Patent Publication Number: US-2021192295-A1

Title: Systems and methods of combining imaging modalities for improved tissue detection

Description:
PRIORITY 
     The present application claims priority to U.S. Provisional Patent Application No. 62/949,830, titled SYSTEMS AND METHODS OF COMBINING IMAGING MODALITIES FOR IMPROVED TISSUE DETECTION, filed Dec. 18, 2019, which is hereby incorporated by reference herein in its entirety. 
    
    
     BACKGROUND 
     Although molecular chemical imaging (MCI) is a powerful technique for analyzing organic, inorganic, and biological samples of interest, enhancement of its performance may advance its utilization in industries such as biological or medical applications. Accordingly, MCI enhancements that improve the ability to control and modulate illumination sources to achieve single or multiple modes of imaging can provide benefits over conventional MCI applications. 
     SUMMARY 
     The disclosure contemplates various embodiments of imaging techniques that combine two or more images generated from samples of interest. 
     In one embodiment, there is a method of fusing images, the method comprising illuminating a sample with illuminating photons; obtaining a first sample image from interacted photons that have interacted with the sample and have traveled to a first camera chip; obtaining a second sample image from interacted photons that have interacted with the sample and have traveled to a second camera chip; and fusing the first sample image and the second sample image by weighting the first sample image and the second sample image, wherein the weighting the first sample image and the second sample image is performed by one or more of Partial Least Squares Discriminant Analysis (PLS-DA), linear regression, logistic regression, Support Vector Machines (SVM), Relative Vector Machines (RVM), naïve Bayes, neural network, or Linear Discriminant Analysis (LDA), to thereby generate a fused score image. 
     In another embodiment, the method further comprises detecting glare in each of the first sample image and the second sample image and not classifying the portions of the first sample image and the second sample image that are identified as glare. 
     In another embodiment, the method further comprises receiving a selection of an area in each of the first sample image and the second sample image that corresponds to glare and replacing values of pixels in the selected area with updated values that are classifiable. 
     In another embodiment, the method further comprises normalizing the intensities of the first sample image and the second sample image. 
     In another embodiment, the first sample image is selected from the group consisting of X-Ray, EUV, UV fluorescence, autofluorescence, RGB, VIS-NIR, SWIR, linear Raman, non-linear Raman, NIR-eSWIR, eSWIR, magnetic resonance, ultrasound, optical coherence tomography, speckle, light scattering, photothermal, photoacoustic, terahertz radiation and radio frequency imaging, and the second sample image is selected from the group consisting of X-ray, EUV, UV, RGB, VIS-NIR, SWIR, Raman, NIR-eSWIR, eSWIR, magnetic resonance, ultrasound, optical coherence tomography, speckle, light scattering, photothermal, photoacoustic, terahertz radiation and radio frequency imaging. 
     In another embodiment, the first sample image is RGB, and the second sample image is VIS-NIR. 
     In another embodiment, the illuminating photons are generated by a tunable illumination source. 
     In one embodiment, a system for fusing images comprises an illumination source configured to illuminate a sample with illuminating photons; a first camera chip configured to obtain a first sample image from interacted photons that have interacted with the sample; a second camera chip configured to obtain a second sample image from interacted photons that have interacted with the sample; and a processor that during operation causes fusion of the first sample image and the second sample image by weighting the first sample image and the second sample image, wherein the weighting the first sample image and the second sample image is performed by one or more of Partial Least Squares Discriminant Analysis (PLS-DA), linear regression, logistic regression, Support Vector Machines (SVM), Relative Vector Machines (RVM), naïve Bayes, neural network, or Linear Discriminant Analysis (LDA) to thereby generate a fused score image. 
     In another embodiment, the processor detects glare in each of the first sample image and the second sample image and does not classify the portions of the first sample image and the second sample image that are identified as glare. 
     In another embodiment, the processor receives a selection of an area in each of the first sample image and the second sample image that corresponds to glare and replaces values of pixels in the selected area with updated values that are classifiable. 
     In another embodiment, the processor normalizes the intensities of the first sample image and the second sample image. 
