Patent Description:
The present disclosure relates to a method for discriminating between different types of tissue lesions. In particular, the present disclosure is directed to a method for discriminating between malignant and benign tissue lesions.

Malignant melanoma is one of the most rapidly increasing cancers in the world. Successful treatment of melanoma depends on early detection by clinicians with subsequent surgical removal of tumors. In recent years, considerable effort has been expended on developing optical methods for characterizing tissue and monitoring changes. In <NUM>, the Canadian Agency for Drugs and Technologies in Health published a report on optical scanners for melanoma detection, discussing three different devices (Aura, MelaFind, and SIMSYS-MoleMate) approved for marketing in Canada and/or USA. Foerster, "Optical scanners for melanoma detection" [Issues in emerging health technologies, Issue <NUM>]. Ottawa: Canadian Agency for Drugs and Technologies in Health (<NUM>). As the report confirms, the <NUM>-year survival rate is <NUM> to <NUM>% for melanoma detected at an early stage, but drops to between <NUM> and <NUM>% for advanced stage detection, implying that there is a need for accurate diagnostic devices to enable early detection while avoiding unnecessary biopsies. The devices profiled included Aura (Verisante Technology, Inc. , Vancouver, British Columbia, Canada), MelaFind (MELA Sciences, Inc. , Irvington, New York, USA), and SIMSYS-MoleMate Skin Imaging System (MedX Health, Inc. , Hamilton, Ontario, Canada).

Aura utilizes near-infrared laser light and Raman spectroscopy to distinguish malignant from benign skin lesions and has shown sensitivities ranging from <NUM> to <NUM>% for specificities ranging from <NUM> to <NUM>% for discriminating between benign and malignant lesions.

MelaFind illuminates the skin at <NUM> wavelengths, measures light scattered back from the skin, and uses image analysis algorithms combined with a skin disorder database to provide treatment suggestion. For discrimination between melanoma and benign pigmented lesions in a population of suspicious lesions, MelaFind showed <NUM>% sensitivity and <NUM>% specificity in a clinical study involving <NUM>,<NUM> patients with <NUM>,<NUM> pigmented skin lesions.

SIMSYS-MoleMate Skin Imaging System is based on using a handheld, multispectral scanner and computer software to provide dermatoscopic images, dermal and epidermal pathological characteristics, and the ability to catalogue, monitor, and compare lesions over time. In a randomized controlled trial involving <NUM>,<NUM> patients with <NUM>,<NUM> suspicious pigmented lesions it was found that adding MoleMate to best practices resulted in lower agreement with expert assessment that the lesion was benign and led to a higher proportion of referrals. Relevant prior art includes <CIT>.

Because so much is at stake with regard to early detection and treatment of cancerous skin lesions, the sensitivity and specificity numbers of the existing optical analysis devices leave room for improvement.

Accordingly there is provided a method, as defined in claim <NUM>. Further optional features are provided in the dependent claims. The specification further includes description of exemplary related systems, not part of the present claims.

The objects and features of the present disclosure, which are believed to be novel, are set forth with particularity in the appended claims. The present disclosure, both as to its organization and manner of operation, together with further objectives and advantages, may be best understood by reference to the following description, taken in connection with the accompanying drawings as set forth below:.

The present invention relates to methods for discriminating between different types of tissue lesions. In particular, the present invention is directed to optical methods for discriminating between malignant and benign tissue lesions.

In arrangements of the specification, an optical transfer device is used to image a tissue lesion for analysis. An optical transfer diagnosis (OTD) device, of arrangements, is a spectral radiometer that records a set of <NUM> images, constituting a lesion measurement, in less than <NUM> seconds. Images are recorded at <NUM> different wavelengths (from about <NUM>-about <NUM>) from multiple angles of illumination and detection.

As shown in <FIG>, the OTD system <NUM> may consist of a handheld unit <NUM>, a docking station <NUM>, and a laptop PC or other computing device <NUM> comprising a processor <NUM> coupled to a tangible, non-transient memory <NUM>. The handheld unit <NUM> may include a release button to initiate image recording. Other controls may be performed via a user interface on the attached computing device <NUM>. When not in use, the handheld unit <NUM> is placed in the docking station <NUM>, where the observation window of the device is placed against a calibration target.

<FIG> shows the inner parts of an exemplary handheld OTD unit. A sensor head may contain an illuminating system consisting of, for example, <NUM> LED or other light-providing devices <NUM> and an imaging system comprising at least one camera <NUM> and a series of mirrors <NUM>, as shown in <FIG>.

