacent to	AK127775.1	0.001742
		zinc finger domain, 2A
11732899_s_at	SULT1AI	sulfotransferase family,	NM_177528.1	0.001887
		cytosolic, 1A, phenol-
		preferring, member 1
11716708_a_at	DDR1	discoidin domain receptor	NM_013993.2	0.001925
		tyrosine kinase 1
11757623_s_at	RNF5	ring finger protein 5	AA923467	0.00209
11715799_s_at	BAT2L1	HLA-B associated	NM_013318.3	0.002325
		transcript 2-like 1
11756190_a_at	CLK3	CDC-like kinase 3	CD743118	0.002384
11726634_a_at	MYST3	MYST histone	NM_001099412.1	0.002824
		acetyltransferase
		(monocytic leukemia) 3
11752331_s_at	SULT1A4	sulfotransferase family,	BC111011.1	0.002837
		cytosolic, 1A, phenol-
		preferring, member 4
11731093_s_at	BRD1	bromodomain containing	NM_014577.1	0.002905
		1
11744831_a_at	RPAIN	RPA interacting protein	AY775316.1	0.002976
11744173_x_at	DNAJC4	DnaJ (Hsp40) homolog,	BQ267791	0.00329
		subfamily C, member 4
11723546_s_at	PLD1	phospholipase D1,	BF434088	0.003418
		phosphatidylcholine-
		specific
11732589_a_at	ZNF467	zinc finger protein 467	NM_207336.1	0.004153
11721165_a_at	KHNYN	KH and NYN domain	NM_015299.2	0.00435
		containing
11730324_s_at	SLC38A9	solute carrier family 38,	NM_173514.2	0.004534
		member 9
11739669_at	SS18L1	synovial sarcoma	AB014593.1	0.004553
		translocation gene on
		chromosome 18-like 1
11758140_s_at	CPSF6	cleavage and	BU689332	0.004569
		polyadenylation specific
		factor 6, 68kDa
11721912 at	MDM4	Mdm4 p53 binding	NM_002393.3	0.004611
		protein homolog (mouse)
11744830_x_at	NPIPL3	nuclear pore complex	AK303166.1	0.004653
		interacting protein-like 3
11729100_a_at	TTC18	tetratricopeptide repeat	NM_145170.3	0.004727
		domain 18
11757896_s_at	C1orf63	chromosome 1 open	R81538	0.004766
		reading frame 63
11715976_a_at	VGLL4	vestigial like 4	NM_001128219.1	0.004868
		(Drosophila)
11729196_a_at	STX16	syntaxin 16	6E782754	0.004954
11758055_x_at	RGPD8	RANBP2-like and GRIP	BQ005433	0.005005
		domain containing 8
11721624_s_at	WSB1	WD repeat and SOCS box-	NM_015626.8	0.005017
		containing 1
11720589_s_at	PHF21A	PHD finger protein 21A	BU733437	0.005058
11720895_at	SOS1	son of seven less homolog	BM970418	0.005891
		1 (Drosophila)
11761133_at	KDM5C	lysine (K)-specific	EF613277.1	0.006011
		demethylase 5C
11726189_x_at	HCFC1R1	host cell factor C1	NM_017885.2	0.006166
		regulator 1 (XPO1
		dependent)
11721598_a_at	EFS	embryonal Fyn-associated	NM_032459.1	0.006547
		substrate
11745431_a_at	SVIL	supervillin	BC092440.1	0.006666
11740447_x_at	BTN3A1	butyrophilin, subfamily 3,	NM_194441.2	0.006686
		member Al
11726515_a_at	CLK4	CDC-like kinase 4	AF294429.1	0.006691
11746529_x_at	TNFRSF14	tumor necrosis factor	BC029848.1	0.006897
		receptor superfamily,
		member 14 (herpesvirus
		entry mediator)
11759308_s_at	MAGI1	membrane associated	AL050184.1	0.006929
		guanylate kinase, WW
		and PDZ domain
		containing 1
11749473_a_at	MEF2D	myocyte enhancer factor	BC040949.1	0.007372
		2D
11719128_a_at	LMF2	lipase maturation factor 2	NM_033200.1	0.007569
11762365_x_at	KIAA0415	KIAA0415	AB007875.1	0.007605
11716129_at	IGF2R	insulin-like growth factor	NM_000876.2	0.007692
		2 receptor
11717989_a_at	SUN1	Sad1 and UNC84 domain	NM_001130965.1	0.007807
		containing 1
11755196_a_at	CORO6	coronin 6	AK092430.1	0.007848
11755758_s_at	NLRC5	NLR family, CARD domain	AK090439.1	0.00788
		containing 5
11716283_at	PAPD7	PAP associated domain	NM_006999.3	0.008191
		containing 7
11730449_a_at	DHRS12	dehydrogenase/reductase	NM_024705.1	0.008218
		(SDR family) member 12
11718728_a_at	ZNF655	zinc finger protein 655	NM_001083956.1	0.008286
11718820_at	TSC1	tuberous sclerosis 1	NM_000368.3	0.008558
11729483_a_at	KLF8	Kruppel-like factor 8	NM_007250.4	0.008607
11754192_s_at	SRSF11	serine/arginine-rich	CR614713.1	0.009136
		splicing factor 11
11758557_s_at	ZFP36L1	zinc finger protein 36,	AI758505	0.009209
		C3H type-like 1
11723598_x_at	MAP2K7	mitogen-activated protein	NM_145185.2	0.009355
		kinase kinase 7
11754541_a_at	CCDC45	coiled-coil domain	AW167096	0.00982
		containing 45
11757630_s_at	HERPUD2	HERPUD family member 2	AA709265	0.010052
11718536_s_at	NKTR	natural killer-tumor	NM_005385.3	0.010291
		recognition sequence
11755674_s_at	RALGAPAI	Ral GTPase activating	DQ786317.1	0.010335
		protein, alpha subunit 1
		(catalytic)
11757591_s_at	PAN3	PAN3 poly(A) specific	DB314869	0.010593
		ribonuclease subunit
		homolog (S. cerevisiae)
11724312_a_at	SH3BP2	SH3-domain binding	NM_001145855.1	0.010664
		protein 2
11757197_s_at	NCRNA00201	non-protein coding RNA	NR_026778.1	0.010882
		201
11759150_at	CNOT4	CCR4-NOT transcription	BC035590.1	0.011523
		complex, subunit 4
11718939_s_at	TNFAIP3	tumor necrosis factor,	NM_006290.2	0.011563
		alpha-induced protein 3
11738035_s_at	RTN4	reticulon 4	AK302741.1	0.011615
11719084_a_at	SMARCC2	SWI/SNF related, matrix	BF663402	0.011872
		associated, actin
		dependent regulator of
		chromatin, subfamily c,
		member 2
11736501_x_at	SS18	synovial sarcoma	NM_005637.2	0.011911
		translocation,
		chromosome 18
11755811_a_at	ZNF266	zinc finger protein 266	AL833503.1	0.012172
11720362_at	PHIP	pleckstrin homology	CR600369.1	0.012352
		domain interacting
		protein
11724758_s_at	GPBP1L1	GC-rich promoter binding	NM_021639.4	0.012429
		protein 1-like 1
		solute carrier family 38,
11754821_s_at	SLC38AI	member 1	AI476037	0.012431
11758907_at	ZNF827	zinc finger protein 827	AA031947	0.012473
		trinucleotide repeat
11736498_a_at	TNRC6B	containing 6B	NM_015088.2	0.012866
11716010_s_at	DYNC1LI2	dynein, cytoplasmic 1,	NM_006141.2	0.01317
		light intermediate chain 2
11745723_a_at	MALAT1	metastasis associated	BX538238.1	0.013758
		lung adenocarcinoma
		transcript 1 (non-protein
		coding)
11758584_s_at	STYX	serine/threonine/tyrosine	N34305	0.013878
		interacting protein
11757558_s_at	LONRF1	LON peptidase N-terminal	BF680438	0.014197
		domain and ring finger 1
11750922_x_at	AMT	aminomethyltransferase	AK296177.1	0.0143
11718558_s_at	MKRN1	makorin ring finger	NM_001145125.1	0.014465
		protein 1
11723112_a_at	CCDC84	coiled-coil domain
		containing 84	NM_198489.1	0.014471
11757808_s_at	RERE	arginine-glutamic acid	BM706668	0.014565
		dipeptide (RE) repeats
11763191_at	PRICKLE3	prickle homolog 3	AK303308.1	0.014697
		(Drosophila)
11757821_s_at	LDB1	LIM domain binding 1	AW271288	0.014809
11755194_s_at	CCN L2	cyclin L2	AK000685.1	0.014941
11720122_at	GIGYF1	GRB10 interacting GYF	NM_022574.4	0.014956
		protein 1
		hypothetical protein
11763351_at	LOC286052	LOC286052	CK819455	0.014973
11722752_a_at	C14orf43	chromosome 14 open	NM_194278.3	0.015053
		reading frame 43
11757958_s_at	POGZ	pogo transposable	AI374931	0.015063
		element with ZNF domain
11734056_at	PTGR2	prostaglandin reductase 2	NM_152444.2	0.015377
11722715_at	STK35	serine/threonine kinase	NM_080836.2	0.015673
		35
11722134_a_at	TNFRSF25	tumor necrosis factor	NM_148965.1	0.015688
		receptor superfamily,
		member 25
11715192_s_at	C7orf46	chromosome 7 open	g188219621	0.015694
		reading frame 46
11720795_s_at	NUPL1	nucleoporin like 1	NM_014089.3	0.016154
11729510_a_at	WDR33	WD repeat domain 33	NM_001006623.1	0.016469
11724066_s_at	HCFC1R1	host cell factor C1	NM_001002018.1	0.016491
		regulator 1 (XPO1
		dependent)
11718534_at	NKTR	natural killer-tumor	AI361805	0.016611
		recognition sequence
11741625_a_at	SLC22A23	solute carrier family 22,	NM_021945.5	0.016631
		member 23
11722305_at	ARHGAP23	Rho GTPase activating	NM_020876.1	0.01665
		protein 23
11764248_s_at	LDLRAD3	low density lipoprotein	AW043782	0.016656
		receptor class A domain
		containing 3