     In another embodiment, the sample image is selected form the group consisting of X-Ray, EUV, UV, RGB, VIS-NIR, SWIR, linear Raman, non-linear Raman, NIR-eSWIR, eSWIR, magnetic resonance, ultrasound, optical coherence tomography, speckle, light scattering, photothermal, photoacoustic, terahertz radiation and radio frequency imaging, and the second sample image is selected from the group consisting of X-ray, EUV, UV, RGB, VIS-NIR, SWIR, linear Raman, non-linear Raman, NIR-eSWIR, eSWIR, magnetic resonance, ultrasound, optical coherence tomography, speckle, light scattering, photothermal, photoacoustic, terahertz radiation and radio frequency imaging. 
     In another embodiment, the first sample image is RGB, and the second sample image is VIS-NIR. 
     In another embodiment, the illumination source is tunable. 
     In one embodiment, there is a computer program embodied on a non-transitory computer readable storage medium for fusing images, which when executed by a processor causes an illumination source to illuminate a sample with illuminating photons; a first camera chip to obtain a first sample image from interacted photons that have interacted with the sample; a second camera chip to obtain a second sample image from interacted photons that have interacted with the sample; and a processor that during operation fuses the first sample image and the second sample image by weighting the first sample image and the second sample image, wherein the weighting the first sample image and the second sample image is performed by one or more of Image Weighted Bayesian Fusion (IWBF), Partial Least Squares Discriminant Analysis (PLS-DA), linear regression, logistic regression, Support Vector Machines (SVM), Relative Vector Machines (RVM), naïve Bayes, neural network, or Linear Discriminant Analysis (LDA) to thereby generate a fused score image. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The accompanying drawings, which are incorporated in and form a part of the specification, illustrate the embodiments of the invention and together with the written description serve to explain the principles, characteristics, and features of the invention. In the drawings: 
         FIG. 1  illustrates a target detection system using fused images, according to an embodiment of the present disclosure. 
         FIG. 2  illustrates a flow diagram of a process for registering a RGB image with a MCI image for tissue detection, according to an embodiment of the present disclosure. 
         FIG. 3  illustrates a flow diagram of a process for fusing a RGB image with a MCI image for tissue detection, according to an embodiment of the present disclosure. 
     
    
    
     DETAILED DESCRIPTION 
     This disclosure is not limited to the particular systems, methods, and computer program products described, as these may vary. The terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope. 
     As used in this document, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Nothing in this disclosure is to be construed as an admission that the embodiments described in this disclosure are not entitled to antedate such disclosure by virtue of prior invention. As used in this document, the term “comprising” means “including, but not limited to.” 
     The embodiments described below are not intended to be exhaustive or to limit the teachings to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art may appreciate and understand the principles and practices of the present teachings. 
     Target Detection Systems 
     The disclosure contemplates systems, methods, and computer program products that are designed to illuminate a sample with illuminating photons, collect interacted photons from the sample by way of a camera chip, generate two or more sample images from the interacted photons that have been collected and imaged by the camera chip, and fuse the two or more sample images so as to generate a target score image. The target score image is generated by applying mathematical operations to the two or more sample images in order to fuse the two or more sample images. The target score image has greater contrast and information than would be possible with any one of the two or more sample images that are formed from the interacted photons. 
     One embodiment of a target detection system  100  using combined imaging modalities is illustrated in  FIG. 1 . In one embodiment, the target detection system  100  can include an illumination source assembly  102  that is configured to generate light in one or more wavelength ranges, as described below. In various embodiments, the illumination source assembly  102  can include one or multiple illumination sources that are configured to generate light in different wavelength ranges. In various embodiments, the illumination source  102  can include tunable or non-tunable illumination sources. Additional details regarding various embodiments of illumination sources usable in the target detection system  100  are described below. 
     The system  100  can further include an endoscope  104  or another optical device that is optically coupled to the illumination source assembly  102 . During operation, the endoscope  104  can be configured to direct the light generated by the illumination source assembly  102  at a sample  106  (e.g., a tissue) and receive light (i.e., interacted photons) therefrom. The sample  106  may include organic, inorganic, and/or biological samples. The system  100  can further include a first camera chip  110  and a second camera chip  112  that are optically coupled to the endoscope  104  via an optical path  108 . In one embodiment, the first camera chip  110  can be configured to generate images from (i.e., be sensitive to) light in a first wavelength range, and the second camera chip  112  can be configured to generate images from (i.e., be sensitive to) light in a second wavelength range. In other words, the camera chips  110 ,  112  can be configured to generate images using different imaging modalities. Additional details regarding various embodiments of camera chips usable in the target detection system  100  are described below. 