An exemplary illuminating system shown consists of <NUM> fixed light-emitting diode (LED) lamps. Each LED is placed at a different angle relative to the skin to enhance the ability to retrieve depth information. The polar angles of the LEDs vary between <NUM> and <NUM> degrees and the relative azimuth angles between <NUM> and <NUM> degrees. The polar angles for the detectors vary between <NUM> and <NUM> degrees, and the relative azimuth angles between <NUM> and <NUM> degrees.

An exemplary imaging system for a handheld OTD device consists of one correcting lens placed inside the handle plus another correcting lens and five mirrors placed inside a sensor head and a sapphire glass observation window that contacts the area of the skin lesion. OTD devices may comprise a camera sensor consisting of, for example, an IEEE (Institute of Electrical and Electronics Engineers) <NUM> FireWire camera.

As indicated in <FIG>, the five mirrors may be used to image the same area of the skin viewed from three different angles on three different sections of the camera sensor. To compensate for different object distances for the three angular views, the camera sensor may be slightly tilted relative to the optical axis. <FIG> illustrates a ray trace of the OTD imaging system according to certain embodiments, where IS: Image sensor; L1: Camera lens; L2: Correcting lens <NUM>; L3: Correcting lens <NUM>; M1: Plane mirror for central view image; M2, M3: Plane mirrors for upper <NUM> degree oblique image; M4, M5: Plane mirrors for lower <NUM> degree oblique image; and W: Sapphire glass window.

An alcohol-based gel interface may be used where the sapphire observation window contacts the skin to provide refractive-index matching and avoid rough-surface scattering, and to obtain illumination and imaging of a selected area of the skin through the circular sapphire observation window. In preferred arrangements, the observation window may be between about <NUM> and about <NUM> in diameter and may be, for example, about <NUM>.

In certain embodiments, images for analysis using methods of the invention may be obtained using imaging devices such as a dermatoscope, digital camera, smartphone, or tablet. Single or multiple images may be obtained for analysis and, where multiple images are obtained, they may be obtained at different angles of illumination and detection. Where images are obtained using a dermatoscope, digital camera or a mobile device including a camera (e.g., mobile phone or tablet with camera and LED or other source of illumination or flash), the device may prompt a user, via a program stored on a non-transient, tangible memory, to capture a series of images at prescribed orientations relative to a lesion. In certain embodiments, the device camera and/or orienting devices such as gyroscopic or global positioning system features of the device may be used to determine orientation of the camera and light source with respect to the lesion. The imaging device may be configured to determine when the desired orientation has been achieved and to automatically capture an image or series of images or prompt a user to capture the image once the appropriate orientation is reached. Each image may be tagged by the device with the angles of illumination and detection at which the image was obtained.

On the basis of established absorption and transmission spectra for known skin chromophores and mathematical modeling of skin reflectance, a set of recorded images may be used to create maps of physiology properties and morphological parameters of the lesion, which are assumed to be different for benign and malignant tissue. Exemplary maps are shown in <FIG> and <FIG>. The map creation is based on (i) a bio-optical model that relates physiological properties of skin tissue to its inherent optical properties, (ii) a radiative transfer model that for a given set of inherent optical properties computes the light backscattered from the skin for a given wavelength and direction of illumination, and (iii) a nonlinear inversion algorithm that compares the computed backscattered light at various wavelengths and directions with that of the recorded image set.

The data acquisition geometry is designed in such a way that for each combination of illumination and detection directions, the same area of the skin is interrogated. This allows a one-dimensional treatment when the independent-column approximation is invoked and the skin tissue is assumed to have a layered structure: an uppermost layer, the epidermis, consisting of an upper part and a lower part; the dermis, containing the blood circulation; and the subcutis, a strongly scattering fat-containing layer. The inherent optical properties of each layer are the absorption and scattering coefficients as well as the scattering phase function (describing the angular variation of the scattered light), each varying with wavelength. The retrieved physiology properties and morphological parameters are (<NUM>) percentage of hemoglobin concentration, (<NUM>) percentage of hemoglobin oxygenation, (<NUM>) upper epidermal thickness, (<NUM>) lower epidermal thickness, (<NUM>) percentage of melanosome concentration in upper epidermis, (<NUM>) percentage of melanosome concentration in lower epidermis, and (<NUM>) percentage of keratin concentration. Each of these seven physiology properties or morphological parameters is retrieved pixel by pixel in the compressed image to create a map covering the zoomed lesion area.

From each map, an entropy value may be calculated and cross entropy values are calculated for different pairs of maps. The entropy concept used here is similar to that used in statistical physics and information theory. For example, from the spatial distribution of the melanosome concentration, the entropy of this parameter is computed as the melanosome concentration multiplied by its logarithm and integrated over the area of the lesion. These entropy and cross entropy values may be used to define diagnostic parameters, as discussed below.