TABLE 14
Type II Epidermis; Down-regulated

GeneTitan_ID	Gene	Title	Public ID	p
		homeodomain interacting
11719408_a_at	HIPK2	protein kinase 2	BM679184	0.000155
11739028_s_at	CLTC	clathrin, heavy chain (Hc)	BX395378	0.00019
11747337_x_at	EIF3I	eukaryotic translation	U36764.1	0.000378
		initiation factor 3, subunit I
		TBC1 domain family,
11749845_a_at	TBC1D22A	member 22A	AK301445.1	0.000577
		sec1 family domain
11723960_at	SCFD2	containing 2	BC032453.1	0.000699
		proteasome (prosome,
		macropain) subunit, beta
11717105_a_at	PSMB5	type, 5	NM_001144932.1	0.00071
		proteasome (prosome,
		macropain) 26S subunit,
11716545_x_at	PSMC1	ATPase, 1	NM_002802.2	0.00077
		1-acylglycerol-3-phosphate
		O-acyltransferase 5
		(lysophosphatidic acid
11730754_s_at	AGPAT5	acyltransferase, epsilon)	CB306609	0.00077
11750994_a_at	SYAP1	synapse associated protein 1	AK295322.1	0.000788
11754977_x_at	CTSB	cathepsin B	CR614817.1	0.000808
		ATPase, H+ transporting,
		lysosomal 9kDa, V0 subunit
200096_PM_s_at	ATP6V0E1	e1	AI862255	0.000889
		serpin peptidase inhibitor,
		clade B (ovalbumin),
11738899_a_at	SERPINB12	member 12	NM_080474.1	0.000913
		G-rich RNA sequence
11747533_a_at	GRSF1	binding factor 1	AK298883.1	0.000973
		proteasome (prosome,
		macropain) 26S subunit,
11733918_a_at	PSMD14	non-ATPase, 14	BC066336.1	0.001091
11753572_a_at	TMEM85	transmembrane protein 85	AY336092.1	0.001121
		glucosidase, alpha; neutral
11738988_a_at	GANAB	AB	AK302752.1	0.001195
		golgi reassembly stacking
11751303_s_at	GORASP2	protein 2, 55kDa	AK293640.1	0.001298
		mitochondrial ribosomal
11719482_a_at	MRPL21	protein L21	NM_181515.1	0.001366
		proteasome	(prosome,
		macropain) subunit, beta
11715943_x_at	PSMB1	type, 1	NM_002793.3	0.001475
11749935_s_at	TPM3	tropomyosin 3	AK298678.1	0.001523
		succinate dehydrogenase
		complex, subunit C, integral
11736759_s_at	SDHC	membrane protein, 15kDa	AB211234.1	0.001635
		tyrosine 3-
		monooxygenase/tryptophan
		5-monooxygenase	activation
11731397_a_at	YWHAB	protein, beta polypeptide	AI866370	0.001646
		mediator complex subunit
11751557_s_at	MED27	27	AK298436.1	0.001692
		transmembrane BAX
11747146_s_at	TMBIM6	inhibitor motif containing 6	AK304577.1	0.001727
		N-ethylmaleimide-sensitive
11716972_s_at	NSF	factor	NM_006178.2	0.001747
		proteasome (prosome,
		macropain) subunit, beta
11754009_a_at	PSMB5	type, 5	BT006777.1	0.001747
		mitochondrial ribosomal
11717459_a_at	MRPL39	protein L39	NM_017446.3	0.001824
		mitochondrial ribosomal
11742273_a_at	MRPL33	protein L33	AF420602.1	0.001825
11739599_a_at	ZNF398	zinc finger protein 398	BU736496	0.001891
11747534_a_at	RSU1	Ras suppressor protein 1	BC008691.1	0.002033
		nucleosome assembly
11747507_x_at	NAP1L4	protein 1-like 4	AK316548.1	0.002069
		nucleosome assembly
11747506_a_at	NAP1L4	protein 1-like 4	AK316548.1	0.002092
		phosphatidylinositol binding
11748665_a_at	PICALM	clathrin assembly protein	AK300275.1	0.002111
		peptidylprolyl isomerase
11718035_at	PPIL1	(cyclophilin)-like 1	AF151882.1	0.002124
11751336_x_at	MKRN1	makorin ring finger protein 1	AK297361.1	0.002138
		activating signal
		cointegrator 1 complex
11720264_at	ASCC3	subunit 3	NM_006828.2	0.002301
11725037_a_at	5EC23IP	5EC23 interacting protein	AK000698.1	0.002534
		mitochondrial ribosomal
11715772_x_at	MRPL13	protein L13	NM_014078.4	0.002536
		prolyl 4-hydroxylase, beta
11716173_a_at	P4HB	polypeptide	AK296206.1	0.002544
		proteasome (prosome,
		macropain) subunit, beta
11717106_x_at	PSMB5	type, 5	NM_001144932.1	0.002579
		ras homolog gene family,
200059_PM_s_at	RHOA	member A	BC001360.1	0.002604
11746655_a_at	ACAAI	acetyl-CoA acyltransferase 1	AK303251.1	0.002689
		ATP synthase, H+
		transporting, mitochondrial
		Fo complex, subunit C3
11739201_a_at	ATP5G3	(subunit 9)	6E736890	0.002714
		ATP synthase, H+
		transporting, mitochondrial
		F1 complex, alpha subunit 1,
11728637_a_at	ATP5AI	cardiac muscle	NM_001001937.1	0.002718
		BCL2-like 10 (apoptosis
11756013_a_at	BCL2L10	facilitator)	BC143227.1	0.002726
		proteasome (prosome,
		macropain) subunit, beta
11754271_a_at	PSMB4	type, 4	BM849884	0.002734
		proteasome (prosome,
		macropain) 26S subunit,
11731415_a_at	PSMD6	non-ATPase, 6	NM_014814.1	0.002807
		succinate dehydrogenase
		complex, subunit C, integral
11715840_s_at	SDHC	membrane protein, 15kDa	BC020808.1	0.002866
		succinate-CoA ligase, ADP-
11755266_x_at	SUCLA2	forming, beta subunit	AK001458.1	0.003146
		sec1 family domain
11750876_a_at	SCFD1	containing 1	AK301406.1	0.003266
		SWI/SNF related, matrix
		associated, actin dependent
		regulator of chromatin,
11752770_a_at	SMARCE1	subfamily e, member 1	AK294666.1	0.003311
		SERPINE1 mRNA binding
11758800_x_at	SERBP1	protein 1	AF151813.1	0.003464
11751835_a_at	LTV1	LTV1 homolog (S. cerevisiae)	AY326463.1	0.003472
11758319_x_at	UBC	ubiquitin C	BF672950	0.003583
11729168_x_at	DCTD	dCMP deaminase	BC001286.1	0.003633
		NADH dehydrogenase
		(ubiquinone) 1 beta
11717159_a_at	NDUFB3	subcomplex, 3, 12kDa	NM_002491.2	0.003697
		phenylalanyl-tRNA
11744181_a_at	FARS2	synthetase 2, mitochondrial	BG192794	0.003735
		ADP-ribosylation factor-like
11751412_x_at	ARL1	1	AK301701.1	0.003805
		proteasome (prosome,
		macropain) subunit, alpha
11734682_a_at	PSMA7	type, 7	NM_002792.2	0.003878
11750059_a_at	MLX	MAX-like protein X	AK296114.1	0.003884
		zinc finger, HIT-type
11715718_a_at	ZNHIT1	containing 1	NM_006349.2	0.003894
		REX2, RNA exonuclease 2
11751360_x_at	REX02	homolog (S. cerevisiae)	BC107887.1	0.003907
		phosphoserine
11747349_s_at	PSAT1	aminotransferase 1	BT006840.1	0.003982
		mitochondrial ribosomal
11763975_a_at	MRPS11	protein S11	DB346141	0.004073
11716381_x_at	BRP44	brain protein 44	NM_015415.2	0.00408
		transmembrane emp24
		protein transport domain
11751523_a_at	TMED5	containing 5	AK293308.1	0.004086
		small nuclear
		ribonucleoprotein
11753974_s_at	SNRPG	polypeptide G	CR456918.1	0.004159
		penta-EF-hand domain
11732216_s_at	PEF1	containing 1	CR542139.1	0.004221
		calpain 2, (m/II) large
11718978_x_at	CAPN2	subunit	BC021303.2	0.004238
		ATPase, H+ transporting,
		lysosomal 38kDa, V0 subunit
11763422_a_at	ATP6V0D1	dl	BX397389	0.004241
11754060_a_at	DAD1	defender against cell death	CR542204.1	0.004283
		signal peptidase complex
		subunit 1 homolog (S.
11743905_a_at	SPCS1	cerevisiae)	6E782150	0.004361
		proteasome (prosome,
		macropain) subunit, beta
11715732_at	PSMB3	type, 3	NM_002795.2	0.004369
		Yip1 domain family, member
11751505_a_at	YIPF1	1	AK300240.1	0.004409
		chromosome 11 open
11742925_a_at	C11orf59	reading frame 59	CR457247.1	0.004503
		S-phase kinase-associated
11715417_s_at	SKP1	protein 1	BC020798.1	0.004548
		phosphoglycerate mutase 1
11750438_x_at	PGAM1	(brain)	AK296619.1	0.004563
11752939_x_at	PGK1	phosphoglycerate kinase 1	AK298855.1	0.004575
		cell division cycle 123
11723478_s_at	CDC123	homolog (S. cerevisiae)	NM_006023.2	0.004585
		retinol dehydrogenase 11
11743034_x_at	RDH11	(all-trans/9-cis/11-cis)	AK289427.1	0.004593
		VAMP (vesicle-associated
		membrane protein)-
11754086_x_at	VAPA	associated protein A, 33kDa	BT019618.1	0.004657
		heterogeneous nuclear
		ribonucleoprotein D (AU-
		rich element RNA binding
11749303_s_at	HNRNPD	protein 1, 37kDa)	AK300149.1	0.004671
		proteasome (prosome,
		macropain) 26S subunit,
11753142_a_at	PSMD11	non-ATPase, 11	AK300342.1	0.004673
11747719_a_at	KIAA0391	KIAA0391	AK304066.1	0.004719
		CWF19-like 1, cell cycle
11748974_s_at	CWF19L1	control (S. pombe)	AK295303.1	0.004746
		ATPase, H+ transporting,
		lysosomal 56/58kDa, V1
11751133_a_at	ATP6V1B2	subunit B2	AK298819.1	0.004759
		inner membrane protein,
11715552_a_at	IMMT	mitochondrial	NM_006839.2	0.004766
11747365_a_at	QARS	glutaminyl-tRNA synthetase	AK302867.1	0.004855
		succinate dehydrogenase
		complex, subunit D, integral
11758248_s_at	SDHD	membrane protein	BF696015	0.004909
		eukaryotic translation
11753592_x_at	EEF1G	elongation factor 1 gamma	AK299876.1	0.004961
		NADH dehydrogenase
		(ubiquinone) 1 alpha
11715369_s_at	NDUFA4	subcomplex, 4, 9kDa	BC105295.1	0.005125
11715499_x_at	CBX3	chromobox homolog 3	U26312.1	0.005141
		ATP synthase, H+
11715874_s_at	ATP5H	transporting, mitochondrial	NM_006356.2	0.005143
		Fo complex, subunit d
		succinate dehydrogenase
		complex, subunit D, integral
11758311_s_at	SDHD	membrane protein	BF697775	0.005199
11715883_x_at	DAP3	death associated protein 3	NM_004632.2	0.005251
		poly(A) binding protein,
		cytoplasmic 4 (inducible
11754030_a_at	PABPC4	form)	BC118568.1	0.00537
		exocyst complex component
11749682_s_at	EXOC5	5	AK303531.1	0.005371
		tetratricopeptide repeat
11718142_a_at	TTC27	domain 27	NM_017735.3	0.005424
		thioredoxin domain
11754067_a_at	TXNDC9	containing 9	CR456935.1	0.005482
		aldo-keto reductase family
		1, member A1 (aldehyde
11716509_a_at	AKR1A1	reductase)	NM_006066.2	0.005483

