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• • G—PHYSICS
  • G06—COMPUTING; CALCULATING OR COUNTING
  • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
  • G06T7/00—Image analysis
  • G06T7/0002—Inspection of images, e.g. flaw detection
  • G06T7/0012—Biomedical image inspection
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
  • G16H30/00—ICT specially adapted for the handling or processing of medical images
  • G16H30/40—ICT specially adapted for the handling or processing of medical images for processing medical images, e.g. editing
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
  • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
  • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
  • G16H70/00—ICT specially adapted for the handling or processing of medical references
  • G16H70/60—ICT specially adapted for the handling or processing of medical references relating to pathologies
• • G—PHYSICS
  • G06—COMPUTING; CALCULATING OR COUNTING
  • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
  • G06T2207/00—Indexing scheme for image analysis or image enhancement
  • G06T2207/10—Image acquisition modality
  • G06T2207/10056—Microscopic image
• • G—PHYSICS
  • G06—COMPUTING; CALCULATING OR COUNTING
  • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
  • G06T2207/00—Indexing scheme for image analysis or image enhancement
  • G06T2207/10—Image acquisition modality
  • G06T2207/10068—Endoscopic image
• • G—PHYSICS
  • G06—COMPUTING; CALCULATING OR COUNTING
  • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
  • G06T2207/00—Indexing scheme for image analysis or image enhancement
  • G06T2207/30—Subject of image; Context of image processing
  • G06T2207/30004—Biomedical image processing
  • G06T2207/30028—Colon; Small intestine

Definitions

• the present invention relates to a method for quantifying intestinal mucosal changes induced by chronic inflammatory bowel disease in an individual, an ex vivo method for diagnosing a chronic inflammatory bowel disease in an individual as well as an ex vivo method for the differential diagnosis of Crohn's disease versus ulcerative colitis in an individual.
• the present invention finds particular application in the medical field, including diagnosis.
• Crohn's disease is a chronic inflammatory disease that can reach any segment of the digestive tract, but especially the terminal small bowel (ileum) and colon, and may be accompanied by extraintestinal manifestations (articular, cutaneous, ocular). ..). In France, its incidence is of the order of 5 per 100 000 inhabitants per year. Although Crohn's disease can occur at any age, it is most often diagnosed at an age between 20 and 30 years of age. It is a cryptogenic disease, where different factors are found and discussed (genetic predisposition, immunological and environmental factors). It is also favored by smoking and lifestyle in industrialized countries. The diagnosis of Crohn's disease is based on a combination of clinical and paraclinical arguments. The diagnosis is usually made during a push period.
• the clinical manifestations depend on the localization of the disease: abdominal pain, diarrhea and / or dysenteric syndrome, most often muco-haemorrhagic, affecting the ano-perineal region, sometimes with general signs and / or systemic manifestations. Associated with it are biological abnormalities (inflammatory syndrome, deficiencies ). Thus, the diagnosis of Crohn's disease can be difficult and need to rule out other causes of intestinal organ damage (infectious, ischemic, drug, radiation or neoplastic). In addition, the distinction between Crohn's disease, especially colic, and ulcerative colitis may be difficult.
• Ulcerative colitis is a persistent inflammation of the intestinal mucosa. It always reaches the rectum and, more or less extensively, the colon. HCR is a condition that is characterized by alternating phases of activity (or “flare-ups”), of variable intensity, and phases without symptoms. More common in industrialized countries, this condition is favored by genetic predispositions and immune system dysfunction.
• inflammatory gastrointestinal diseases are characterized by structural changes in the mucosa. These changes are correlated with the severity of the disease, and may be a predictor of change or response to treatment.
• CPP detection methods remain essentially descriptive, although recent studies have shown that a quantitative, computerized approach to image analysis increases the sensitivity of the classification and decreases analysis variations between operators.
• CME confocal endomicroscopy
• Kiesslich et al. propose a classification of the severity of inflammation of ulcerative colitis in three grades (None, Medium to moderate, Severe). This classification is based on:
• Li et al. propose a classification of ulcerative colitis in four grades (from A to D) according to morphological criteria of the crypt colic and arrangement of crypts in the mucosa appreciated qualitatively by the operator (Am J Gastroenterol 2010; 105: 1391-1396 ([3])). This analysis is significantly correlated with histological analysis.
• Neumann et al. demonstrate the utility of confocal endomicroscopy for the evaluation of Crohn's disease and propose an endomicroscopic activity score for Crohn's disease based on an evaluation of the architectural modifications of crypts, vessels and lamina intestinal ( Inflamm Bowel Dis 2012 Dec; 18 (12): 2261 -9 ([4])).