According to certain arrangements of the specification, lesion measurements may comprise a set of <NUM> images recorded by an OTD scanner. For a given wavelength and direction of illumination, the OTD scanner of the invention records three images simultaneously at different detection angles. This procedure may be repeated for <NUM> other wavelengths in the range from the near ultraviolet to the near infrared at different illumination angles to produce a lesion measurement that comprises a set of <NUM> images.

For any of the <NUM> images, each pixel corresponds to (i) a particular distance from one of the <NUM> LED sources of different intensity, (ii) a particular size of the of skin area for each of the <NUM> images that are recorded by one of the two side-viewing cameras; and (iii) a particular location of the illuminated skin area because of possible movement of the skin with respect to the OTD scanner during the few seconds of sequential illumination by the <NUM> LEDs.

To address issues (i)-(iii) above, a series of pre-processing steps may be performed, including (<NUM>) according to claim <NUM> relative calibration such that the intensity of each pixel is measured in units of the intensity due to backscattering for a corresponding pixel from a target having a Lambert surface; (<NUM>) geometrical calibration such that an ellipse of illuminated skin area for a side-viewing camera is transformed into a circle; (<NUM>) image registration such that each pixel in any of the <NUM> images corresponds to the same area of the skin; (<NUM>) compression such that the raw image having about <NUM> × <NUM><NUM> pixels with a spatial resolution of about <NUM> is replaced by a smoothed image with a total number of pixels that is <NUM> times less than that of the raw image. Thus, the compressed image has <NUM> times less spatial resolution than the raw image, and a byproduct of compression is filtering of spatial high-frequency noise in the raw images due to possible spikes, specular points, and hairs.

Automated zooming is employed to provide a lesion mask that circumferences the lesion and is characteristic of its shape, and a surrounding mask that creates an area outside the lesion of suitable size and the same outer shape as that of the lesion mask. The zooming can provide rotation, translation, and scaling invariant characteristics of the lesion under investigation, both for calibrated images and maps of physiology properties and morphological parameters. Also, zooming can accelerate the processing since only pixels of the lesion and surrounding masks are considered.

<FIG> shows a dermatoscopic image of a melanoma, while <FIG> shows the corresponding RGB image and maps of physiology properties and morphological parameters obtained from OTD recordings and processing using systems and methods of the invention. <FIG> and <FIG> show corresponding results for a compound nevus. Clearly, the maps of physiology properties and morphological parameters in <FIG> for a melanoma are quite different from those in <FIG> for a compound nevus, indicating that these maps may prove useful in discriminating between benign pigmented lesion and melanomas. As noted above, from these maps, entropy and cross entropy values are calculated and used to define diagnostic parameters, as discussed below.

From the calibrated, registered, compressed, and zoomed OTD image of a lesion obtained from nadir illumination by green light (hereafter referred to as the `nadir green image') the following <NUM> morphological parameters may be derived: (<NUM>) Size; (<NUM>) Histogram width (providing a measure of inhomogeneity of the reflected intensity); (<NUM>) Fractal dimension; (<NUM>) Moment of inertia; (<NUM>) Asphericity; (<NUM>) Center distance (representing the physical distance between the geometrical center of the lesion and the center of mass of absorptance); (<NUM>) Border length; (<NUM>) Average darkness; (<NUM>) Area divided by fractal dimension; and (<NUM>) Border length divided by fractal dimension.

From the seven maps created from the images, seven entropies and <NUM> cross entropies are derived, providing a total of <NUM> physiology properties and morphological parameters. By including also the logarithm of each of the <NUM> morphological parameters obtained from the nadir green image and the <NUM> entropy and cross entropy values derived from the seven maps, one obtains a total of <NUM> diagnostic parameters.

Another <NUM> diagnostic parameters are derived from the maps of physiology properties:.

Above, natural RoI represents a rectangular area that is oriented in accordance with the shape of the lesion, and "standard gridding" means that along the longest side of the natural RoI there are <NUM> grid points. The "original RoI" is the rectangular zoom area of the compressed digital image. As discussed above, there are N = <NUM> diagnostic parameters pj (j = <NUM>, <NUM>,. , N): <NUM> × <NUM> morphological parameters derived from the nadir green image; <NUM> × <NUM> entropies and cross entropies derived from maps of physiology properties and morphological parameters; and <NUM> additional physiology parameters derived from maps of physiology properties.

For each independent lesion measurement, a diagnostic index D may be defined as a weighted sum of the diagnostic parameters pj: <MAT>.

Here the weight vector w consists of N weights wj (j = <NUM>, <NUM>,. , N), and p is a vector of N diagnostic parameters pj.