TABLE 15
Type II Dermis; Up-regulated

GeneTitan_ID	Gene	Title	Public ID	p
11715351_at	COL1AI	collagen, type I, alpha 1	NM_000088.3	0.000139
11715352_x_at	COL1AI	collagen, type I, alpha 1	NM_000088.3	0.000375
11734105 a_at	PNMAL2	PNMA-like 2	AB033009.1	0.001583
11763844_s_at	UBXN6	UBX domain protein 6	CR590857.1	0.001819
11756896_a_at	COL6A6	collagen, type VI, alpha 6	AL713792.1	0.002188
		chromosome 15 open reading
11715284_x_at	C15orf40	frame 40	g237858663	0.003648
		platelet-derived growth
		factor receptor, beta
11715852_at	PDGFRB	polypeptide	NM_002609.3	0.005919
		phosphatidylinositol-5-
		phosphate 4-kinase, type II,
11715888_s_at	PIP4K2B	beta	NM_003559.4	0.006199
		chromosome 5 open reading
11724481_a_at	C5orf13	frame 13	NM_004772.2	0.006404
11758388_s_at	LHX8	LIM homeobox 8	DB302169	0.006562
		G protein-coupled receptor
11727836_a_at	GPR78	78	NM_001014447.1	0.007388
		family with sequence
11729827_at	FAM110B	similarity 110, member B	BCO24294.1	0.009523
		family with sequence
11744562_x_at	FAM176B	similarity 176, member B	BC071697.1	0.009813
11725867_s_at	EBF3	early B-cell factor 3	NM_001005463.1	0.009883
		progestin and adipoQ
11749069_a_at	PAQR4	receptor family member IV	AK295348.1	0.010054
		corticotropin releasing
11723068_at	CRHBP	hormone binding protein	NM_001882.3	0.011101
		fibronectin type III domain
11723174_a_at	FNDC1	containing 1	NM_032532.2	0.011173
11717274_s_at	COL5AI	collagen, type V, alpha 1	BQ007762	0.012177
		calcium/calmodulin-
		dependent protein kinase
11729541_a_at	CAMKK2	kinase 2, beta	AB081337.1	0.012395
11724848_a_at	DIXDC1	DIX domain containing 1	DB358954	0.013451
11726830_at	ANTXR1	anthrax toxin receptor 1	NM_018153.3	0.013945
		transforming growth factor,
11727296_s_at	TGFB3	beta 3	NM_003239.2	0.014199
		exonuclease 3′-5′ domain
11759905_a_at	EXD3	containing 3	BC110879.1	0.01495
		transcription factor 7-like 1
11721372_at	TCF7L1	(T-cell specific, HMG-box)	NM_031283.1	0.01515
		fibroblast activation protein,
11755955_a_at	alpha	AL832166.1
		FAP	0.015704
		matrix metallopeptidase 14
11725989_x_at	MMP14	(membrane-inserted)	NM_004995.2	0.019095
11717272_at	COL5AI	collagen, type V, alpha 1	AB371583.1	0.020092
		chromosome 19 open reading
11739544_a_at	C19orf12	frame 12	BX328123	0.021
		C-type lectin domain family 3,
11727867_a_at	CLEC3B	member B	NM_003278.2	0.024069
		calcium/calmodulin-
		dependent protein kinase
11731645_a_at	CAMKK2	kinase 2, beta	BCO26060.2	0.024228
		aldo-keto reductase family 1,
		member C2 (dihydrodiol
		dehydrogenase 2; bile acid
		binding protein; 3-alpha
		hydroxysteroid
11729101_a_at	AKR1C2	dehydrogenase, type III)	NM_205845.1	0.024814
		hairy and enhancer of split 4
11726474_a_at	HES4	(Drosophila)	NM_021170.3	0.025047
11725224_a_at	ZNF193	zinc finger protein 193	NM_006299.3	0.026826
11715350_a_at	COL1AI	collagen, type I, alpha 1	BC036531.2	0.026857
		matrix metallopeptidase 2
		(gelatinase A, 72kDa
		gelatinase, 72kDa type IV
11741377_a_at	MMP2	collagenase)	NM_001127891.1	0.02687
		NYN domain and retroviral
11722292_a_at	NYNRIN	integrase containing	NM_025081.2	0.027121
11730404_at	MEX3B	mex-3 homolog B (C. elegans)	NM_032246.3	0.027161
		thyroid hormone receptor,
		alpha (erythroblastic
		leukemia viral (v-erb-a)
11759126_a_at	THRA	oncogene homolog, avian)	CB054873	0.02738
11744348_x_at	COL6A2	collagen, type VI, alpha 2	BC002484.2	0.027551
11720845_a_at	CD248	CD248 molecule, endosialin	NM_020404.2	0.02836
11720372_at	TESC	tescalcin	NM_017899.2	0.028677
		syntrophin, alpha 1
		(dystroph in-associated
		protein Al, 59kDa, acidic
11752890_a_at	SNTAI	component)	AK301800.1	0.029777
11717273_at	COL5AI	collagen, type V, alpha 1	BQ007762	0.030174
		aldehyde dehydrogenase	1
11754184_a_at	ALDH1A3	family, member A3	BX538027.1	0.030605
		TRIO and F-actin binding
11727155_a_at	TRIOBP	protein	NM_007032.5	0.030721
11727031_a_at	SQSTM1	sequestosome 1	NM_003900.4	0.031363
11720846_at	CD248	CD248 molecule, endosialin	NM_020404.2	0.031411
		triple functional domain
11761938_a_at	TRIO	(PTPRF interacting)	AB115332.1	0.032433
11718096_a_at	MEF2A	myocyte enhancer factor 2A	BC013437.2	0.03254
		neuro-oncological ventral
11734906_a_at	NOVAI	antigen 1	NM_002515.2	0.032886
		R-spondin 3 homolog
11724619_at	RSPO3	(Xenopus laevis)	NM_032784.3	0.033442
		shisa homolog 3 (Xenopus
11726188_at	SHISA3	laevis)	NM_001080505.1	0.033466
		glutathione peroxidase 8
11729644_a_at	GPX8	(putative)	AK074216.1	0.033979
		adrenergic, alpha-2C-,
11756359_s_at	ADRA2C	receptor	CR590957.1	0.034296
11747064_x_at	ANXAll	annexin All	AK301047.1	0.034459
		chromosome 16 open reading
11732785_a_at	Cl6orf45	frame 45	NM_001142469.1	0.035589
		microtubule-associated
11727030_s_at	MAP1A	protein 1A	NM_002373.5	0.036125
		sema domain,
		immunoglobulin domain (Ig),
		short basic domain, secreted,
11748738_a_at	SEMA3E	(semaphorin) 3E	AK303925.1	0.036605
		leucine rich repeat containing
11721995_a_at	LRRC32	32	NM_001128922.1	0.038953
		host cell factor Cl regulator 1
11726189_x_at	HCFC1R1	(XPO1 dependent)	NM_017885.2	0.039807
		RGM domain family, member
11754792_a_at	RGMA	A	AK125204.1	0.040435
		protein phosphatase 1,
		regulatory (inhibitor) subunit
11717123_a_at	PPP1R12B	12B	NM_032105.1	0.043242
		triple functional domain
11724260_a_at	TRIO	(PTPRF interacting)	AF091395.1	0.044219
11759962_at	TPRKB	TP53RK binding protein	AY643713.1	0.045288
11733167_at	LRRN4CL	LRRN4 C-terminal like	BC053902.1	0.045766
		trinucleotide repeat
11721703_s_at	TN RC18	containing 18	NM_001080495.2	0.045935
		ATPase, aminophospholipid
		transporter (APLT), class I,
11725568_a_at	ATP8AI	type 8A, member 1	NM_001105529.1	0.046173
		membrane metallo-
11741562_a_at	MME	endopeptidase	NM_007287.2	0.046616
		pleiomorphic adenoma gene-
11745820_s_at	PLAGL1	like 1	BQ026948	0.046856
		C-type lectin domain family
11743696_at	CLEC14A	14, member A	CA412481	0.047788
11720277_a_at	OLFML2A	olfactomedin-like 2A	NM_182487.2	0.049248

TABLE 16
Type II Dermis; Down-regulated

GeneTitan_ID	Gene	Title	Public ID	p
		microtubule-associated
11749128_x_at	MAP7	protein 7	AK299355.1	0.000033
		eukaryotic translation
11720184_x_at	EEF162	elongation factor 1 beta 2	NM_001959.3	0.000101
		sulfotransferase family 1E,
		estrogen-preferring, member
11724155_at	SULT1E1	1	U08098.1	0.000109
200062_PM_s_at	RPL30	ribosomal protein L30	L05095.1	0.000123
11742734_s_at	WDR3	WD repeat domain 3	AK292438.1	0.000139
		nucleosome assembly protein
11732205_x_at	NAP1L1	1-like 1	BX413854	0.000141
11743604_s_at	RRM1	ribonucleotide reductase M1	6E618815	0.000164
		heterogeneous nuclear
11723197_at	HNRNPA3	ribonucleoprotein A3	BX434302	0.000178
		ATP-binding cassette, sub-
11732684_a_at	ABCAI2	family A (ABC1), member 12	AF418105.1	0.000237
		discs, large homolog 1
11739308_s_at	DLG1	(Drosophila)	BM681931	0.000254
11725875_at	WDR66	WD repeat domain 66	NM_144668.4	0.000271
200082_PM_s_at	RPS7	ribosomal protein S7	AI805587	0.00036
200081_PM_s_at	RPS6	ribosomal protein S6	6E741754	0.000371
		nucleophosmin (nucleolar
		phosphoprotein 623,
200063_PM_s_at	NPM1	numatrin)	BC002398.1	0.000404
11757356_x_at	RPL30	ribosomal protein L30	BM855760	0.000405
11719783_at	RPS23	ribosomal protein S23	D14530.1	0.000416
		sulfotransferase family 1E,
		estrogen-preferring, member
11724156_at	SULT1E1	1	NM_005420.2	0.000461
		eukaryotic translation
11720183_s_at	EEF162	elongation factor 1 beta 2	NM_001959.3	0.000477
11745154_a_at	NCL	nucleolin	BC006516.2	0.000485
11715958_s_at	RPL7	ribosomal protein L7	NM_000971.3	0.000491
11749558_a_at	CYP4F8	cytochrome P450, family 4,	AK300530.1	0.000497
		subfamily F, polypeptide 8
11755203_x_at	RPL21	ribosomal protein L21	BX647669.1	0.000511
11728022_a_at	TMEM45A	transmembrane protein 45A	NM_018004.1	0.000533
		eukaryotic translation
11718273_a_at	EIF3L	initiation factor 3, subunit L	NM_016091.2	0.000658
		protein kinase, DNA-activated,
11757399_s_at	PRKDC	catalytic polypeptide	AV760328	0.000698
		chromosome 10 open reading
11736055_at	C10orf32	frame 32	BG696280	0.000732
		steroid-5-alpha-reductase,
		alpha polypeptide 1 (3-oxo-5
		alpha-steroid delta 4-
11749267_a_at	SRD5A1	dehydrogenase alpha 1)	AK315996.1	0.000744
		transmembrane 9 superfamily
11716946_s_at	TM9SF3	member 3	AF269150.1	0.000758
11726461_a_at	PDCD2	programmed cell death 2	NM_144781.1	0.000759
11763318_s_at	CSNK1A1	casein kinase 1, alpha 1	BC040473.1	0.000792
		eukaryotic translation
11727794_s_at	EIF3E	initiation factor 3, subunit E	NM_001568.2	0.000802
		phosphoinositide-3-kinase,
11731690_a_at	PIK3C2G	class 2, gamma polypeptide	NM 004570.4	0.000846
11748052_x_at	E124	etoposide induced 2.4 mRNA	AK316539.1	0.000851
11743094_at	SPRR4	small proline-rich protein 4	BC069445.1	0.000998
11717236_x_at	RPS7	ribosomal protein S7	NM_001011.3	0.001062
11718719_at	K1AAI797	K1AAI797	NM_017794.3	0.001102
		transcription elongation factor
11752908_a_at	TCEA1	A (SII), 1	AK297729.1	0.001141
11753659_x_at	RPL30	ribosomal protein L30	BC095426.1	0.001161
11717058_x_at	RPL5	ribosomal protein L5	NM_000969.3	0.001214
		chromosome 10 open reading
11736057_s_at	C10orf32	frame 32	BU685637	0.00123
		phosphoserine
11742991_a_at	PSAT1	aminotransferase 1	AK295222.1	0.001244
11758357_x_at	RPL9	ribosomal protein L9	BF172613	0.00126
200010_PM_at	RPL11	ribosomal protein L11	NM_000975.1	0.001282
		transcription factor AP-2
		gamma (activating enhancer
11749776_a_at	TFAP2C	binding protein 2 gamma)	AK301572.1	0.001283
		serine peptidase inhibitor,
11727995_a_at	SPINK5	Kazal type 5	DQ149928.1	0.001284
		chromosome 14 open reading
11722185_at	C14orf147	frame 147	NM_138288.3	0.001309
		eukaryotic translation
11750883_a_at	EIF2A	initiation factor 2A, 65kDa	AF109358.1	0.001327
200017_PM_at	RPS27A	ribosomal protein S27a	NM_002954.1	0.001414
		cytochrome P450, family 4,
11749559_x_at	CYP4F8	subfamily F, polypeptide 8	AK300530.1	0.001416
11722308_a_at	TP63	tumor protein p63	NM_003722.4	0.001433
		nucleophosmin (nucleolar
		phosphoprotein 623,
11754066_x_at	NPM1	numatrin)	BT007011.1	0.001448
11743603_a_at	RRM1	ribonucleotide reductase M1	6E618815	0.001462
		serine peptidase inhibitor,
11754963_a_at	SPINK5	Kazal type 5	AK301660.1	0.001558
		hydroxysteroid (17-beta)
11747333_a_at	HSD1764	dehydrogenase 4	AK295440.1	0.001571
		nucleophosmin (nucleolar
		phosphoprotein 623,
11757386_x_at	NPM1	numatrin)	AL563600	0.00169
		cytochrome P450, family 4,
11751437_a_at	CYP4F8	subfamily F, polypeptide 8	AK300539.1	0.001708
11726258_at	RNF141	ring finger protein 141	BX503543	0.001716
11720766_a_at	METTL9	methyltransferase like 9	AK074529.1	0.001743
		coiled-coil domain containing
11743729_at	CCDC47	47	AL575693	0.001771
		heterogeneous nuclear
11749786_x_at	HNRNPF	ribonucleoprotein F	AK296696.1	0.001879
		eukaryotic translation
11729152_a_at	EIF3M	initiation factor 3, subunit M	NM_006360.3	0.001895
		UDP glucuronosyltransferase 2
11737634_a_at	UGT2A1	family, polypeptide Al	NM_006798.2	0.001986
11748044_a_at	SCEL	sciellin	BCO20726.1	0.002038
		eukaryotic translation
11752912_x_at	EIF3M	initiation factor 3, subunit M	AK292139.1	0.002066
11736309_a_at	CSNK1A1	casein kinase 1, alpha 1	L37042.1	0.002093
11727421_a_at	CANX	calnexin	C6243867	0.002106
11727425_s_at	CANX	cal nexin	M94859.1	0.002182
		ribosomal protein SA
11757305_x_at	RPSAP58	pseudogene 58	61762726	0.002211
		transmembrane emp24
200087_PM_s_at	TMED2	domain trafficking protein 2	AK024976.1	0.002219
		RAB11A, member RAS
11718030_at	RAB11A	oncogene family	NM_004663.3	0.002258
11742887_a_at	BAGS	BCL2-associated athanogene 5	6Q008934	0.00227
11746199_a_at	METTL9	methyltransferase like 9	AA524199	0.002298
		phosphoserine
11756182_s_at	PSAT1	aminotransferase 1	AAI73918	0.002312
11727658_s_at	KLK10	kallikrein-related peptidase 10	AF024605.1	0.002335
		nucleosome assembly protein
11732204_a_at	NAP1L1	1-like 1	BX413854	0.002341
11744334_x_at	RPS17	ribosomal protein S17	BC071928.1	0.002403
		DIM1 dimethyladenosine
		transferase 1-like (S.
11748536_a_at	DIMT1L	cerevisiae)	BC002841.2	0.002406
11745155_s_at	NCL	nucleolin	BC006516.2	0.002458
		nucleophosmin (nucleolar
		phosphoprotein B23,
11730790_x_at	NPM1	numatrin)	AK290652.1	0.002509
		cytochrome P450, family 4,
11740643_a_at	CYP4F8	subfamily F, polypeptide 8	AF133298.1	0.002616
		ATPase, Ca++ transporting,
11755057_s_at	ATP2C1	type 2C, member 1	AB037768.1	0.002687
		phosphoserine
11742992_s_at	PSAT1	aminotransferase 1	AK295222.1	0.002716
11757424_x_at	RPL37	ribosomal protein L37	F34903	0.002789
		peroxisomal membrane
11723312_a_at	PXMP2	protein 2, 22kDa	NM_018663.1	0.002819
11756137_x_at	BTF3	basic transcription factor 3	CA772090	0.002824
11754054_x_at	RPL3	ribosomal protein L3	L22453.1	0.002905
11750667_a_at	RRM1	ribonucleotide reductase M1	AK297988.1	0.00292
		RAB11A, member RAS
11751326_a_at	RAB11A	oncogene family	AK300008.1	0.002998
11749040_a_at	PGM2	phosphoglucomutase 2	AK297752.1	0.003008
11715376_a_at	RPS11	ribosomal protein S11	NM_001015.3	0.003035
		DEAD (Asp-Glu-Ala-Asp) box
11715849_a_at	DDX47	polypeptide 47	NM_016355.3	0.003047
		tRNA-yW synthesizing protein
11726829_at	TYW1B	1 homolog B (S. cerevisiae)	NM_001145440.1	0.003195
		chromosome 14 open reading
11756267_x_at	C14orf166	frame 166	BX349547	0.003217
11756437_x_at	RPS18	ribosomal protein S18	BQ057441	0.003368
11715648_x_at	ADIPOR1	adiponectin receptor 1	AY424279.1	0.003389
		prostaglandin E synthase 3
11747662_x_at	PTGES3	(cytosolic)	AK298147.1	0.003391
		solute carrier family 39 (zinc
11749546_a_at	5LC39A6	transporter), member 6	AK301539.1	0.003463
		protein disulfide isomerase
11745720_s_at	PDIA6	family A, member 6	D49489.1	0.00351
200074_PM_s_at	RPL14	ribosomal protein L14	U16738.1	0.003587
		phosphogluconate
11746023_a_at	PGD	dehydrogenase	AK304423.1	0.003624