• Liu et al. quantified the density of "epithelial holes” in patients with Crohn's disease or ulcerative colitis. They demonstrated a significant increase in the density of these "holes” in the diseased population compared to the healthy population (Gastrointest, Endosc 201 1, 73: 1 174-1 180 ([5]).
• Musquer et al. quantified the ratio of the axes of light opening of colonic crypts in patients with Crohn's disease and established an association between an increase in this ratio and the presence of the disease and its stage (remission / inflammation) ( Dig Liver Dis 2013, 45: 487-1992 ([6])).
• the present invention makes it possible precisely to solve and overcome the aforementioned obstacles and disadvantages of the prior art by providing on the one hand an analysis method as well as characteristic parameters of the IBD, on the other hand the application of this method for discriminate healthy patients, IBD patients.
• the present invention also provides imaging biomarkers of IBD.
• the Applicant has managed to develop, according to important research, a process based on the analysis of images, including endomicroscopic, and thus defined a score from the quantitative analysis of these images, data to meet to the needs defined above.
• the Applicant has in particular developed a differential diagnosis method based on the analysis of confocal endomicroscopy (CME) images.
• CME confocal endomicroscopy
• the Applicant surprisingly uses EMC to evaluate structural changes of the mucosa in inflammatory bowel diseases and perform a diagnosis of IBD, as well as a differential diagnosis of MC vs. the RCH.
• the quantitative score created by the Applicant advantageously makes it possible to differentiate MC from UC with a positive predictive factor of about 83.3% for MC and about 100% for UC.
• the diagnostic sensitivity of MC is about 100% with a specificity of about 87.5%.
• the diagnostic sensitivity of the RCH is advantageously about 81.8% with a specificity of about 100%.
• the proposed score is based on a simple examination performed by a gastroenterologist, without anesthesia, without biopsies or techniques requiring stool culture.
• the proposed score allows a direct diagnosis, that is to say without processing time by another service.
• the proposed method can be implemented with other imaging techniques providing dynamic images of the microscopic architecture of the digestive mucosa, such as images obtained using endocytoscopes and / or endoscopes. high magnification.
• a first object of the invention relates to an ex vivo method of quantifying changes in the intestinal mucosa possibly induced by a chronic inflammatory bowel disease in an individual, said method comprising the steps of: 1) measures, on a confocal endomicroscopic image of the digestive mucosa of an individual, the parameters of the following cryptic well profiles (CPP):
• intestinal mucosal modifications possibly induced by a chronic inflammatory bowel disease means any microscopic modification, in particular cell modification, of the intestinal mucosa caused by inflammation due to IBD. This may be, for example, changes in the structure of the cryptic wells of the colonic mucosa and / or the cells forming the wells.
• the modification can be architectural and / or dynamic.
• the modification may relate to at least one of the following parameters: Mucosal Fluorescence Leak (FF), Crypt Well Opening Perimeter (PO), Crypt Shaft Rotundity (Roto), Roundness Crypt Well (Round), Feret Diameter of Crypt Well (Feret), Crypt Well Extender (FE),
• FF Mucosal Fluorescence Leak
• PO Crypt Well Opening Perimeter
• Roto Crypt Shaft Rotundity
• Round Roundness Crypt Well
• Feret Feret Diameter of Crypt Well
• FE Crypt Well Extender
• the term "digestive mucosa” means all or part of the most superficial layer of epithelial cells of the wall of the digestive tract.
• the digestive mucosa designate all or part of the intestinal mucosa. It may be for example all or part of the colonic mucosa.
• the method of the invention makes it possible, on a medical image of all or part of the digestive mucosa of an individual, to measure / calculate parameters chosen by the Applicant according to important research, in order to quantify changes in the mucosa intestinal tract possibly induced by chronic inflammatory bowel disease in an individual.
• the imaging technique used is preferably confocal endomicroscopic.
• the methods of the invention can be transposed to equivalent medical imaging techniques, such as endocytoscopy (Neumann et al., Aliment Pharmacol Ther 201 1 Jun; 33 (11): 1,183-93 ([1]). 7])) or endoscopy at high magnification (Kanesaka et al., Dig Endosc 2014 Jan; 26 (1): 57-62 ([8])).
• the term "fluorescence leakage of the mucosa” is intended to mean increasing the amount of fluorescence of the intestinal mucosa, relative to a fluorescence level at a time t and measured within ten minutes. intravenous injection of a fluorescent molecule into an individual.
• the fluorescent molecule may be any molecule known to those skilled in the art, for example fluorescein. Any method of measuring the amount of intestinal mucosal fluorescence known to those skilled in the art can be used. For example, the amount of fluorescence can be measured image by image (12 frames / second) from the recorded endomicroscopy sequences. In this case, the fluorescence leak is the result of the slope obtained by the linear regression of the amount of fluorescence over time.