Clustering is used to obtain a reliable and robust discrimination between class <NUM> and class <NUM> lesions through the identification of a set of class <NUM> clusters, each comprising a certain number of independent measurements on class <NUM> lesions, and another set of class <NUM> clusters, each comprising a certain number of independent measurements on class <NUM> lesions. A diagnostic indication algorithm can be trained by considering a set of lesions, some belonging to class <NUM> and others to class <NUM>, for each of which the diagnosis is known, and letting each independent lesion measurement be characterized by N diagnostic parameters pj (j = <NUM>, <NUM>,. The first step of the clustering procedure is to discretize the diagnostic parameter pj as follows:.

The definition of a clustering index for an independent lesion measurement is based on constructing coincidence vectors C+ and C- and probabilistic vectors t+ and t-: <MAT> where the components Tj± are coincidence parameters given by Tj+ = <NUM> if p*j = +<NUM> and Tj+ = <NUM> otherwise; Tj- = <NUM> if p*j = -<NUM> and Tj- = <NUM> otherwise; and where tj± = (ΣTj±)<NUM>/<NUM>, the sum being over all independent measurements on lesions of the class under consideration. Thus, each component tj+ (or tj-) (j = <NUM>, <NUM>,. , N) is the square root of an integer that is equal to the total number of times p*j has the value +<NUM> (or -<NUM>) among all independent measurements on lesions of the class under consideration.

The clustering index C for an independent measurement on either a class <NUM> or a class <NUM> lesion is given by: <MAT>.

The independent measurements are ordered in accordance with the value of the clustering index, and independent measurements having values of the clustering index in a specific interval are taken to belong to the same cluster.

To construct clusters of independent measurements on class <NUM> lesions relative to the entire set of independent measurements on class <NUM> lesions, the class <NUM> measurement having the highest clustering index is taken, as given by Eq. (<NUM>). Then cm independent measurements are added to this one to obtain a total of cm+<NUM> independent measurements in this first cluster, where cm is obtained from the requirement that the function F(c), given by <MAT> shall have its maximum value when c = cm. Here C is the total number of independent measurements belonging to the available set of independent measurements on class <NUM> lesions, and S(c) is the specificity, i.e. the ratio between the number of correctly classified independent measurements on class <NUM> lesions and the total number of independent measurements on class <NUM> lesions. The second factor on the right-hand side of Eq. (<NUM>), which increases monotonically with c, linearly for small values and then more slowly, allows for inclusion of many independent measurements in a cluster, but its influence gets weaker as the number c increases, making the specificity decisive.

The number cm of ordered independent measurements on class <NUM> lesions relative to the entire set of independent measurements on class <NUM> lesions may then found such that the corresponding cluster provides a maximum value of the function F(c) in Eq. (<NUM>) for ic = cm. Here ordered implies that the independent measurements are placed in sequential order in accordance with the value of the clustering index. Let us define a virtual cluster as a cluster with a number c of ordered independent measurements on class <NUM> lesions relative to the entire set of independent measurements on class <NUM> lesions, whereas the corresponding actual cluster contains the optimum number c = cm of ordered independent measurements on class <NUM> lesions relative to the entire set of independent measurements on class <NUM> lesions. The details of an exemplary cluster construction procedure is as follows:.

Suppose a total of L<NUM> clusters is constructed of independent measurements on class <NUM> lesions relative to the entire set of independent measurements on class <NUM> lesions. Similarly to what was done in the construction of clusters of independent measurements on class <NUM> lesions, the independent measurement on class <NUM> lesions having the highest clustering index are taken, as defined in Eq. (<NUM>), and cm independent measurements are added to this independent measurement to obtain a total of cm + <NUM> measurements in this first cluster among class <NUM> lesions, where cm is obtained from the requirement that the function F(c), given by Eq. (<NUM>), shall have its maximum value when c = cm. Here C is the total number of measurements belonging to the available set of independent measurements on class <NUM> lesions, and S(c) is the sum of specificities for the cluster under construction vs. each of the clusters of class <NUM> lesions. The specificity S(c) for the cluster under construction vs. cluster #i of class <NUM> lesions is the ratio between the number of correctly classified measurements of class <NUM> lesions and the total number of measurements on class <NUM> lesions contained in the cluster under construction. Thus, S(c) is given by <MAT>.

The clustering procedure can then be carried out similarly to the procedure enumerated above for class <NUM> lesions relative to the entire set of class <NUM> lesions.

Optimal values of the weights in Eq. (<NUM>) are then determined for separation between the two classes of lesions, called class <NUM> and class <NUM>. The dimension of the optimization problem is reduced by (i) introducing a covariance matrix for independent measurements on lesions of class <NUM> and class <NUM>, where the two classes are chosen such that the trace of the covariance matrix for class <NUM> lesions is larger than that for class <NUM> lesions, (ii) defining a discriminating operator in terms of the two covariance matrices, (iii) constructing eigenvectors and eigenvalues on the basis of the discriminating operator and using only those eigenvalues that are larger than a threshold value, chosen so as to ensure that sufficiently large variations of the diagnostic parameters associated with independent measurements on class <NUM> lesions are accounted for, and (iv) defining for each independent measurement on a lesion of class <NUM> or class <NUM> a set of generalized diagnostic parameters. As a result, Eq. (<NUM>) becomes <MAT> where w̃ and p̃ are generalized weight and diagnostic parameter vectors, respectively, each having a dimension Ñ that is typically only one third of the number N of original diagnostic parameters.