TABLE 17
Type III Epidermis; Up-regulated

GeneTitan_ID	Gene	Title	Public ID	p
11725675_a_at	RORA	RAR-related orphan receptor A	AA034012	0.00064
11732366_a_at	SCAPER	S-phase cyclin A-associated	BC015212.1	0.001096
		protein in the ER
11739639_at	CDK12	cyclin-dependent kinase 12	AW968504	0.001477
11745215_a_at	KBTBD4	kelch repeat and BTB (POZ)	CR457270.1	0.001496
		domain containing 4
11730873_a_at	RASSF5	Ras association (RalGDS/AF-6)	NM_182665.2	0.001694
		domain family member 5
11718966_at	NUFIP2	nuclear fragile X mental	BU533767	0.001959
		retardation protein interacting
		protein 2
11718513_x_at	TSPAN14	tetraspanin 14	NM_030927.2	0.002425
11744585_a_at	ATRN	attractin	AK302730.1	0.003547
11755420_a_at	KDM4B	lysine (K)-specific demethylase 4B	AK126854.1	0.003701
11720895_at	SOS1	son of sevenless homolog 1	BM970418	0.003776
		(Drosophila)
11734873_a_at	SCAPER	S-phase cyclin A-associated	NM_020843.2	0.00429
		protein in the ER
11759897_x_at	OFD1	oral-facial-digital syndrome 1	BC042830.1	0.004666
11754251_a_at	USP36	ubiquitin specific peptidase 36	AK022913.1	0.005023
11736059_a_at	KIF5B	kinesin family member 5B	BC065267.1	0.005318
11754824_a_at	HSPC159	galectin-related protein	DB323149	0.005358
11757991_s_at	ANKRD12	ankyrin repeat domain 12	AA399583	0.006238
11744468_at	SYNCRIP	synaptotagmin binding,	AK056188.1	0.007087
		cytoplasmic RNA interacting
		protein
11754992_a_at	CHD1	chromodomain helicase DNA	BE535223	0.007613
		binding protein 1
11716283_at	PAPD7	PAP associated domain	NM_006999.3	0.00802
		containing 7
11722973_s_at	FOXK1	forkhead box K1	NM_001037165.1	0.008695
11748149_a_at	FNBP1	formin binding protein 1	AK293743.1	0.009063
11722125_a_at	C3orf19	chromosome 3 open reading	AL526467	0.009976
		frame 19
11720007_a_at	STEAP4	STEAP family member 4	NM_024636.2	0.011197
11731506_a_at	RAD23B	RAD23 homolog B (S. cerevisiae)	NM_002874.3	0.011526
11724759_s_at	CALM1	calmodulin 1 (phosphorylase	NM_006888.3	0.011622
		kinase, delta)
11718161_at	KLF13	Kruppel-like factor 13	AF132599.1	0.012064
11726305_at	C10orf84	chromosome 10 open reading	BC023577.2	0.012188
		frame 84
11723962_at	KIAAI143	KIAAI143	BC008468.1	0.012597
11740956_x_at	PLEKHN1	pleckstrin homology domain	NM_032129.1	0.013256
		containing, family N member 1
11722305_at	ARHGAP23	Rho GTPase activating protein 23	NM_020876.1	0.01353
		family with sequence similarity
11726022_a_at	FAM177AI	177, member AI	BC029559.1	0.01364
11754010_x_at	GOLGA2	golgin A2	BT007248.1	0.013918
11729523_a_at	NLRC5	NLR family, CARD domain	NM_032206.3	0.014235
		containing 5
11723113_a_at	CENPC1	centromere protein C 1	BC041117.1	0.0145
		UPF1 regulator of nonsense
11754616_a_at	UPF1	transcripts homolog (yeast)	AI690963	0.014647
11722291_s_at	ZBTB43	zinc finger and BTB domain	AI745225	0.014686
		containing 43
11739805_a_at	RASAL2	RAS protein activator like 2	AK075169.1	0.014761
11723502_at	PRLR	prolactin receptor	AI435838	0.014945
11726244_a_at	RORA	RAR-related orphan receptor A	U04898.1	0.01551
11736104_a_at	ZNF750	zinc finger protein 750	BC109037.1	0.015749
11723184_x_at	CNOT6L	CCR4-NOTt ranscription complex,	BQ025327	0.015988
		subunit 6-like
11755058_a_at	BAZ1A	bromodomain adjacent to zinc	BC020636.1	0.016704
		finger domain, 1A
11759600_at	SFRS18	Splicing factor, arginine/serine-	AK027751.1	0.016758
		rich 18
11744829_s_at	HLA-E	major histocompatibility	AK296822.1	0.016828
		complex, class I, E
		guanylate binding protein 2,
11719447_s_at	GBP2	interferon-inducible	BC073163.1	0.016832
11720541_at	HSPC159	galectin-related protein	NM_014181.2	0.017088
		pleckstrin and Sec7 domain
11719028_a_at	PSD3	containing 3	DB314358	0.017377
11754462_a_at	RSPRY1	ring finger and SPRY domain	AU253443	0.017904
		containing 1
11725676_a_at	RORA	RAR-related orphan receptor A	NM_002943.3	0.018226
11722290_a_at	ZBTB43	zinc finger and BTB domain	AI745225	0.018329
		containing 43
11723821_a_at	SMURF2	SMAD specific E3 ubiquitin	AY014180.1	0.018461
		protein ligase 2
11720111_at	SNTB2	syntrophin, beta 2 (dystrophin-	BC036429.1	0.018669
		associated protein AI, 59kDa,
		basic component 2)
11736432_x_at	PPP4R2	protein phosphatase 4,	BC128136.1	0.01869
		regulatory subunit 2
11744000_a_at	NFKBIA	nuclear factor of kappa light	BX367826	0.018695
		polypeptide gene enhancer in B-
		cells inhibitor, alpha
11759512_x_at	CWC25	CWC25 spliceosome-associated	CR748127	0.018768
		protein homolog (S. cerevisiae)
11716095_s_at	KLF6	Kruppel-like factor 6	CD366698	0.019227
11754447_a_at	RPS6KA5	ribosomal protein S6 kinase,	BM968829	0.019584
		90kDa, polypeptide 5
11719085_a_at	SMARCC2	SWI/SNF related, matrix	AL544435	0.01997
		associated, actin dependent
		regulator of chromatin, subfamily
		c, member 2
11727506_x_at	RAB21	RAB21, member RAS oncogene	BC021901.1	0.020551
		family
11720276_s_at	TREX1	three prime repair exonuclease 1	NM_016381.3	0.020671
11724549_a_at	RSBN1	round spermatid basic protein 1	AK292552.1	0.020675
11731645_a_at	CAMKK2	calcium/calmodulin-dependent	BC026060.2	0.020762
		protein kinase kinase 2, beta
11737413_at	MICALCL	MICAL C-terminal like	NM_032867.2_	0.020903
11715938_x_at	KHDRBS1	KH domain containing, RNA	BC000717.1	0.021833
		binding, signal transduction
		associated 1
11747192_x_at	NFIC	nuclear factor I/C (CCAAT-binding	AK289885.1	0.022039
		transcription factor)
11729396_a_at	NEK1	NIMA (never in mitosis gene a)-	Z25431.1	0.022138
		related kinase 1
11727064_a_at	ANKRD11	ankyrin repeat domain 11	BU674634	0.022386
11752626_a_at	PBX1	pre-B-cell leukemia homeobox 1	AK299673.1	0.022397
11721119_a_at	ANKHD1-	ANKHD1-EIF4EBP3 readthrough	AF217646.1	0.022562
	EIF4EBP3
11743648_a_at	DCAF6	DDB1 and CUL4 associated factor	BF672818	0.022893
		6
11740362_a_at	FOXN3	forkhead box N3	U68723.1	0.023025
11718869_x_at	PALMD	palmdelphin	CF552454	0.023068
11727604_a_at	EPB41L4A	erythrocyte membrane protein	NM_022140.3	0.023101
		band 4.1 like 4A
11726633_s_at	TRIM8	tripartite motif-containing 8	BCO21925.1	0.023187
11732370_a_at	CUX1	cut-like homeobox 1	NM_181552.2	0.023258
11726113_a_at	FAM46B	family with sequence similarity	NM_052943.3	0.023515
		46, member B
11729100_a_at	TTC18	tetratricopeptide repeat domain	NM_145170.3	0.023862
		18
11729259_a_at	ZNF644	zinc finger protein 644	BQ014639	0.023971
11745806_a_at	AMMECR1L	AMME chromosomal region gene	AK095871.1	0.024186
		1-like
11717894_s_at	PTP4AI	protein tyrosine phosphatase	BC023975.2	0.024306
		type IVA, member 1
11728765_a_at	PVRL4	poliovirus receptor-related 4	BC010423.1	0.024371
11740747_a_at	DNMT3A	DNA (cytosine-5-)-	AF480163.1	0.024617
		methyltransferase 3 alpha
11718868_a_at	PALMD	palmdelphin	CF552454	0.025394
11758133_s_at	COL4A3BP	collagen, type IV, alpha 3	BE046819	0.026883
		(Goodpasture antigen) binding
		protein
11749969_a_at	TSPAN5	tetraspanin 5	AK295385.1	0.027108
11733899_a_at	TROVE2	TROVE domain family, member 2	BX445026	0.027171
11747743_x_at	MTF2	metal response element binding	AK302776.1	0.027946
		transcription factor 2
11746790_a_at	BECN1	beclin 1, autophagy related	AK298619.1	0.027999
11731573_a_at	FRMD4B	FERM domain containing 4B	AU147415	0.028099
11724271_a_at	HLF	hepatic leukemia factor	EL952952	0.028251
		KRR1, small subunit (SSU)
		processome component,
11728683_x_at	KRR1	homolog (yeast)	U55766.1	0.02827
11758327_s_at	BAZ1A	bromodomain adjacent to zinc	BF852255	0.02853
		finger domain, 1A
11743300_a_at	SRP72	signal recognition particle 72kDa	AK225430.1	0.028582
11719103_at	CPNE3	copine III	CB250550	0.028667
11755895_a_at	FAM129A	family with sequence similarity	AK095547.1	0.029014
		129, member A
11721326_at	C3orf14	chromosome 3 open reading	AF236158.1	0.029423
		frame 14
11738035_s_at	RTN4	reticulon 4	AK302741.1	0.029458
11746122_s_at	ZC3H11A	zinc finger CCCH-type containing	DA094705	0.029486
		11A
11724085_at	DAPL1	death associated protein-like 1	NM_001017920.2	0.030615
11735181_a_at	DLX2	distal-less homeobox 2	NM_004405.3	0.030619