     The system  100  can further include a computer system  114  that is communicably coupled to the camera chips  110 ,  112  such that the computer system  114  is configured to receive signals, data, and/or images therefrom. In various embodiments, the computer system  114  can include a variety of different hardware, software, firmware, or any combination thereof for executing the various processes and techniques described herein. In the illustrated embodiment, the computer system  114  includes a processor  116  coupled to a memory  118 , wherein the processor  116  is configured to execute instructions stored in the memory  118  to cause the computer system  114  to perform the processes and techniques described herein. Additional details regarding various embodiments of the algorithms for creating score images, detecting tissue(s), registering images, and fusing images, among others, that are executable by the target detection system  100  are described below. 
     Target Detection Processes 
     The target detection system  100  can be configured to execute various processes for visualizing a target in a sample by combining imaging modalities, such as the processes  200 ,  250  shown in  FIGS. 2 and 3 . In one embodiment, the processes  200 ,  250  can be embodied as instructions stored in a memory  118  of the computer system  114  that, when executed by the processor  116 , cause the computer system  114  to perform the enumerated steps of the processes  200 ,  250 . 
     Turning to the process  200  shown in  FIG. 2 , the computer system  114  can receive  202  a first image of the sample  106  from the first camera chip  110  and receive  204  a second image of the sample  106  from the second camera chip  112 . In one particular embodiment, the first image can include an MCI image (e.g., a dual polarization MCI image), and the second image can include a RGB image. Accordingly, the computer system  114  can create  206  a score image from the received first image. Various techniques for creating  206  score images are described below. The computer system  114  can use the score image in a variety of different manners in this process  200 . In particular, the computer system  114  can register  208  the score image created  206  from the first image with the second image. Various techniques for registering images to each other are described below. Additionally, the computer system  114  can detect  210  or identify the target in the score image. In one embodiment, the computer system  114  can be configured to execute one or more detection algorithms to detect  210  the target and/or identify the boundary of the target within the score image. Various detection algorithms and detection techniques are described below. In one illustrative application, the target could include a tumor in a biological sample, for example. Accordingly, the computer system  114  can overlay  212  the detected  210  area or boundary of the target on the second image and provide  214  or output the second image with the detection overlay. In one embodiment, the computer system  114  could display the second image with the detection overlay. 
     The process  250  shown in  FIG. 3  is similar in many respects to the process  200  shown in  FIG. 2 , except that it includes an additional step. In this process  250 , the computer system  114  additionally fuses  252  the score image created  206  from the first image (e.g., an MCI image) and the second image (e.g., a RGB image) registered  208  to the first image. Accordingly, the detection algorithm  210  executed by the computer system  114  is based upon the fused image, rather than the score image as in the process  200  shown in  FIG. 2 . In all other respects, the process  250  shown in  FIG. 3  functions substantially the same as the process  200  shown in  FIG. 2 . 
     In some embodiments, the computer system  114  can be configured to perform various preprocessing techniques before the images are registered  208  and/or fused  252  together. For example, the computer system  114  can be configured to adjust the images to compensate for any glare. In one embodiment, the computer system  114  can be configured to detect any glare in either the first image or the second image and execute an image correction algorithm to adjust the images to remove or compensate for the glare. In another embodiment, the computer system  114  can be configured to receive a selection of an area in the first image and/or the second image that corresponds to glare (e.g., from a user) and replace values of pixels in the selected area with updated values that are classifiable by the computer system  114 . 
     In some embodiments, the computer system  114  can be configured to execute one or more of the processes  200 ,  250  in real-time during the visualization of the sample. In one illustrative implementation, the computer system  114  may be used to intraoperatively detect and display a target (e.g., a tumor) located at or within a tissue being visualized using an endoscope  104 . Accordingly, the systems and methods described herein could assist surgical staff in visualizing a target during the surgical procedure in order to improve the surgical staff&#39;s performance and, thus, patient outcomes. 
     The processes  200 ,  250  described above are beneficial because they provide improved visualization and identification of a target within a sample by combining imaging modalities. Using multiple imaging modalities in this manner allows for the target to be better identified against the background of the sample. The processes and techniques described herein have wide application across a number of different technical disciplines and should not be construed to be limited to any of the specific examples described herein. 