In order to reduce the dimension of the optimization problem, a set of generalized diagnostic parameters is defined by introducing a covariance matrix for each of the two classes of lesions, given by <MAT> <MAT> where the superscript T denotes the transpose, <MAT> is the vector of diagnostic parameters comprised of N components for independent measurement #i on lesions belonging to class q = <NUM> or q = <NUM>, 〈p(q)〉 is the average value of the diagnostic vectors for all independent measurements on lesions belonging to class q, and Mq is the number of independent measurements on lesions belonging to class q. Note that by definition, independent measurements on lesions belonging to class <NUM> have a larger value of the trace of the covariance matrix than those belonging to class <NUM>, i.e. Tr{Ṽ(<NUM>)} > Tr{V̂(<NUM>)}. The next step is to introduce a discriminating operator, defined by <MAT> which is a generalization of the signal-to-noise ratio for multivariate random signals. To discriminate between independent measurements on lesions belonging to class <NUM> and class <NUM> and reduce the dimension of the optimization problem we extract eigenvectors dα according to <MAT> and introduce a subset of eigenvectors dαk for each of which the eigenvalue αk > αmin, where αmin is chosen to be equal to or larger than <NUM> in order to ensure that one accounts for sufficiently large variations of the diagnostic parameters associated with independent measurements on class <NUM> lesions.

For an independent measurement on a lesion of class <NUM> or class <NUM>, we define a vector p̃ of generalized diagnostic parameters: <MAT> Here Δp = p - 〈p(<NUM>)〉 where p is the vector of original diagnostic parameters in Eq. (<NUM>) and 〈p(<NUM>)〉 is the average of the vectors of diagnostic parameters for all independent measurements on class <NUM> lesions.

The condition αk > αmin leads to a substantial reduction in the number of diagnostic parameters. Thus, the number Ñ of generalized diagnostic parameters is typically only one third of the number N = <NUM> of original diagnostic parameters. The generalized diagnostic index for an independent measurement on a lesion of class <NUM> or class <NUM> is given by: <MAT> where w̃ has the same dimension as p̃.

To determine optimal values of the weights in Eq. (<NUM>) a cost function is defined, consisting of a master term and a constraint term, where the latter is used to constrain the length of the weight vector to lie on the surface of a hypersphere in Ndimensions of radius equal to <NUM>. For discussion of the master term of the cost function, consider a set of independent lesion measurements that is divided into one subset of independent measurements on lesions belonging to class <NUM> and another subset of independent measurements on lesions belonging to class <NUM>. As an example, class <NUM> could comprise independent measurements on malignant lesions and class <NUM> independent measurements on benign lesions.

For each generalized weight vector w̃, the corresponding generalized diagnostic index D<NUM>(w̃) is computed for each of the class <NUM> independent lesion measurements as well as the corresponding generalized diagnostic index D<NUM>(w̃) for each of the class <NUM> independent lesion measurements. Next, the mean values 〈D<NUM>〉 and 〈D<NUM>〉 and the corresponding standard deviations σ<NUM> and σ<NUM> are computed. The master term of the cost function is given in terms of these parameters as <MAT> where D*(w̃) is the point of intersection of the two Gaussian distributions in Eq. (<NUM>), and the value of J<NUM>(w̃) is the area of overlap of the two Gaussian distributions. The minimization of J<NUM>(w̃) will provide the smallest degree of overlap between the two Gaussian distributions, and hence the best separation between independent measurements on class <NUM> and class <NUM> lesions. After minimization of the cost function, Eq. (<NUM>) becomes <MAT> where e is an optimal generalized weight vector, hereafter referred as an expert regarding the separation between independent measurements belonging to the two classes of lesions.

For a pair of opposite clusters, consisting of cluster #i of class <NUM> lesions and cluster #j of class <NUM> lesions, a probabilistic characterization of an expert can be obtained by proceeding as follows:.

For an independent lesion measurement having a certain D value, the corresponding points on the two distribution curves in <FIG> may be interpreted as partial reliabilities of a diagnostic indication.

If <MAT> represents the red (class <NUM>) curve in <FIG> and <MAT> represents the blue (class <NUM>) curve, then, by definition, <MAT> represents the partial reliability of a diagnostic indication in favor of the measurement belonging to a class <NUM> [class <NUM>] lesion.