TABLE 18
Type III Epidermis; Down-regulated

GeneTitan_ID	Gene	Title	Public ID	p
11743060_s_at	COMMD10	COMM domain containing 10	AL572695	0.000211
11720515_s_at	C9orf150	chromosome 9 open reading	NM_203403.1	0.000414
		frame 150
11716897_x_at	PPIE	peptidylprolyl isomerase E	NM_006112.2	0.000535
		(cyclophilin E)
11725787_a_at	C4orf43	chromosome 4 open reading	NM_018352.2	0.000571
		frame 43
11729680_a_at	KHK	ketohexokinase (fructokinase)	CR456801.1	0.000981
11745494_x_at	ERCC8	excision repair cross-	U28413.1	0.001042
		complementing rodent repair
		deficiency, complementation
		group 8
11745948_a_at	CHEK1	CHK1 checkpoint homolog (S.	AK299783.1	0.0011
		pombe)
11758965_at	ATG4C	ATG4 autophagy related 4	AK027773.1	0.001439
		homolog C (S. cerevisiae)
11724079_s_at	E2F2	E2F transcription factor 2	NM_004091.2	0.001667
11718280_s_at	TRIAP1	TP53 regulated inhibitor of	NM_016399.2	0.001683
		apoptosis 1
11720459_s_at	CAPRIN1	cell cycle associated protein 1	BQ002768	0.001735
11720615_a_at	TUBG2	tubulin, gamma 2	NM_016437.2	0.00174
11757673_x_at	RPL39	ribosomal protein L39	BX435916	0.001879
11720398_a_at	NBN	nibrin	BC146797.1	0.002186
11734661_a_at	CLSTN3	calsyntenin 3	NM_014718.3	0.0022
11726529_s_at	BRCC3	BRCA1/BRCA2-containing	NM_024332.2	0.002236
		complex, subunit 3
11758291_s_at	MRPS10	mitochondrial ribosomal	BF701142	0.002439
		protein S10
11726660_a_at	GPN3	GPN-loop GTPase 3	AY359078.1	0.002577
11734619_x_at	ALOX15B	arachidonate 15-	NM_001141.2	0.002749
		lipoxygenase, type B
11719482_a_at	MRPL21	mitochondrial ribosomal	NM_181515.1	0.002874
		protein L21
11716896_a_at	PPIE	peptidylprolyl isomerase E	NM_006112.2	0.002936
		(cyclophilin E)
11757498_s_at	TMEM106C	transmembrane protein 106C	A1278554	0.003263
11722842_s_at	ENAH	enabled homolog (Drosophila)	BC095481.1	0.003561
11722415_a_at	HBS1L	HBS1-like (S. cerevisiae)	BC040849.1	0.003563
11742050_a_at	API5	apoptosis inhibitor 5	AK294724.1	0.003612
11719499_at	MAOB	monoamine oxidase B	NM_000898.4	0.003642
11717099_at	HIST1H2BK	histone cluster 1, H2bk	NM_080593.1	0.003648
11744666_at	FAN1	FANCD2/FANCI-associated	BC047882.1	0.003687
		nuclease 1
11756910_x_at	FANCD2	Fanconi anemia,	AL832427.1	0.00395
		complementation group D2
11758535_s_at	GPAM	glycerol-3-phosphate	AI074401	0.003969
		acyltransferase, mitochondrial
11719920_at	FXC1	fracture callus 1 homolog (rat)	BC011014.1	0.004197
		ring finger and CHY zinc finger
11719571_a_at	RCHY1	domain containing 1	BC047393.1	0.004345
11763339_a_at	SIVA1	SIVA1, apoptosis-inducing	AK128704.1	0.004492
		factor
11740706_a_at	NFRKB	nuclear factor related to	NM_006165.3	0.004845
		kappaB binding protein
11730410_a_at	PXMP4	peroxisomal membrane	NM_007238.4	0.005105
		protein 4, 24 kDa
11739973_s_at	NUAK1	NUAK family, SNF1-like	BU686994	0.005564
		kinase, 1
11757687_x_at	DAD1	defender against cell death 1	BU535881	0.005572
11721430_a_at	SYBU	syntabulin (syntaxin-	NM_001099744.1	0.005683
		interacting)
11722555_sat	HADH	hydroxyacyl-CoA	CR591982.1	0.005987
		dehydrogenase
11736367_a_at	MCM10	minichromosome	NM_182751.1	0.006448
		maintenance complex
		component 10
11739660_x_at	PPCS	phosphopantothenoylcysteine	NM_001077447.1	0.0065
		synthetase
11757604_a_at	SAMM50	sorting and assembly	BQ186212	0.006505
		machinery component 50
		homolog (S. cerevisiae)
11722398_s_at	RWDD4	RWD domain containing 4	NM_152682.2	0.00654
11733866_a_at	RARS2	arginyl-tRNA synthetase 2,	NM_020320.3	0.006608
		mitochondrial
11722351_at	SRSF8	serine/arginine-rich splicing	NM_032102.2	0.006693
		factor 8
11726320_at	ERO1L	ERO1-like (S. cerevisiae)	NM_014584.1	0.006774
		up-regulated during skeletal
		muscle growth 5 homolog
11744384_x_at	USMG5	(mouse)	BC072683.1	0.006853
11733975_a_at	DDHD2	DDHD domain containing 2	BU631346	0.007241
11727533_a_at	FEZ2	fasciculation and elongation	NM_001042548.1	0.007345
		protein zeta 2 (zygin II)
11723462_a_at	PHKB	phosphorylase kinase, beta	NM_001031835.2	0.007666
11718475_s_at	IDH1	isocitrate dehydrogenase 1	NM_005896.2	0.007717
		(NADP+), soluble
11744822_a_at	NDUFB2	NADH dehydrogenase	BC063026.1	0.007876
		(ubiquinone) 1 beta
		subcomplex, 2, 8 kDa
11757589_a_at	NDUFA12	NADH dehydrogenase	BU537124	0.008475
		(ubiquinone) 1 alpha
		subcomplex, 12
11726186_x_at	C12orf48	chromosome 12 open reading	NM_017915.2	0.008601
		frame 48
11739972_at	NUAK1	NUAK family, SNF1-like	BU686994	0.008782
		kinase, 1
11755294_x_at	NEB	nebulin	BC063136.1	0.008985
11740962_a_at	UBA5	ubiquitin-like modifier	NM_198329.2	0.009092
		activating enzyme 5
11753867_a_at	NDUFA1	NADH dehydrogenase	AB451304.1	0.009324
		(ubiquinone) 1 alpha
		subcomplex, 1, 7.5 kDa
11757665_x_at	NDUFS5	NADH dehydrogenase	AA977996	0.009487
		(ubiquinone) Fe-S protein 5,
		15 kDa (NADH-coenzyme Q
		reductase)
11757684_a_at	TPD52L2	tumor protein D52-like 2	A1806821	0.009563
11731068_s_at	FIGNL1	fidgetin-like 1	NM_022116.3	0.009587
11743064_at	CDC6	cell division cycle 6 homolog	CR598029.1	0.009677
		(S. cerevisiae)
11746036_s_at	CBR1	carbonyl reductase 1	AK311219.1	0.009851
11729763_a_at	LSM10	LSM10, U7 small nuclear RNA	NM_032881.1	0.010114
		associated
11719268_at	TNNC1	troponin C type 1 (slow)	NM_003280.2	0.010462
11758199_s_at	RAD23B	RAD23 homolog B	BG571600	0.010584
		(S. cerevisiae)
11723291_a_at	NDUFA1	NADH dehydrogenase	NM_004541.3	0.010596
		(ubiquinone) 1 alpha
		subcomplex, 1, 7.5 kDa
11715771_a_at	MRPL13	mitochondrial ribosomal	NM_014078.4	0.010834
		protein L13
11746174_s_at	IDH1	isocitrate dehydrogenase 1	BC012846.1	0.011295
		(NADP+), soluble
11724432_x_at	TRAPPC2	trafficking protein particle	NM_001011658.2	0.01144
		complex 2
11746489_x_at	GPAA1	glycosylphosphatidylinositol	BC006383.2	0.011462
		anchor attachment protein 1
		homolog (yeast)
11724120_a_at	TRIM59	tripartite motif-containing 59	NM_173084.2	0.01188
11764061_s_at	NDUFB3	NADH dehydrogenase	AA887183	0.012144
		(ubiquinone) 1 beta
		subcomplex, 3, 12 kDa
11758083_s_at	HPGD	hydroxyprostaglandin	AI743714	0.012171
		dehydrogenase 15-(NAD)
11729715_a_at	CBR1	carbonyl reductase 1	NM_001757.2	0.012312
11734864_x_at	SARNP	SAP domain containing	NM_033082.3	0.012428
		ribonucleoprotein
11717314_a_at	HAUS1	HAUS augmin-like complex,	NM_138443.3	0.012462
		subunit 1
11751523_a_at	TMED5	transmembrane emp24	AK293308.1	0.012569
		protein transport domain
		containing 5
11754800_s_at	GFM1	G elongation factor,	AK092293.1	0.012699
		mitochondrial 1
11746042_s_at	TRA2B	transformer 2 beta homolog	AK098191.1	0.01285
		(Drosophila)
11736741_a_at	MKI67	antigen identified by	NM_001145966.1	0.012861
		monoclonal antibody Ki-67
11729333_at	PADI1	peptidyl arginine deiminase,	NM_013358.2	0.013091
		type!
11751291_a_at	SFXN4	sideroflexin 4	AY269785.1	0.013333
11717991_a_at	SIDT2	SIDI transmembrane family,	NM_001040455.1	0.013344
		member 2
11748896_s_at	CCRL1	chemokine (C-C motif)	AK304461.1	0.013521
		receptor-like 1
11716395_a_at	GPR56	G protein-coupled receptor 56	NM_001145774.1	0.013559
11729716_s_at	CBR1	carbonyl reductase 1	NM_001757.2	0.01399
11716063_at	TNC	tenascin C	NM_002160.2	0.014267
11758011_x_at	EEF1A1	eukaryotic translation	BI495952	0.014362
		elongation factor 1 alpha 1
11720317_a_at	DAD1	defender against cell death 1	NM_001344.2	0.014754
11720186_s_at	MAD2L1	MAD2 mitotic arrest deficient-	NM_002358.3	0.014969
		like 1 (yeast)
11725960_s_at	CALM3	calmodulin 3 (phosphorylase	NM_005184.2	0.015262
		kinase, delta)
11730753_at	AGPAT5	1-acylglycerol-3-phosphate 0-	NM_018361.3	0.015361
		acyltransferase 5
		(lysophosphatidic acid
		acyltransferase, epsilon)
11735839_at	STX19	syntaxin 19	NM_001001850.1	0.015426
11746655_a_at	ACAA1	acetyl-CoA acyltransferase 1	AK303251.1	0.015895
11744002_s_at	MTHFD2	methylenetetrahydrofolate	BG026531	0.015966
		dehydrogenase (NADP+
		dependent) 2,
		methenyltetrahydrofolate
		cyclohydrolase
11721296_a_at	NDUFB1	NADH dehydrogenase	NM_004545.3	0.016187
		(ubiquinone) 1 beta
		subcomplex, 1, 7 kDa
11725125_a_at	NEB	nebulin	NM_004543.3	0.016335
11716624_s_at	XPO1	exportin 1 (CRM1 homolog,	NM_003400.3	0.016341
		yeast)
11759922_a_at	PARD3	par-3 partitioning defective 3	BC071566.1	0.016372
		homolog (C. elegans)