     Illumination Source 
     As noted above, the illumination source assembly  102  can include a variety of different illumination sources and combinations thereof. The illumination source is not limited and can be any source that is useful in providing the necessary illumination while meeting other ancillary requirements, such as power consumption, emitted spectra, packaging, thermal output, and so forth. In some embodiments, the illumination source is an incandescent lamp, halogen lamp, light emitting diode (LED), quantum cascade laser, quantum dot laser, external cavity laser, chemical laser, solid state laser, supercontinuum laser, organic light emitting diode (OLED), electroluminescent device, fluorescent light, gas discharge lamp, metal halide lamp, xenon arc lamp, induction lamp, or any combination of these illumination sources. In some embodiments, the illumination source is a tunable illumination source, which means that the illumination source is monochromatic and can be selected to be within any desired wavelength range. The selected wavelength of the tunable illumination source is not limited and can be any passband within the X-ray, extreme ultraviolet (EUV), ultraviolet (UV), visible (VIS), near infrared (NIR), visible-near infrared (VIS-NIR), shortwave infrared (SWIR), extended shortwave infrared (eSWIR), near infrared-extended shortwave infrared (NIR-eSWIR), mid-wave infrared (MIR), and long-wave infrared (LWIR) ranges. 
     The above ranges of light correspond to wavelengths of about 0.03 to about 3 nm (X-rays), about 10 nm to about 124 nm (EUV), about 180 nm to about 380 nm (UV), about 380 nm to about 720 nm (VIS), about 400 nm to about 1100 nm (VIS-NIR), about 850 nm to about 1800 nm (SWIR), about 1200 nm to about 2450 nm (eSWIR), about 720 nm to about 2500 nm (NIR-eSWIR), about 3000 nm to about 5000 nm (MIR), or about 8000 nm to about 14000 nm (LWIR). The above ranges may be used alone or in combination of any of the listed ranges. Such combinations include adjacent (contiguous) ranges, overlapping ranges, and ranges that do not overlap. The combination of ranges may be achieved by the inclusion of multiple light sources, by filtering light sources, or by the addition of at least one component such as phosphors and/or quantum dots that convert high energy emissions such as UV or blue light into lower energy light having longer wavelengths. 
     In some embodiments, the illumination source is tunable. Tunable illumination sources include one or more of a tunable LED, a tunable LED array, a tunable laser, a tunable laser array, or a filtered broadband light source. As set forth in the preceding list, broadband light sources that can be filtered include one or more of incandescent lamps, halogen lamps, light emitting diode arrays when those arrays include multiple colored LEDs in the red, green, and blue spectral ranges, supercontinuum lasers, gas discharge lamps, xenon arc lamps, or induction lamps. In some embodiments, a single tunable light source is provided. In other embodiments, more than one tunable light source is provided, and each of the more than one tunable light source is capable of simultaneous operation. In other embodiments, a tunable light source is provided that is capable of simultaneous operation with a light source that is not tunable. 
     Sample 
     After the illuminating photons are emitted from the illumination source, they interact with a sample  106 . The sample  106  is not limited and can be any chemical or biological sample where the location of a region of interest is desired to be known versus the sample at large. In some embodiments, the sample  106  is a biological sample and the illuminating photons are used to determine the boundary between a tumor and surrounding non-tumor cells. In some embodiments, the sample  106  is a biological sample and the photons are used to determine the boundary between a tissue experiencing blood restriction and a tissue experiencing blood perfusion. In some embodiments, the sample  106  is a biological structure and the illuminating photons are used to determine a boundary between one biological sample and another biological sample. 
     Examples of biological samples include ureters, nerves, blood vessels, lymph nodes, ducts, healthy organs, organs experiencing blood restriction, organs experiencing blood perfusion, and tumors. In some embodiments, the biological sample is located within a living organism, that is, it is an “in vivo” biological sample. In some embodiments, the sample is not located within a living organism, that is, it is an “ex vivo” biological sample. In some embodiments, the illuminating photons are used to distinguish the biological sample from other structures. In some embodiments, the illuminating photons are used to distinguish one biological sample from another biological sample. 