The number of class <NUM> and class <NUM> clusters may be represented by L<NUM> and L<NUM>, respectively, and a modified diagnostic index D̃ can be defined by <MAT> where L = L<NUM> × L<NUM> and <MAT> with |δi|max being the largest of the |δi| values for i = <NUM>, <NUM>,. The value ε = <NUM>:<NUM> is used to avoid zeros appearing in the products in Eq. (<NUM>).

The diagnostic indication by a team of experts associated with a randomly drawn training ensemble comprised of L<NUM> and L<NUM> clusters of class <NUM> and class <NUM>, respectively, is that if D given by Eq. (<NUM>) is greater than or equal to zero, then the measurement is regarded to represent a class <NUM> lesion. Typically three measurements are taken of each lesion, and the diagnostic indication for a lesion by a team of experts associated with this randomly drawn training ensemble is that if the mean value of the modified diagnostic indices D given by Eq. (<NUM>) for the measurements taken is greater than or equal to zero, the lesion is regarded to be of class <NUM>. This diagnostic indication constitutes a nonlinear binary classifier.

In order to construct a final diagnostic indication tool, a large number of different training and validation ensembles may be drawn at random (for example, K = <NUM> such ensembles, see <FIG> and <FIG>) by proceeding as follows:.

The best combination of experts for the final diagnostic indication tool can be obtained by constructing the matrices <MAT>, where ek',λ represents one of the <NUM>L* possible combinations of experts, and choosing that particular combination ek',λ of L* experts among the <NUM>L* possible combinations, which gives the L* largest values for the determinant of these matrices. A typical number of principal components or "best" experts is L* = <NUM>.

The final diagnostic indication tool described above may be applied to an unknown lesion measurement as follows:.

In order to increase the robustness of the maps of physiology properties and morphology parameters obtained by the OTD inversion procedure, statistical information extracted from multiple measurements (typically three) of each lesion may be employed. After compression, each of the <NUM> images comprising a lesion measurement consists of approximately <NUM>,<NUM> pixels. For each of the <NUM> different wavelengths λi (i = <NUM>, <NUM>,. , <NUM>), the average value Iλi,m may be computed for measurement #m of the reflected light for each pixel inside the area surrounding the lesion: <MAT> where Iλi, m, n is the reflected light for pixel #n and measurement #m, and Np is the total number of pixels inside the area surrounding the lesion. Next, several measurements of the same lesion are averaged: <MAT> where M is the number of measurements (typically <NUM>). Then column vectors are defined <MAT> <MAT> where T denotes the transpose. A difference vector is defined <MAT> and the covariance matrix Ĉℓ for lesion #ℓ: is estimated as follows: <MAT> which is a <NUM> × <NUM> matrix. All available lesions (ℓ = <NUM>, <NUM>,. , L) are averaged to obtain <MAT> which represents the uncertainties in the measurements.

An estimate of the misfit between measured and simulated reflected light for a given pixel (after compression) is given by: <MAT> (See <NPL>). where iλi, n is the measured reflected light for pixel #n and wavelength λi, and iλi,n is the simulated reflected light for pixel #n and wavelength λi.

Use of the result in Eq. (<NUM>) in the inversion procedure makes the resulting maps of physiology properties and morphological parameters more robust. Thus, the difference between maps obtained from different measurements of the same lesion becomes significantly smaller. This modification of the inversion procedure requires that it is possible to identify the same area (in the present case the surrounding area of the lesion, which is much brighter than the lesion area) in images corresponding to different measurements of the same lesion and also in images corresponding to different wavelengths λi. It can be shown that the reduced variance of integrated parameters, such as the entropies, will result in increased robustness in the sense of reduced variance of the diagnostic parameters pij (i = <NUM>, <NUM>,. , N) among multiple measurements on the same lesion #i.

The classification scheme was developed and optimized on a clinical data set consisting of <NUM>,<NUM> lesion images collected in several clinical studies using OTD devices from <NUM> to date. A final diagnostic indication tool was constructed based on K = <NUM> different diagnostic indication rules, each designed to discriminate between suspicious and benign lesions in a population of unselected ("all-comer") lesions. For training of any of these K diagnostic indication rules <NUM>% of all available measurements performed on a total of <NUM> lesions (including <NUM> malignant lesions) were drawn at random, while the remaining <NUM>% of the measurements were used for validation. Typically three measurements were performed on each lesion. For the <NUM> lesions used for training and validation, the histopathological diagnoses for the dermatoscopically suspicious lesions as well as the diagnoses for the dermatoscopically benign lesions are given in Table <NUM>.