TABLE 19
Type III Dermis; Up-regulated

GeneTitan_ID	Gene	Title	Public ID	p
11733167_at	LRRN4CL	LRRN4 C-terminal like	BC053902.1	0.000101
11716549_s_at	ISLR	immunoglobulin superfamily	NM_005545.3	0.00021
		containing leucine-rich repeat
11743191_a_at	NTM	neurotrimin	AI343272	0.000486
11725753_a_at	GRIA3	glutamate receptor, ionotrophic,	U10301.1	0.000741
		AMPA 3
11741377_a_at	MMP2	matrix metallopeptidase 2	NM_001127891.1	0.001476
		(gelatinase A, 72 kDa gelatinase,
		72 kDa type IV collagenase)
11717765_a_at	MGLL	monoglyceride lipase	NM_007283.5	0.001622
11721372_at	TCF7L1	transcription factor 7-like 1 (T-cell	NM_031283.1	0.001646
		specific, HMG-box)
11722839_at	LYAR	Ly1 antibody reactive homolog	AW958593	0.001955
		(mouse)
11762135_at_	PTPRK	protein tyrosine phosphatase,	BC063596.1	0.002158
		receptor type, K
11721467_s_at	CD276	CD276 molecule	NM_001024736.1	0.002325
11761134_at	MYST3	MYST histone acetyltransferase	BC142959.1	0.003233
		(monocytic leukemia) 3
11720440_at	OLFML2B	olfactomedin-like 2B	NM_015441.1	0.003454
11745431_a_at	SVIL	supervillin	BC092440.1	0.003484
11739746_s_at	SVIL	supervillin	CD366976	0.003636
11757808_s_at	RERE	arginine-glutamic acid dipeptide	BM706668	0.003739
		(RE) repeats
11725937_a_at	LGALS3	lectin, galactoside-binding,	BC053667.1	0.003825
		soluble, 3
11720274_x_at	ALKBH6	alkB, alkylation repair homolog 6	NM_032878.3	0.003968
		(E. coli)
11755955_a_at	FAP	fibroblast activation protein, alpha	AL832166.1	0.003989
11724619_at	RSPO3	R-spondin 3 homolog (Xenopus	NM_032784.3	0.004121
		laevis)
11729170_x_at	DUSP10	dual specificity phosphatase 10	AF179212.1	0.004193
11752038_a_at	AQPEP	laeverin	BC068560.1	0.004865
11720846_at	CD248	CD248 molecule, endosialin	NM_020404.2	0.005206
11731143_a_at	GPR133	G protein-coupled receptor 133	NM_198827.3	0.005394
11728451_a_at	PCOLCE2	procollagen C-endopeptidase	NM_013363.2	0.005523
		enhancer 2
11731682_at	CD70	CD70 molecule	NM_001252.3	0.005777
11716226_a_at	LIMA1	LIM domain and actin binding 1	BC136763.1	0.006288
11750244_a_at	MGLL	monoglyceride lipase	AK304844.1	0.00649
11762370_x_at	BNC1	basonuclin 1	L03427.1	0.006531
11729101_a_at	AKR1C2	aldo-keto reductase family 1,	NM_205845.1	0.006587
		member C2 (dihyd rod iol
		dehydrogenase 2; bile acid
		binding protein; 3-alpha
		hydroxysteroid dehydrogenase,
		type III)
11731649_x_at	NTM	neurotrimin	AY358331.1	0.006934
11716238_at	ARHGAP1	Rho GTPase activating protein 1	NM_004308.2	0.006953
11728498_a_at	SVIL	supervillin	NM_003174.3	0.00696
11725517_x_at	ABCG1	ATP-binding cassette, sub-family G	NM_207627.1	0.007347
		(WHITE), member 1
11728605_s_at	LIMS1	LIM and senescent cell antigen-	NM_033514.2	0.007353
		like domains 1
11752843_x_at	SQSTM1	sequestosome 1	AK304877.1	0.007432
11757557_s_at	CADM1	cell adhesion molecule 1	H23245	0.007475
11718269_x_at	ANGPTL2	angiopoietin-like 2	AY358274.1	0.007782
11747944_a_at	PPFIA2	protein tyrosine phosphatase,	AK296380.1	0.008378
		receptor type, f polypeptide
		(PTPRF), interacting protein
		(liprin), alpha 2
11761149_a_at	C5orf45	chromosome 5 open reading	AK293901.1	0.008409
		frame 45
11737357_a_at	CNGA3	cyclic nucleotide gated channel	NM_001298.2	0.008783
		alpha 3
11743250_a_at	MMP2	matrix metallopeptidase 2	BX357054	0.009096
		(gelatinase A, 72 kDa gelatinase,
		72 kDa type IV collagenase)
11725515_a_at	ABCG1	ATP-binding cassette, sub-family G	NM_207627.1	0.009131
		(WHITE), member 1
11759362_x_at	PHKG1	phosphorylase kinase, gamma 1	BC051327.1	0.009194
		(muscle)
11717802_s_at	ATF5	activating transcription factor 5	BE300055	0.009354
11723070_a_at	CYTL1	cytokine-like 1	NM_018659.2	0.009527
11731650_a_at	NTM	neurotrimin	NM_001048209.1	0.009599
11720845_a_at	CD248	CD248 molecule, endosialin	NM_020404.2	0.009838
11716322_s_at	PRKCDBP	protein kinase C, delta binding	NM_145040.2	0.009887
		protein
11718658_s_at	CD34	CD34 molecule	NM_001773.2	0.010659
11747945_x_at	PPFIA2	protein tyrosine phosphatase,	AK296380.1	0.010696
		receptor type, f polypeptide
		(PTPRF), interacting protein
		(liprin), alpha 2
11717764_x_at	MGLL	monoglyceride lipase	BC006230.2	0.010744
11743251_s_at	MMP2	matrix metallopeptidase 2	BX357054	0.010854
		(gelatinase A, 72 kDa gelatinase,
		72 kDa type IV collagenase)
11731303_a_at	DUSP10	dual specificity phosphatase 10	BC020608.1	0.010964
11719737_a_at	FAM134B	family with sequence similarity	BC053326.1	0.011265
		134, member B
11758143_s_at	DUSP8	dual specificity phosphatase 8	BE350906	0.011421
11724441_x_at	PTGIS	prostaglandin 12 (prostacyclin)	NM_000961.3	0.011582
		synthase
11737583_s_at	SGCD	sarcoglycan, delta (35 kDa	NM_001128209.1	0.01169
		dystrophin-associated
		glycoprotein)
11729541_a_at	CAMKK2	calcium/calmodulin-dependent	AB081337.1	0.011881
		protein kinase kinase 2, beta
11737108_a_at	CCRL1	chemokine (C-C motif) receptor-	NM_178445.1	0.012
		like 1
11721507_at	DVL3	dishevelled, dsh homolog 3	NM_004423.3	0.012974
		(Drosophila)
11750245_x_at	MGLL	monoglyceride lipase	AK304844.1	0.013107
11737946_a_at	XPNPEP2	X-prolyl aminopeptidase	BC143901.1	0.01347
		(aminopeptidase P) 2, membrane-
		bound
11727155_a_at	TRIOBP	TRIO and F-actin binding protein	NM_007032.5	0.013526
11720441_x_at	OLFML2B	olfactomedin-like 2B	NM015441.1	0.01374
11727773_at	LARP6	La ribonucleoprotein domain	NM_197958.1	0.013995
		family, member 6
11728499_x_at	SVIL	supervillin	NM_003174.3	0.01402
11745659_s_at	POM121	POM121 membrane glycoprotein	BC130587.1	0.014097
11752562_x_at	CDH13	cadherin 13, H-cadherin (heart)	AK294277.1	0.014197
11720617_at	TRIM9	tripartite motif-containing 9	NM_015163.5	0.014562
11757548_s_at	ADAMTSL1	ADAMTS-like 1	DB329733	0.014859
11753179_s_at	FAM134B	family with sequence similarity	BC030517.1	0.014991
		134, member B
11729285_a_at	NFU1	NFU1 iron-sulfur cluster scaffold
		homolog (S. cerevisiae)	NM_001002755.1	0.01519
11741286_a_at	CCRL1	chemokine (C-C motif) receptor-	AF110640.1	0.015787
		like 1
11732315_a_at	SGCD	sarcoglycan, delta (35 kDa	AF010236.1	0.015795
		dystrophin-associated
		glycoprotein)
11715852_at	PDGFRB	platelet-derived growth factor	NM_002609.3	0.016136
		receptor, beta polypeptide
11730404_at	MEX3B	mex-3 homolog B (C. elegans)	NM_032246.3	0.0163
11751986_at	MMP19	matrix metallopeptidase 19	U38320.1	0.016486
11731122_a_at	VASH2	vasohibin 2	BC051856.1	0.016505
11732785_a_at	C16orf45	chromosome 16 open reading	NM_001142469.1	0.017241
		frame 45
11757765_s_at	SGCD	sarcoglycan, delta (35 kDa	AA401248	0.017347
		dystroph in-associated
		glycoprotein)
11743143_at	COX11	COX11 cytochrome c oxidase	AK293851.1	0.017504
		assembly homolog (yeast)
11724142_s_at	RAB11FIP2	RAB11 family interacting protein 2	DB356544	0.017868
		(class I)
11723075_a_at	BCL9L	B-cell CLL/lymphoma 9-like	AY296059.1	0.017989
11747704_a_at	CLDN11	claudin 11	AK294087.1	0.017998
11716376_at	SERPINA5	serpin peptidase inhibitor, clade A	NM_000624.4	0.018046
		(alpha-1 antiproteinase,
		antitrypsin), member 5
11756879_a_at	STARD9	StAR-related lipid transfer (START)	CR936665.1	0.018874
		domain containing 9
11733166_at	LRRN4CL	LRRN4 C-terminal like	NM_203422.1	0.018933
11720163_at	VEGFC	vascular endothelial growth factor	NM_005429.2	0.018951
		C
11754821_s_at	SLC38A1	solute carrier family 38, member 1	AI476037	0.019062
11720082_at	CBX6	chromobox homolog 6	NM_014292.3	0.020169
11762231_x_at	BBS1	Bardet-Biedl syndrome 1	AK294962.1	0.020213
11732462_at	ADAMTSL1	ADAMTS-like 1	AK123028.1	0.020317
11761563_x_at	HEATR1	HEAT repeat containing 1	BC062442.1	0.0204
11727714_at	KCNJ12	potassium inwardly-rectifying	NM_021012.4	0.020553
		channel, subfamily J, member 12
11727780_a_at	SCARA5	scavenger receptor class A,	NM_173833.4	0.020636
		member 5 (putative)
11749436_a_at	NFIC	nuclear factor I/C (CCAAT-binding	AK297825.1	0.020877
		transcription factor)
11731209_s_at	C15orf59	chromosome 15 open reading	NM_001039614.1	0.021422
		frame 59
11727125_a_at	PVRL3	poliovirus receptor-related 3	BE544927	0.021561
11744741_at	LOH3CR2A	loss of heterozygosity, 3,	AF086709.2	0.021592
		chromosomal region 2, gene A
11717891_a_at	ECM1	extracellular matrix protein 1	BC023505.2	0.021868