     Camera Chip 
     The disclosure contemplates that there is at least one camera chip that collects and images the interacted photons. In the embodiment illustrated in  FIG. 1 , two camera chips  110 ,  112  are shown; however, in other embodiments, the system  100  can include a single camera chip. In some embodiments, the at least one camera chip is characterized by the wavelengths of light that it is capable of imaging. The wavelengths of light that can be imaged by the camera chip are not limited, and include UV, VIS, NIR, VIS-NIR, SWIR, eSWIR, NIR-eSWIR. These classifications correspond to wavelengths of about 180 nm to about 380 nm (UV), about 380 nm to about 720 nm (VIS), about 400 nm to about 1100 nm (VIS-NIR), about 850 nm to about 1800 nm (SWIR), about 1200 nm to about 2450 nm (eSWIR), and about 720 nm to about 2500 nm (NIR-eSWIR). The above ranges may be used alone or in combination of any of the listed ranges. Such combinations include adjacent (contiguous) ranges, overlapping ranges, and ranges that do not overlap. The combination of ranges may be achieved by the inclusion of multiple camera chips, each sensitive to a particular range, or a single camera chip that by the inclusion of a color filter array can sense multiple different ranges. 
     In some embodiments, the at least one camera chip is characterized by the materials from which it is made. The materials of the camera chip are not limited and can be selected based on the wavelength ranges that the camera chip is expected to detect. In such embodiments, the camera chip comprises silicon (Si), germanium (Ge), indium gallium arsenide (InGaAs), platinum silicide (PtSi), mercury cadmium telluride (HgCdTe), indium antimonide (InSb), colloidal quantum dots (CQD), or combinations of any of these. 
     In some embodiments, the camera chip is provided with a color filter array to produce images. The design of the filter array is not limited. It is to be understood that the term “filter” when used in the context of a camera chip means that the referenced light is allowed to pass through the filter. For example, a “green filter” is a filter that appears green to the human eye by only allowing light having a wavelength of about 520 nm to about 560 nm to pass through the filter, corresponding to the visible color green. A similar “NIR filter” only permits NIR light to pass through. In some embodiments, the filter is a color filter array that is positioned over a camera chip. Such color filter arrays are varied in design but are all related to the original “Bayer” filter color mosaic filters. The color filter array includes BGGR, RGBG, GRGB, RGGB, RGBE, CYYM, CYGM, RGBW (2×2), RGBW (2×2 with diagonal colors), RGBW (2×2 with paired colors), RGBW (2×2 with vertical W), and X-TRANS (sold by Fujifilm Corporation of Tokyo, Japan). The X-TRANS sensor has a large 6×6 pixel pattern that reduces Moiré effect artifacts by including RGB tiles in all horizontal and vertical lines. In the listings, B corresponds to blue, G to green, R to red, E to emerald, C to cyan, Y to yellow, and M to magenta. W corresponds to a “white” or a monochrome tile, which will be further described below. 
     The W or “white” tile itself includes several configurations. In some embodiments, the W tile does not filter any light, and so all light reaches the camera chip. In those embodiments, the camera chip will detect all of the light within a given range of wavelengths. Depending on the camera chip, this can be UV, VIS, NIR, VIS-NIR, VIS-NIR, VIS-SWIR, or VIS-eSWIR. In some embodiments, the W tile is a filter for VIS, VIS-NIR, NIR, or eSWIR, allowing only VIS, VIS-NIR, NIR, or eSWIR respectively to reach the camera chip. This may be advantageously combined with any of the camera chip materials or electrical structures listed above. Such a filter array can be useful because it enables a single camera chip to detect both visible light and near infrared light and is sometimes referred to as a four-band filter array. 
     In still further embodiments, the color filter array is omitted and is not provided with the camera chip, which produces a monochromatic image. In such embodiments, the generated image is based solely on the band gap of the materials that make up the camera chip. In other embodiments, a filter is still applied to the camera chip, but only as a monolithic, single filter. For example, the application of a red filter means that the camera chip generates monochromatic images representative of red spectrum. In some embodiments, multiple camera chips, each with a different monolithic, single filter camera chip are employed. As an example, a VIS image can be produced by combining three camera chips having R, G, and B filters, respectively. In another example, a VIS-NIR image can be produced by combining four camera chips having R, G, B, and NIR filters, respectively. In another example, a VIS-eSWIR image can be produced by combining four camera chips having R, G, B, and eSWIR filters, respectively. 
     In some embodiments, the color array is omitted, and the camera chip utilizes vertically stacked photodiodes organized into a pixel grid. Each of the stacked photodiodes responds to the desired wavelengths of light. For example, a stacked photodiode camera chip includes R, G, and B layers to form a VIS image. In another embodiment, the stacked photodiode camera chip includes R, G, B, and NIR layers to form a VIS-NIR image. In another embodiment, the stacked photodiode camera chip includes R, G, B, and eSWIR layers to form a VIS-eSWIR image. 