Clusters of lesions are constructed for each of the two classes of lesions, between which discrimination is desired, say L<NUM> and L<NUM> clusters of class <NUM> and class <NUM>, respectively. Each of the randomly drawn K = <NUM> training and validation ensembles gives its own diagnostic indication rule, so in total there will be <NUM> different diagnostic indication rules, and for each of them there will be L<NUM> × L<NUM> different experts (nonlinear binary classifiers), each between a pair of opposite clusters. Thus, in total there will be about L<NUM> × L<NUM> × <NUM> different experts. Typically, there will be <NUM> or <NUM> clusters of each class. As an example, if there were L<NUM> = <NUM> clusters of class <NUM> and L<NUM> = <NUM> of class <NUM>, the total number of experts would be <NUM>,<NUM>, among which, only the L* "best" experts would be used for construction of the final diagnostic indication tool.

The accuracy A of a binary classifier is a measure of how correctly it can identify elements belonging to each of two classes, i.e. <MAT>.

Alternatively, the accuracy can be expressed in terms of the sensitivity and specificity and the occurrence rates of the elements belonging to the two classes. If the occurrence rate is N<NUM> for class <NUM> and N<NUM> for class <NUM>, and a binary classifier has sensitivity Se and specificity Sp, a measure of the accuracy is given by <MAT> <FIG> shows the performance in terms of sensitivity and specificity of our binary classifiers for discriminating between malignant and benign lesions for <NUM> different, randomly drawn training and validation ensembles. In each of the <NUM> cases included in <FIG>, the data set consisted of <NUM> malignant lesions and <NUM> benign lesions, all taken from a set of lesions considered by experienced dermatologists to be suspicious and therefore biopsied. In each case, the classifier was trained using <NUM>% of the available data, chosen at random, while the remaining <NUM>% of the data not used for training constituted a validation set. From <FIG>, the sensitivity and specificity are estimated to be <NUM> and <NUM>, respectively, so that Eq. (<NUM>) gives <MAT>.

In the US, around <NUM>-<NUM> million skin lesions are biopsied annually and a fraction of these - between <NUM>,<NUM> and <NUM>,<NUM> - are diagnosed as melanoma, implying that according to Eq. (<NUM>), the accuracy is less than <NUM>: <MAT> In comparison, the present binary classifiers for a similar sampling of lesions would give an accuracy, according to Eq. (<NUM>), of <MAT> in spite of no access to medical case histories, which are generally available to dermatologists. Note also that the final diagnostic indication tool above, which is based on the <NUM> "best" experts among the <NUM> binary classifiers for randomly chosen training and validation sets, gave a sensitivity higher than <NUM> for a specificity of <NUM> when applied to a set of clinically suspicious lesions.

This result implies that the final diagnostic indication tool can serve as a well-qualified expert, acting in a fast automatic mode to help dermatologists arrive at the correct decision for complicated cases, and thus help eliminate unnecessary biopsies.

<FIG> shows the performance of the present binary classifiers for discriminating between malignant and benign lesions in a set of unselected ("all-comer") lesions, similar to that a Primary Care Provider (PCP) is faced with. In this case, each training and validation set includes <NUM> malignant lesions (as confirmed by biopsy) and <NUM> benign lesions (as confirmed by dermatoscopy). From <FIG>, the sensitivity and specificity are estimated to be <NUM> and <NUM>, respectively, so that Eq. (<NUM>) gives <MAT>.

Since the occurrence rate of malignant lesions in an all-comer study is very low, the accuracy of our classifier is expected to be close to the value above of <NUM>, which is much higher than the accuracy of a PCP. Thus, our final diagnostic indication tool can be considered as capable of providing a PCP with reliable, real-time decisions regarding melanoma referrals.

Lesions from <NUM> patients were scanned prospectively using an OTD device of the invention. A total of <NUM> lesions from <NUM> referral sources were imaged. Clinically benign lesions from the skin of volunteers accounted for <NUM> lesions. These lesions were chosen on the basis of normal dermatoscopic patterns and the absence of melanoma-specific criteria. In addition, the patients reported no known change in the lesion or any symptoms, and most patients had undergone full-body photography that documented no change. Biopsies were not obtained for these lesions.

Clinically suspicious lesions accounted for the remaining <NUM> scans and were chosen on the basis of clinical and dermatoscopic findings.

The clinically suspicious lesions were removed in toto with a saucerization excision technique and sent for histopathologic processing and examination. Pathologic specimens were processed with hematoxylin-eosin staining and, when indicated, immunohistochemical staining with Melan-A. (One lesion was a seborrheic keratosis and did not undergo immuno staining.

Two dermatopathologists independently reviewed all specimens and rendered the diagnoses. Prior to removal, three OTD image sets were obtained from each lesion. The time needed to acquire each set was less than <NUM> seconds.