TABLE 20
Type III Dermis; Down-regulated

GeneTitan_ID	Gene	Title	Public ID	p
11727158_a_at	STRBP	spermatid perinuclear	NM_018387.3	0.000131
		RNA binding protein
11756850_x_at	CCT8	chaperonin containing	CR612497.1	0.000172
		TCP1, subunit 8 (theta)
11754000_x_at	CD58	CD58 molecule	CR456939.1	0.000222
11737761_a_at	HSD17B4	hydroxysteroid (17-beta)
		dehydrogenase 4	NM_000414.2	0.000267
11754276_a_at	RAD23B	RAD23 homolog B (S.	BG501496	0.000343
		cerevisiae)
11743094_at	SPRR4	small proline-rich protein	BC069445.1	0.000362
		4
11724156_at	SULT1E1	sulfotransferase family	NM_005420.2	0.000395
		1E, estrogen-preferring,
		member 1
11749267_a_at	SRD5A1	steroid-5-alpha-	AK315996.1	0.000399
		reductase, alpha
		polypeptide 1 (3-oxo-5
		alpha-steroid delta 4-
		dehydrogenase alpha 1)
11720183_s_at	EEF1B2	eukaryotic translation	NM_001959.3	0.000428
		elongation factor 1 beta 2
11737053_s_at	HSPD1	heat shock 60 kDa protein	NM_002156.4	0.000467
		1 (chaperonin)
11740377_a_at	PXMP4	peroxisomal membrane	AK297018.1	0.000581
		protein 4, 24 kDa
11726318_s_at	EEF1G	eukaryotic translation	NM_001404.4	0.000583
		elongation factor 1
		gamma
11720184_x_at	EEF1B2	eukaryotic translation	NM_001959.3	0.000595
		elongation factor 1 beta 2
11746149_x_at	BCHE	butyrylcholinesterase	M16474.1	0.000611
11737762_x_at	HSD17B4	hydroxysteroid (17-beta)	NM_000414.2	0.000646
		dehydrogenase 4
11739725_a_at	TC2N	tandem C2 domains,	NM_001128595.1	0.000648
		nuclear
11754918_s_at	HMGCS1	3-hydroxy-3-	AK095492.1	0.000648
		methylglutaryl-CoA
		synthase 1 (soluble)
11741799_a_at	BCOR	BCL6 corepressor	AF317391.1	0.000649
11736831_a_at	SEC23B	Sec23 homolog B (S.	NM_032986.3	0.000656
		cerevisiae)
11744777_s_at	DPY30	dpy-30 homolog (C.	BC015970.1	0.000676
		elegans)
11754418_s_at	G3BP1	GTPase activating protein	AK130003.1	0.000682
		(SH3 domain) binding
		protein 1
11723250_a_at	EML2	echinoderm microtubule	NM_012155.1	0.00072
		associated protein like 2
11752369_a_at	IMPDH2	IMP (inosine 5′-	AK293397.1	0.000726
		monophosphate)
		dehydrogenase 2
11729643_s_at	TPD52	tumor protein D52	CB219128	0.000732
11755057_s_at	ATP2C1	ATPase, Ca++	AB037768.1	0.000739
		transporting, type 2C,
		member 1
11716946_s_at	TM9SF3	transmembrane 9	AF269150.1	0.000773
		superfamily member 3
11756300_a_at	ANP326	acidic (leucine-rich)	BX432546	0.000781
		nuclear phosphoprotein
		32 family, member B
11716134_a_at	MTOR	mechanistic target of	NM_004958.3	0.000785
		rapamycin
		(serine/threonine kinase)
11755203_x_at	RPL21	ribosomal protein L21	BX647669.1	0.000869
11730938_x_at	PYCR1	pyrroline-5-carboxylate	NM_153824.1	0.000877
		reductase 1
11750545_a_at	CNOT7	CCR4-NOT transcription	BC007315.2	0.000884
		complex, subunit 7
11727826_a_at	C2orf56	chromosome 2 open	BC004548.2	0.00093
		reading frame 56
11718344_a_at	CNOT7	CCR4-NOT transcription	NM_013354.5	0.000947
		complex, subunit 7
11756600_a_at	TPD52	tumor protein D52	AK308983.1	0.000999
11734619_x_at	ALOX156	arachidonate 15-	NM_001141.2	0.001036
		lipoxygenase, type B
11715621_at	UFC1	ubiquitin-fold modifier	NM_016406.3	0.001145
		conjugating enzyme 1
11715958_s_at	RPL7	ribosomal protein L7	NM_000971.3	0.001233
11748713_a_at	ASPM	asp (abnormal spindle)	AY971957.1	0.001256
		homolog, microcephaly
		associated (Drosophila)
11758707_s_at	C5orf25	chromosome 5 open	DB526316	0.001417
		reading frame 25
200081_PM_s_at	RPS6	ribosomal protein S6	BE741754	0.00144
11726299_x_at	LGALS8	lectin, galactoside-	AF342815.1	0.001452
		binding, soluble, 8
11756210_a_at	RCL1	RNA terminal phosphate	AL582781	0.001477
		cyclase-like 1
11743604_s_at	RRM1	ribonucleotide reductase	BE618815	0.001487
		M1
11729641_a_at	TPD52	tumor protein D52	BG389015	0.001493
11718461_at	SLC39A11	solute carrier family 39	NM_139177.3	0.001532
		(metal ion transporter),
		member 11
11725053_x_at	TOP1MT	topoisomerase (DNA) I,	NM_052963.1	0.001534
		mitochondrial
11758027_s_at	HOOK1	hook homolog 1	CD243255	0.001606
		(Drosophila)
11745205_s_at	TPD52	tumor protein D52	BC018117.1	0.001623
11760342_a_at	PPP3CB	protein phosphatase 3,	M29550.1	0.001681
		catalytic subunit, beta
		isozyme
11725875_at	WDR66	WD repeat domain 66	NM_144668.4	0.001791
11739308_s_at	DLG1	discs, large homolog 1	BM681931	0.001815
		(Drosophila)
11719666_a_at	STMN1	stathmin 1	BC082228.1	0.001852
11752283_a_at	ALOX15B	arachidonate 15-	AK298095.1	0.001904
		lipoxygenase, type B
11723312_a_at	PXMP2	peroxisomal membrane	NM_018663.1	0.001916
		protein 2, 22 kDa
11719667_s_at	STMN1	stathmin 1	BC082228.1	0.001961
11728791_at	THRSP	thyroid hormone	NM_003251.2	0.001966
		responsive
11734917_a_at	METTL4	methyltransferase like 4	BQ009802	0.001983
11717236_x_at	RPS7	ribosomal protein S7	NM_001011.3	0.002022
11754132_x_at	COMT	catechol-0-	BT007125.1	0.002101
		methyltransferase
11743372_s_at	PTGES3	prostaglandin E synthase	CR611609.1	0.002174
		3 (cytosolic)
11730411_a_at	PXMP4	peroxisomal membrane	BF057649	0.002209
		protein 4, 24 kDa
200063_PM_s_at	NPM1	nucleophosmin	BC002398.1	0.002233
		(nucleolar
		phosphoprotein B23,
		numatrin)
11722642_a_at	DGAT2	diacylglycerol 0-	BC015234.1	0.002305
		acyltransferase 2
11752550_x_at	CCT8	chaperonin containing	AK293705.1	0.002336
		TCP1, subunit 8 (theta)
11758217_s_at	FAM108C1	family with sequence	CB997200	0.002358
		similarity 108, member
		C1
11717182_a_at	PDS5A	PDS5, regulator of	NM_001100399.1	0.002387
		cohesion maintenance,
		homolog A (S. cerevisiae)
11717153_a_at	C20orf3	chromosome 20 open	NM_020531.2	0.002394
		reading frame 3
11742779_a_at	HIBCH	3-hydroxyisobutyryl-CoA	U66669.1	0.002431
		hydrolase
11744264_a_at	SEC11C	SEC11 homolog C (S.	AI816180	0.002433
		cerevisiae)
11753788_x_at	CDKN3	cyclin-dependent kinase	AF213040.1	0.002434
		inhibitor 3
11758709_s_at	RDH11	retinol dehydrogenase 11	A1972157	0.002449
		(all-trans/9-cis/11-cis)
11727320_at	IGFL2	IGF-like family member 2	NM_001002915.2	0.002476
11730803_a_at	PRPF38B	PRP38 pre-mRNA	NM_018061.2	0.002515
		processing factor 38
		(yeast) domain
		containing B
11753740_x_at	CYB5A	cytochrome b5 type A	CR456990.1	0.002572
		(microsomal)
11718246_a_at	KIAA0146	KIAA0146	NM_001080394.1	0.002609
11720768_at	METTL9	methyltransferase like 9	NM_016025.3	0.002613
11755017_a_at	CHCHD7	coiled-coil-helix-coiled-	AK098285.1	0.002843
		coil-helix domain
		containing 7
11732128_s_at	CCT4	chaperonin containing	BC106934.1	0.002855
		TCP1, subunit 4 (delta)
11744900_x_at	FADS2	fatty acid desaturase 2	AF108658.1	0.002865
11715881_a_at	DAP3	death associated protein	NM_004632.2	0.002925
		3
11756875_x_at	COMMD6	COMM domain	CR603325.1	0.002962
		containing 6
11756783_a_at	TF	transferrin	BC045772.1	0.002967
11723197_at	HNRNPA3	heterogeneous nuclear	BX434302	0.003022
		ribonucleoprotein A3
11729941_at	TMEM56	transmembrane protein	NM_152487.2	0.003035
		56
11716813_a_at	GATM	glycine	AK298350.1	0.003053
		amidinotransferase (L-
		arginine:glycine
		amidinotransferase)
11721242_s_at	FDFT1	farnesyl-diphosphate	NM_004462.3	0.003125
		farnesyltransferase 1
11749786_x_at	HNRNPF	heterogeneous nuclear	AK296696.1	0.003153
		ribonucleoprotein F
11723313_s_at	PXMP2	peroxisomal membrane	NM_018663.1	0.003162
		protein 2, 22 kDa
11727286_a_at	ZNF323	zinc finger protein 323	NM_001135215.1	0.003185
11720813_at	INTS10	integrator complex	NM_018142.2	0.003216
		subunit 10
11749874_a_at	OXCT1	3-oxoacid CoA	AK299668.1	0.003244
		transferase 1
11757320_x_at	CYB5A	cytochrome b5 type A	AA706740	0.003263
		(microsomal)
11733591_a_at	C1orf204	chromosome 1 open	NM_001134233.1	0.003297
		reading frame 204
11718135_at	PRPS2	phosphoribosyl	NM_001039091.1	0.003316
		pyrophosphate
		synthetase 2
11716302_s_at	ACSL1	acyl-CoA synthetase long-	NM_001995.2	0.003359
		chain family member 1
11744392_a_at	PAPOLA	poly(A) polymerase alpha	BC000927.1	0.003388
11741012_a_at	SC4MOL	sterol-C4-methyl oxidase-	AK292418.1	0.00342
		like
		synovial sarcoma
		translocation,
11722800_a_at	SS18	chromosome 18	CB241009	0.003458
11755439_x_at	UBAC2	UBA domain containing 2	BC053346.1	0.003608
11756674_s_at	STRBP	spermatid perinuclear	CR596677.1	0.003641
		RNA binding protein

The gene expression signatures provided in Table 9-20 can be used to classify the type of periorbital dyschromia exhibited by person. For example, a person can be classified as exhibiting Type I periorbital dyschromia when the gene expression signature of a skin tissue sample obtained from the periorbital region of the person corresponds to 15% or more (e.g., more than 25%, 50%, 75%, 80%, 90% or even up to 100%) of the genes from Tables 9 to 12. In other words, a person can be classified as exhibiting Type I periorbital dyschromia if the top 100 upregulated genes in the epidermis comprise 15% or more the genes in Table 9; the top 100 downregulated genes in the epidermis comprise 15% or more of the genes in Table 10; the top 100 upregulated genes in the dermis comprise 15% or more of the genes in Table 11; and/or the top 100 downregulated genes in the dermis comprise 15% or more of the genes in Table 12. Similarly, a person can be classified as exhibiting Type II or Type III periorbital dyschromia when the gene expression signature of the skin tissue sample comprises significantly upregulated and downregulated genes that correspond to 15% or more of the genes in at least one of Tables 13 to 16 or Tables 17 to 20, respectively.

Theme analysis may be used to identify biological or phenotypic themes associated with the gene expression data that correspond to Type I, Type II and Type III periorbital dyschromia. Theme analysis is a statistical analysis-based method for detecting biological patterns in gene expression data. The method uses an ontology of controlled vocabulary terms developed by the Gene Ontology (“GO”) Consortium [Ashburner, M. et al. (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet, 25, 25-29] that describe the biological processes, molecular functions and cellular components associated with gene products. Analysis involves statistical comparison of a regulated list of genes and a larger reference list of all the expressed genes, to determine if genes annotated to specific GO terms are significantly enriched in the regulated list. This analysis may reveal biological patterns when multiple genes associated with a given GO term occur on the regulated list at a frequency greater than expected by chance. Such analysis may be performed using Theme Extractor proprietary software and an algorithm that calculates the p-value of each ontology term. Data may be analyzed for statistical significance, for example, by the Fisher's exact test. Conventional approaches and statistical methods such as, for example, Gene Set Enrichment Analysis described by Subramanian, A., et al., in “Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles,” Proc. Natl. Acad Sci U.S.A, 102, 15545-155501 (2005) are suitable for conducting theme analysis herein.

Table 21 shows Gene Ontology Biological Process terms that are significantly enriched in the epidermis of subjects with Type I periorbital dyschromia. The results in Table 21 were generated from differentially expressed genes in those subjects with top ranked genes shown in Tables 13 and 14. Only the most highly significant themes are shown (p-value≤1×10⁻² to p≥1×10⁻⁵) and the theme analysis was done separately for the up- and down-regulated genes. The level of indentation in the terms column (i.e., the number of dots preceding the term) generally indicates the level in the GO hierarchy and parent/child relationships between terms.

TABLE 21
	Type I Epidermis vs N-D

Gene Ontology Biological Process Terms	Up	Down	Directional
GO:0002764 immune response-regulating		**
signaling pathway
GO:0002758 innate immune response-activating		***
signal transduction
GO:0002224 toll-like receptor signaling pathway		**
GO:0048468 cell development	**
GO:0002376 immune system process		****
GO:0002252 immune effector process		****
GO:0002253 activation of immune response		****
GO:0002218 activation of innate immune		***
response
GO:0006955 immune response		****
GO:0045087 innate immune response		****
GO:0071383 cellular response to steroid	**
hormone stimulus
GO:0006954 inflammatory response		*
GO:0045047 protein targeting to ER		****
GO:0032984 macromolecular complex		****
disassembly
GO:0016568 chromatin modification	*
GO:0050776 regulation of immune response		****
GO:0006749 glutathione metabolic process		**
GO:0019752 carboxylic acid metabolic process		*
GO:0007154 cell communication	*
GO:0016042 lipid catabolic process		*
GO:0070588 calcium ion transmembrane	*
transport
*p-value between 1 × 10−2 and 1 × 10−3
**p-value between 1 × 10−3 and 1 × 10−4
***p-value between 1 × 10−4 and 1 × 10−5
****p-value less than 1 × 10−5

Table 21 shows Gene Ontology Biological Process terms that are significantly enriched in the epidermis of subjects with Type II periorbital dyschromia. The results in Table 14 were generated from differentially expressed genes in those subjects with top ranked genes shown in Tables 13 and 14. Only the most highly significant themes are shown (p≤1×10⁻²), and the theme analysis was done separately for the up- and down-regulated genes.

TABLE 22
	Terms Type II Epidermis vs N-D

Gene Ontology Biological Process	Up	Down	Directional
GO:0042770 signal transduction in		****
response to DNA damage
GO:0072331 signal transduction by		****
p53 class mediator
GO:0007173 epidermal growth factor		**
receptor signaling pathway
GO:0001942 hair follicle development		****
GO:0008544 epidermis development		****
GO:0045444 fat cell differentiation	*
GO:0019882 antigen processing and		****
presentation
GO:0071453 cellular response to oxygen			**
levels
GO:0071456 cellular response to hypoxia			**
GO:0031960 response to corticosteroid	*
stimulus
GO:0033554 cellular response to stress		****
GO:0006281 DNA repair		**
GO:0000077 DNA damage checkpoint		****
GO:0006950 response to stress		**
GO:0009268 response to pH		**
GO:0006886 intracellular protein		****
transport
GO:0006605 protein targeting		****
GO:0015031 protein transport		****
GO:0046907 intracellular transport		****
GO:0048193 Golgi vesicle transport		**
GO:0006839 mitochondrial transport		****
GO:0015986 ATP synthesis coupled		***
proton transport
GO:0016568 chromatin modification	**
GO:0031326 regulation of cellular	**
biosynthetic process
GO:0006521 regulation of cellular amino		****
acid metabolic process
GO:0010565 regulation of cellular ketone		****
metabolic process
GO:0051171 regulation of nitrogen
compound metabolic process
GO:0051726 regulation of cell cycle		**
GO:0045454 cell redox homeostasis		**
GO:0032652 regulation of interleukin-1	**
production
GO:0035383 thioester metabolic process		****
GO:0006637 acyl-CoA metabolic process		****
GO:0006099 tricarboxylic acid cycle		****
GO:0006635 fatty acid beta-oxidation		**
GO:0018108 peptidyl-tyrosine	**
phosphorylation
GO:0006082 organic acid metabolic		****
process
GO:0006520 cellular amino acid		**
metabolic process
GO:0043038 amino acid activation		****
GO:0006091 generation of precursor		****
metabolites and energy
GO:0006096 glycolysis		**
GO:0006119 oxidative phosphorylation		****
GO:0042773 ATP synthesis coupled		****
electron transport
GO:0045333 cellular respiration		****
GO:0007049 cell cycle		****
GO:0005975 carbohydrate metabolic		***
process
GO:0006007 glucose catabolic process		***
GO:0016052 carbohydrate catabolic		****
process
GO:0055114 oxidation-reduction process		****

Table 23 shows Gene Ontology Biological Process terms that are significantly enriched in the epidermis of subjects with Type III periorbital dyschromia. The results in Table 23 were generated differentially expressed genes in those subjects with top ranked genes shown in Tables 17 and 18. Only the most highly significant themes are shown (p-value <1×10⁻²), and the theme analysis was done separately for the up- and down-regulated genes.