     For certain images, including X-ray or EUV, the above described camera chips may not be capable of resolving the interacted photons. In such instances, at least one phosphor is configured so that interacted photons strike the phosphor screen, and the phosphor screen emits phosphor photons that are will elicit a signal from the camera chip. 
     Image Generation 
     The disclosure contemplates that a first image is generated by various imaging techniques in a first image generation step. In the first image generation step, photons are generated by one or more illumination sources described above, and the photons travel to the sample. When the photons reach the sample, the photons interact with the sample. The resultant first interacted photons are thereby emitted from the sample and travel to at least one camera chip. The camera chip thereby generates a first image, which is communicated to a processor. 
     Similarly, the disclosure also contemplates that a second image is generated by various imaging techniques in a second image generation step. In the second image generation step, photons are generated by one or more illumination sources described above, and the photons travel to the sample. When the photons reach the sample, the photons interact with the sample. The resulting second interacted photons are thereby emitted from the sample and travel to at least one camera chip. The at least camera chip thereby generates a second image, which is communicated to an image processor. 
     The generated image is not limited and can represent at least one image of the wavelengths of X-ray, EUV, UV, RGB, VIS-NIR, SWIR, Raman, NIR-eSWIR, or eSWIR. As used herein, the above ranges of light correspond to wavelengths of 0.03 to about 3 nm (X-rays), about 10 nm to about 124 nm (EUV), about 180 nm to about 380 nm (UV), about 180 nm to about 380 nm (UV), about 380 nm to about 720 nm (VIS), about 400 nm to about 1100 nm (VIS-NIR), about 850 nm to about 1800 nm (SWIR), about 1200 nm to about 2450 nm (eSWIR), and about 720 nm to about 2500 nm (NIR-eSWIR). In one embodiment, the first image is a RGB image and the second image is a VIS-NIR image. 
     The image generation techniques are not limited, and in addition to the above discussion, the image generation includes one or more of laser induced breakdown spectroscopy (LIBS), stimulated Raman spectroscopy, coherent anti-Stokes Raman spectroscopy (CARS), elastic scattering, photoacoustic imaging, intrinsic fluorescence imaging, labeled fluorescence imaging, and ultrasonic imaging. 
     Image Fusion 
     Two or more images, which include at least first and second images that are generated by the interaction of the above photons with a sample, are fused by an image processor. As mentioned above, the images are not limited and there can be more than two images that are generated. In one embodiment, the first image is a RGB image and the second image is a VIS-NIR ratiometric image. However, these are not the only possibilities, and image fusion can be performed with any two images of the wavelength ranges X-Ray, EUV, UV, RGB, VIS-NIR, SWIR, Raman, NIR-eSWIR, or eSWIR, or any of the other wavelengths or wavelength ranges that are described throughout this disclosure. Such combinations can be used to generate ratiometric images based on the above wavelengths. 
     In one embodiment of image fusion, a score image is first created, followed by detection or segmentation. To create the score image, RGB and VIS-NIR images are combined using mathematical algorithms to create a score image. The score image shows contrast for the target. For example, in some embodiments, the target will appear as a bright “highlight” while the background will appear as a dark “shadow.” The mathematical algorithm that is used for image fusion is not limited, and the algorithm includes Image Weighted Bayesian Fusion (IWBF), Partial Least Squares Discriminant Analysis (PLS-DA), linear regression, logistic regression, Support Vector Machines (SVM), Relative Vector Machines (RVM), naïve Bayes, Linear Discriminant Analysis (LDA), and neural networks. 
     When the mathematical algorithm is IWBF, a weighting constant modulates the probability image from respective sensors, and the overall target probability is estimated with different combinations of image cross terms. When detecting multiple target types with the IWBF algorithm, each sensor modality has a single weighting constant for each target type. The selection of each weighting constant for each sensor modality can be achieved by various techniques. Such techniques include Monte Carlo methods, Receiver Operating Characteristic (ROC) curves, linear regression, neural networks, fuzzy logic, naïve Bayes, Dempster-Shafer theory, and combinations of the above. 