The OTD device used comprises a spectral reflectance meter that records <NUM> spectral reflectance images (<NUM> image set) that constitute <NUM> measurement of a lesion under examination. Images were recorded at <NUM> different wavelengths (<NUM>-<NUM>) from multiple polar and azimuth angles of illumination and detection. The image sets were recorded on a digital video disc and processed independently for creation of physiologic-morphologic maps, as described below. Although dermatoscopic images were also obtained for each lesion, these images were not used in the analysis.

Established absorption and transmission spectra for known skin chromophores and mathematical modeling of skin reflectance were used in analyzing the images. The images from each set were used to derive physiologic-morphologic maps of the lesions for the following seven parameters: percentage of hemoglobin concentration, percentage of hemoglobin oxygenation, upper epidermal thickness, lower epidermal thickness, percentage of upper melanin concentration, percentage of lower melanin concentration, and percentage of keratin concentration. From each physiologic-morphologic map, an entropy value was calculated and cross-entropy values were calculated between different pairs of maps. The entropy value provides a measure of the disorder in any one of the maps, and the cross-entropy value provides a measure of the correlation between <NUM> different maps. In addition, from a single green image for a wavelength of <NUM>, the following <NUM> morphological parameters were generated: <NUM>) size; <NUM>) histogram width (providing a measure of inhomogeneity of the reflected intensity); <NUM>) fractal dimension; <NUM>) moment of inertia; <NUM>) asphericity; <NUM>) center distance (representing the physical distance between the geometrical center of the lesion and its center of mass of absorptance); <NUM>) border length; <NUM>) average darkness; <NUM>) area divided by fractal dimension; and <NUM>) border length divided by fractal dimension.

For the <NUM> physiologic-morphologic maps, <NUM> weights were assigned to the entropy and cross-entropy values, and <NUM> weights to their logarithms. Similarly, <NUM> weights were assigned to the <NUM> morphological parameters and <NUM> to their logarithms. Another <NUM> diagnostic parameters were derived from the <NUM> maps, giving a total of <NUM> assigned weights. An OTD indication algorithm of the invention was optimized on a clinical data set consisting of <NUM>,<NUM> lesion images collected in several clinical studies from <NUM> to present. By comparing the OTD diagnosis of melanoma or nonmelanoma with pathology or dermatoscopy results obtained from clinical data from <NUM> lesions, an OTD indication algorithm of the present invention was optimized and developed.

A total of <NUM> lesions were imaged, including <NUM> clinically and dermatoscopically benign lesions, <NUM> clinically suspicious but histopathologically benign lesions, and <NUM> malignant lesions (<NUM> melanomas, <NUM> basal cell carcinomas, and <NUM> squamous cell carcinomas). The developed OTD algorithm misdiagnosed <NUM> of the melanomas as benign (sensitivity, <NUM>%). The OTD specificity for the dermatoscopically benign lesions was <NUM>% (<NUM>/<NUM>); for the lesions that were clinically suspicious but histopathologically benign, the OTD specificity was <NUM>% (<NUM>/<NUM>); and for all benign lesions included in the study, the OTD specificity was <NUM>% (<NUM>/<NUM>).

Claim 1:
A method for discriminating between benign and malignant skin lesions, the method comprising the steps of:
generating an image of a skin lesion;
performing relative reflectance calibration of the image, wherein the image undergoes relative reflectance calibration comprising measuring intensity of each pixel due to backscattering for a corresponding pixel from a target having a Lambert surface;
performing compression of the image wherein the image of the skin lesion is replaced with a smoothed image having <NUM> times less spatial resolution than the image;
performing zooming of the image to create lesion and surrounding area masks in the image;
creating, for each of a plurality of physiological properties and morphological parameters, a spatial distribution map covering the area of the skin lesion from the image of the skin lesion;
determining entropy values for each of the spatial distribution maps;
determining cross entropy values between pairs of the spatial distribution maps;
determining, from image, a plurality of morphological parameters;
deriving, from the spatial distribution maps of physiological properties and morphological parameters, a plurality of additional diagnostic parameters, the additional diagnostic parameters being selected from the group consisting of maximum value of melanin optical depth; architectural disorder; blood filling; angiogenesis; ratio of blood oxygenation in an area surrounding a lesion border; melanin contrast; blood contrast; high spatial Fourier-components of a map of total melanin optical depth over a lesion area; and entropy of contrast of the map of total melanin optical depth over the lesion area;
creating one or more diagnostic indices from the weighted sum of the entropy values, the cross entropy values, the plurality of morphological parameters, and the plurality of additional diagnostic parameters, using one or more weight vectors;
determining for each of the one or more diagnostic indices, a reliability value for classification as benign and a reliability value for classification as malignant; and
classifying the skin lesion as benign where the reliability value for classification as benign is greater than the reliability value for classification as malignant.