TABLE 23
	Type III Epidermis
	vs N-D

Gene Ontology Biological Process Terms	Up	Down	Directional
GO:0048731 system development	**
GO:0048856 anatomical structure development	***
GO:0030154 cell differentiation	**
GO:0070482 response to oxygen levels	*
GO:0033365 protein localization to organelle		**
GO:0045047 protein targeting to ER		**
GO:0006605 protein targeting		**
GO:0006612 protein targeting to membrane		**
GO:0006839 mitochondrial transport		**
GO:0001934 positive regulation of protein	**
phosphorylation
GO:0051347 positive regulation of transferase	**
activity
GO:0010627 regulation of intracellular protein	**
kinase cascade
GO:0080135 regulation of cellular response	*
to stress
GO:0051320 S phase		***
GO:0006414 translational elongation		****
GO:0006091 generation of precursor		***
metabolites and energy
GO:0006119 oxidative phosphorylation		**
GO:0022900 electron transport chain		****
GO:0045333 cellular respiration		****
GO:0055114 oxidation-reduction process		***

Table 24 shows Gene Ontology Biological Process terms that are significantly enriched in the dermis of subjects with Type I periorbital dyschromia. The results in Table 24 were generated from differentially expressed genes in those subjects with top ranked genes shown in Tables 11 and 12. Only the most highly significant themes are shown (p≤1×10⁻²), and the theme analysis was done separately for the up- and down-regulated genes.

TABLE 24
	Type I Dermis vs N-D

Gene Ontology Biological Process Terms	Up	Down	Directional
GO:0000165 MAPK cascade	**
GO:0048011 nerve growth factor receptor	*
signaling pathway
GO:0007179 transforming growth factor beta	*
receptor signaling pathway
GO:0050877 neurological system process	***
GO:0007596 blood coagulation	*
GO:0050878 regulation of body fluid levels	*
GO:0001944 vasculature development	****
GO:0001568 blood vessel development	****
GO:0048514 blood vessel morphogenesis	****
GO:0001525 angiogenesis	****
GO:0030183 B cell differentiation			*
GO:0007399 nervous system development	****
GO:0022008 neurogenesis	***
GO:0048699 generation of neurons	***
GO:0030182 neuron differentiation	**
GO:0048666 neuron development	**
GO:0048870 cell motility	**
GO:0043627 response to estrogen stimulus	**
GO:0006281 DNA repair		****
GO:0001666 response to hypoxia	*
GO:0006979 response to oxidative stress	*
GO:0009611 response to wounding	***
GO:0070482 response to oxygen levels	**
GO:0033365 protein localization to organelle		****
GO:0045047 protein targeting to ER		****
GO:0006605 protein targeting		****
GO:0015031 protein transport		****
GO:0046907 intracellular transport		****
GO:0034330 cell junction organization	**
GO:0030198 extracellular matrix organization	*
GO:0007010 cytoskeleton organization	*
GO:0051276 chromosome organization		***
GO:0032200 telomere organization		**
GO:0006338 chromatin remodeling		*
GO:0043408 regulation of MAPK cascade	***
GO:0051924 regulation of calcium ion transport	*
GO:0010827 regulation of glucose transport		***
GO:0030334 regulation of cell migration	****
GO:0010564 regulation of cell cycle process		**
GO:0010646 regulation of cell communication	****
GO:0022402 cell cycle process		**
GO:0022403 cell cycle phase		***
GO:0007049 cell cycle		**
GO:0000278 mitotic cell cycle		****
GO:0007154 cell communication	****
GO:0008202 steroid metabolic process	*
GO:0006694 steroid biosynthetic process		**
GO:0016126 sterol biosynthetic process		****
GO:0006695 cholesterol biosynthetic process		****
GO:0061061 muscle structure development	*

Table 25 shows Gene Ontology Biological Process terms that are significantly enriched in the dermis of subjects with Type II periorbital dyschromia. The results in Table 25 were generated from differentially expressed genes in those subjects with top ranked genes shown in Tables 15 and 16. Only the most highly significant themes are shown (p<1×10⁻²), and the theme analysis was done separately for the up- and down-regulated genes.

TABLE 25
	Type II Dermis vs. N-D

Gene Ontology Biological Process Terms	Up	Down	Directional
GO:0019226 transmission of nerve impulse	*
GO:0050877 neurological system process	**
GO:0007399 nervous system development	**
GO:0022008 neurogenesis	****
GO:0048699 generation of neurons	***
GO:0030182 neuron differentiation	***
GO:0048666 neuron development	***
GO:0031175 neuron projection development	**
GO:0007409 axonogenesis	**
GO:0048667 cell morphogenesis involved in	**
neuron differentiation
GO:0048468 cell development	***
GO:0006281 DNA repair		****
GO:0033365 protein localization to organelle		****
GO:0070972 protein localization to endoplasmic		****
reticulum
GO:0006605 protein targeting		****
GO:0006612 protein targeting to membrane		****
GO:0015031 protein transport		****
GO:0006810 transport		****
GO:0051641 cellular localization		****
GO:0016043 cellular component organization		****
GO:0022411 cellular component disassembly		****
GO:0030198 extracellular matrix organization	*
GO:0032984 macromolecular complex		****
disassembly
GO:0043624 cellular protein complex		****
disassembly
GO:0071156 regulation of cell cycle arrest		**
GO:0010646 regulation of cell communication	*
GO:0051320 S phase		**
GO:0044248 cellular catabolic process		****
GO:0006457 protein folding		**
GO:0007049 cell cycle		*
GO:0000278 mitotic cell cycle		**
GO:0007154 cell communication	*
GO:0006694 steroid biosynthetic process		**
GO:0006695 cholesterol biosynthetic process		***

Table 26 shows Gene Ontology Biological Process terms that are significantly enriched in the epidermis of subjects with Type III periorbital dyschromia. The results in Table 26 were generated from differentially expressed genes in those subjects with top ranked genes shown in Tables 19 and 20. Only the most highly significant themes are shown (p≤1×10⁻²), and the theme analysis was done separately for the up- and down-regulated genes.

TABLE 26
	Type III Dermis vs. N-D

Gene Ontology Biological Process Terms	Up	Down	Directional
GO:0007155 cell adhesion	**
GO:0019226 transmission of nerve impulse	*
GO:0051403 stress-activated MAPK cascade	***
GO:0007254 JNK cascade	**
GO:0000165 MAPK cascade	****
GO:0016055 Wnt receptor signaling pathway	*
GO:0050877 neurological system process	**
GO:0001944 vasculature development	***
GO:0001568 blood vessel development	**
GO:0048514 blood vessel morphogenesis	**
GO:0022008 neurogenesis	**
GO:0030182 neuron differentiation	**
GO:0048666 neuron development	**
GO:0061061 muscle structure development	**
GO:0042692 muscle cell differentiation	**
GO:0048646 anatomical structure formation	****
involved in morphogenesis
GO:0033554 cellular response to stress		*
GO:0006281 DNA repair		****
GO:0001666 response to hypoxia	**
GO:0070482 response to oxygen levels	***
GO:0036293 response to decreased oxygen levels	**
GO:0034613 cellular protein localization		****
GO:0033365 protein localization to organelle		****
GO:0070972 protein localization to endoplasmic		****
reticulum
GO:0045047 protein targeting to ER		****
GO:0006886 intracellular protein transport		****
GO:0006605 protein targeting		****
GO:0006612 protein targeting to membrane		****
GO:0015031 protein transport		****
GO:0006811 ion transport	***
GO:0006812 cation transport	**
GO:0030001 metal ion transport	**
GO:0050000 chromosome localization		****
GO:0022411 cellular component disassembly		****
GO:0034330 cell junction organization	*
GO:0034622 cellular macromolecular complex		****
assembly
GO:0007010 cytoskeleton organization	**
GO:0000226 microtubule cytoskeleton		**
organization
GO:0070925 organelle assembly		****
GO:0051276 chromosome organization		***
GO:0032200 telomere organization		***
GO:0000819 sister chromatid segregation		****
GO:0043408 regulation of MAPK cascade	****
GO:0010646 regulation of cell communication	****
GO:0019725 cellular homeostasis	*
GO:0022402 cell cycle process		****
GO:0035383 thioester metabolic process		**
GO:0071616 acyl-CoA biosynthetic process		**
GO:0035337 fatty-acyl-CoA metabolic process		***
GO:0044248 cellular catabolic process		****
GO:0046394 carboxylic acid biosynthetic process		***
GO:0044255 cellular lipid metabolic process		*
GO:0006631 fatty acid metabolic process		**
GO:0019752 carboxylic acid metabolic process		****
GO:0007049 cell cycle		****
GO:0007154 cell communication	***
GO:0005975 carbohydrate metabolic process		**
GO:0006694 steroid biosynthetic process		**
GO:0006695 cholesterol biosynthetic process		****
GO:0008610 lipid biosynthetic process		**
GO:0055114 oxidation-reduction process		**

The theme analysis of Type I periorbital dyschromia may be broadly correlated to cellular physiological responses associated with cell stress and cell communication in the epidermis and metabolism, stress and structure in the dermis. In particular, a theme analysis of epidermal gene expression related to Type I periorbital dyschromia revealed, generally, an increase in gene expression associated with calcium ion trans-membrane transport, chromatin modification and cell communication and a decrease in gene expression associated with immune response and toll-like receptor pathway. Dermal gene expression revealed the following general themes: an increase in gene expression associated with response to estrogen stimulus, regulation of body fluid levels, regulation of cell migration, hypoxic stress, oxidative damage, response to wounding, blood vessel development, extracellular matrix organization, cytoskeleton organization, cell junction organization, neuron development and muscle structure development and a decrease in gene expression associated with cholesterol synthesis, regulation of glucose transport and protein transport.

The theme analysis of Type II periorbital dyschromia appears to show a general correlation with the cellular physiological responses associated with metabolism and energy production, cell stress and cell communication in the epidermis and metabolism and structure in the dermis. In particular, a theme analysis of epidermal gene expression related to Type II periorbital dyschromia revealed, generally, an increase in gene expression associated with chromatin modification and a decrease in gene expression associated with glycolysis, ATP synthesis, cell cycle, TCA cycle, response to pH, antigen presentation and processing. Dermal gene expression revealed the following general themes: an increase in gene expression associated with transmission of nerve impulses and neuron development and a decrease in gene expression associated with cholesterol synthesis.

Theme analysis of Type III periorbital dyschromia may be broadly correlated to cellular physiological responses associated with metabolism in the epidermis and metabolism and nutrition, stress and cell communication, and structure in the dermis. In particular, a theme analysis of epidermal gene expression related to Type III periorbital dyschromia revealed, generally, a decrease in gene expression associated with oxidation and reduction process. A theme analysis of dermal gene expression revealed the following general themes: an increase in gene expression associated with ion and metal transport, regulation of the MAPK signaling cascade, regulation of Jun Kinase activity, blood vessels and neuron development and a decrease in gene expression associated with cholesterol synthesis, fatty acid metabolic process, microtubule cytoskeleton organization, organelle assembly, and carbohydrate metabolic process.

Products for treating different types of periorbital dyschromia are described in U.S. Provisional Application No. 61/798,278, filed by Osorio, et al., on Mar. 15, 2013 and titled “Array of Products.” Methods of treating different types of periorbital dyschromia are described in U.S. Provisional App. No. 61/798,340, filed by Osorio et al., on Mar. 15, 2013 and titled “Methods of Treating Periorbital Dyschromia.”

The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as “40 mm” is intended to mean “about 40 mm” Additionally, properties described herein may include one or more ranges of values. It is to be understood that these ranges include every value within the range, even though the individual values in the range may not be expressly disclosed.

All documents cited in the Detailed Description of the Invention are, in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.