     The weighting of each sensor modality for a single target type is represented by the following formula: 
         P   Target =((1− A )× W+AP   T     S1   )×((1− B )× W+BP   T1     s   )× . . . ×((1− C )× W+CP   T     Sn   )  Formula 1
 
     The weighting of each sensor modality for multiple target types is represented by the following formulas: 
         P   T1 =((1− A )× W+AP   T1     S1   )×((1− B )× W+BP   T1     S2   )× . . . ×((1− C )× W   +   CP   T1     Sn   )  Formula 2
 
         P   T2 =((1− D )× W+DP   T2     S1   )×((1− E )× W+EP   T2     S2   )× . . . ×((1− F )× W+FP   T2     Sn   )  Formula 3
 
         P   T3 =((1− G )× W+GP   T3     S1   )×((1− H )× W+HP   T3     S2   )× . . . ×((1− I )× W+IP   T3     Sn   )  Formula 4
 
         P   Target =((1− J )× W+JP   T1 )×((1− K )× W+KP   T2 )×((1− L )× W+LP   T3 )  Formula 5
 
     In the above Formulas 1-5, the Target Type is denoted by T, sensor type by S, number of sensors by n, white image (grayscale consisting only of 1&#39;s) by W, detection probability for each target is P T1 , P T2 , and P T3 , and the weights for combining the images are the variables A, B, C, D, E, F, G, H, I, J, K, and L. 
     The resulting fusion score image or probability image shows enhanced contrast for the target in which a higher pixel intensity corresponds to higher likelihood that the pixel belongs to the target. Similarly, a low pixel intensity corresponds to a low likelihood that the pixel belongs to the target. Detection algorithms utilizing various computer vision and machine learning methods, such as adaptive thresholding and active contours, are applied to the fusion score image to detect the target and find the boundary of the target. 
     In some embodiments, a score image is not generated using the above equations. Instead, detection or segmentation algorithms are utilized with all N images. Such techniques require multispectral methods where multiple images are assembled into a hypercube. The hypercube has N images and can include any combination of one or more of UV, RGB, VIS-NIR, SWIR, Raman, NIR-eSWIR, or eSWIR. In such embodiments, a score image is not generated. Instead, segmentation algorithms use all N images and thereby identify the target. The multispectral methods are not particularly limited. In some embodiments, the multispectral methods are spectral clustering methods that include one or more of k-means and mean shift methods. In other embodiments, the multispectral detection or segmentation method is a texture based method that groups pixels together based on similar textures measured across spectral bands using Haralick texture features. 
     In some embodiments, the image fusion in generated from images from two cameras. In other embodiments, the image fusion is generated from three cameras. In embodiments where three cameras are used to generate the image fusion, the first camera generates a first tuning state which forms a first molecular chemical image, the second camera generates a second tuning state which forms a second molecular image, and the third camera generates a RGB image. 
     In some embodiments where two or more camera chips are included, a stereoscopic image is generated based on the images from each of the two or more camera chips. Stereoscopic images are useful because they permit a viewer to perceive depth in the image, which increases accuracy and realism of the perception. For example, during surgery or other similar activities that are performed with endoscopes, stereoscopic images are useful for manipulating instruments and performing tasks, with greater safety and accuracy than with monoscopic endoscopes. This is because monoscopic endoscopes, having only one camera chip position, cannot provide depth perception. In some embodiments, the stereoscopic image is formed by at least two camera chips and where the camera chips are the same. In some embodiments, the stereoscopic image is formed by at least two camera chips where the camera chips are different. In either of the above embodiments, the camera chips may have the same color filter array, or they may have a different color filter array. In some embodiments, the stereoscopic image is formed by two camera chips that are different, with only one camera chip being provided a color filter array, and the other camera chip being provided either a monochromatic filter or no filter array at all. Anytime that there is more than one camera chip provided, a stereoscopic image can be generated by using the output of each camera chip and combining or fusing the output of each camera chip. 
     EXAMPLES 
     Example 1 
     In one illustrative embodiment, to obtain the fused image, a molecular chemical image was collected and, simultaneously, a RGB image was also collected. Both the molecular chemical image and RGB image collections were performed within the same in vivo surgical procedure. In this illustrative application, the molecular chemical image was collected using an internally developed MCI endoscope and the RGB image was collected using a Hopkins® Telescope 0° NIR/ICG ϕ 10 mm, available from Karl Storz Endoscopy. 
     Two wavelength images were collected with the MCI endoscope. To fuse the collected MCI and RGB images, the two wavelength images were mathematically combined to produce a ratiometric score image for the target of interest within the in vivo surgical procedure. Next, MCI and RGB images were registered with each other so that each pixel of the MCI image corresponds to the same physical location in the RGB image. The registration was achieved using a hybrid approach that combines features-based and intensity-based methods. The feature-based method is initially applied to estimate geometric transformation between MCI and RGB images. This is achieved by matching the KAZE features. KAZE is a multiscale two-dimensional feature detector and descriptor. An intensity-based method based on similarity metric and optimizer is used to refine the results of the KAZE feature detection. The registration is accomplished by aligning the MCI image to the RGB image using the estimated geometric transformation. 
     Next, pre-processing is performed. First, a glare correction step can be executed. In one embodiment, a glare mask is generated by detecting glare in each of the MCI and RGB images. Pixels identified as glare are not classified. In another embodiment, a user can manually select areas of glare in each of the images. In various embodiments, the values of the pixels in the selected area can be replaced with updated values that are classifiable or, as with the aforementioned embodiment, pixels in the images identified as glare can be omitted from the classification. Second, the MCI and RGB images are normalized so that the intensities of the pixels from the two images are on an equal range and the intensity does not influence the contribution of each image modality to the fused image. 
     After pre-processing is performed, the fusion is performed. Using labeled data that was generated by a prior training step, the classifier detects pixels belonging to the target of interest. To perform the fusion, three (3) frames of RGB image and a MCI ratiometric score image are input into the classifier. In the Example, IWBF is the method used to find optimal weights for the images that minimize prediction error on the training set. Weights determined by IWBF on the training set are applied to the images and the weighted images are thereby mathematically combined to create the fused score image. The final fused score image is then displayed and shows increased contrast for the target compared to the background. This increased contrast allows for improved detection performance of the target from the background. In some embodiments, detection algorithms that use computer vision and machine learning methods are applied to the fused score image to locate or determine a final detection of the target. The final detection is overlaid onto the RGB image. The final detection overlaid onto the RGB image is particularly useful for when a user desires to locate a feature that would otherwise be difficult to identify. In one embodiment, the user is a surgeon that desires to have improved visualization of an organ. 
     Example 2 
     As described above, the image generation system can include a first illumination source and a second illumination source. In one illustrative embodiment, the first illumination source can include a tunable laser that is configured to generate monochromatic illuminating photons having a wavelength of 625 nm. Further, the second illumination source can include a tunable laser that is configured to generate monochromatic photons having a wavelength of 800 nm, which detects reflectance. The two images generated from the illumination sources can be combined or fused using any of the techniques described above. In operation, the monochromatic photons of each of the first illumination source and the second illumination source are directed to a sample. An autofluorescence image is generated by excitation at illumination photons having a wavelength of 625 nm. The interacted photons that are generated are directed to a camera chip that is capable of detecting at least VIS photons. A ratiometric score image is generated and analyzed. 
     Example 3 
     In one illustrative embodiment, the first illumination source can include a high-voltage filament tube that is configured to generate monochromatic X-ray illuminating photons. Further, the second illumination source can include a quartz bulb that is configured to generate broadband illuminating photons in the SWIR spectral range. In operation, the X-ray illuminating photons and the SWIR illuminating photons are directed to a sample. The resultant interacted photons from the sample are directed to a camera chip that is capable of detecting at least VIS photons. A ratiometric score image is generated and analyzed. 
     In the above detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be used, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that various features of the present disclosure, as generally described herein, and illustrated in the Figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein. 
     The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as illustrations of various features. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. 
     With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. 
     It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (for example, bodies of the appended claims) are generally intended as “open” terms (for example, the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” et cetera). While various compositions, methods, and devices are described in terms of “comprising” various components or steps (interpreted as meaning “including, but not limited to”), the compositions, methods, and devices can also “consist essentially of” or “consist of” the various components and steps, and such terminology should be interpreted as defining essentially closed-member groups. It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. 
     For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (for example, “a” and/or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. 
     In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (for example, the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, et cetera” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, et cetera). In those instances where a convention analogous to “at least one of A, B, or C, et cetera” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, et cetera). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.” 
     In addition, where features of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. 
     As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, et cetera. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, et cetera. As will also be understood by one skilled in the art all language such as “up to,” “at least,” and the like include the number recited and refer to ranges that can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth. 
     Various of the above-disclosed and other features and functions, or alternatives thereof, may be combined into many other different systems or applications. Various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art, each of which is also intended to be encompassed by the disclosed embodiments.