• the increase may be an increase of at least 5%, or at least 10%, or at least 20%, or at least 50%, or at least 60%, or at least 80%, or at least 90%, or 100%, fluorescence compared to the level fluorescence at time t.
• this parameter is a dynamic parameter, the value of which can change over time.
• the measurement of the parameters b) to h) is carried out after definition of the contour of the opening of the crypt by the method implementing an active contour according to the segmentation method using exponential splines ( Delgado-Gonzalo et al., "Snakes on a Plane: A Perfect Snap for Bioimage Analysis," IEEE Signal Processing Magazine, Vol 32, No. 1, pp. 41-48 ([9])).
• the term "crypt pit opening perimeter" is intended to mean the length of the outline of the opening of the crypt.
• the length of the outline of the opening of the crypt can be measured by any known and appropriate method, for example by the method of Delgado-Gonzalo et al. ([9]).
• Crypt Shaft Rotundity refers to the parameter given by the formula 4 x ⁇ x Area / Crypt Shaft Opening Perimeter 2 (Wadell, H., 1932, Volume, Shape, and Roundness of Rock Particles. Journal of Geology 40: 443-51 ([1 0])).
• roundness of the crypt pit means the parameter following the definition of the ISO 101 standard (ISO 101: 2012 (E)). It corresponds to the normalized ratio between the radii of the minimum and maximum circles inscribed in the crypt pit, expressed as a percentage.
• the term "Feret diameter of the crypt pit” is understood to mean the maximum distance between two points on the surface of the crypt opening (M. R. Walter, Stromatolites, Elsevier, pp. 47-.)
• the term "Crypt shaft elongation factor” is understood to mean a scale factor given by the ratio between the diameter of the long axis elipse having a shape closest to the opening. of the crypt (Dgrand axis) and the diameter of the small axis elipse the elipse having a shape closest to the opening of the crypt (D pe tit axis).
• the elongation factor being given by Dgrand axis D pe tit axis.
• ratio of the axes of opening of the crypt pit within the meaning of the present invention, the ratio between the major axis and the minor axis of the rectangle containing the crypt opening.
• field crypt density is intended to mean a ratio between the area occupied by the crypt well openings in a field of view and the total area of the field of view.
• the term "quantification method” is intended to mean a process making it possible to quantitatively evaluate changes in the intestinal mucosa, with respect to a healthy individual, that is to say not suffering from a disease. inflammatory digestive pathology.
• confocal endomicroscopic image is understood to mean an image, a series of images, or the reconstruction of a single image from a series of images resulting from the implementation of confocal endomicroscopy.
• the image series can for example represent a dynamic visualization, particularly in real time, of the object under study. It can for example be a video.
• Confocal endomicroscopy allows the acquisition of images in a patient, without biopsies, following the injection of a fluorescent contrast agent, for example fluorescein, during an endoscopy.
• a fluorescent contrast agent for example fluorescein
• Another subject of the invention relates to an ex vivo method for diagnosing a chronic inflammatory bowel disease in an individual, said method comprising the following steps:
• the score of 0 is assigned to the corresponding parameter
• a total greater than 204 ⁇ 1 10 defines the individual as suffering from a chronic inflammatory bowel disease.
• the parameters a) to h) measured in step 1) have been specifically selected by the Applicant, after a rigorous research process, as biomarkers of imaging of interest, among many other architectural and dynamic parameters likely to undergo changes in IBD.
• the combination of these biomarkers also results from a rigorous and innovative selection.
• This group of selected biomarkers thus constitutes a group of parameters from which the diagnostic methods of the invention are implemented.
• the Applicant has also been able to define a threshold, for each of these parameters, making it possible to select, for each parameter, the values of interest to be considered in the diagnosis process of the IBDs.
• step 2) allows the selection of the values of interest, qualified as "extreme higher” values, for each of the parameters.
• step 2) represent thresholds for each parameter PO Roto, Round, Feret, FE, AM / AM and Dens, the 90 th percentile, or the lowest value of 10% of the highest values, obtained from a healthy population. The threshold is excluded from the interest values.
• the Applicant has also succeeded in defining a "pathological threshold", making it possible to discriminate the values likely to indicate the presence of an IBD.
• the pathological threshold represents, for each parameter PO, Roto, Round, Feret, FE, Ma / ma and Dens, the value allowing to include at least 60% of the IBD population studied and to exclude at least 80% of the healthy population studied, these values being calculated for example on samples comprising about ten healthy patients and twenty patients with IBD, especially as illustrated in Example 1 below.
• the Applicant teaches the comparison of this pathological threshold with, on the one hand, the average of the "higher extreme" values of each of the parameters b) to h) and, on the other hand, of the average value of FF. .
• the multiplication of the sum of the notes by the sum of the number of values of each parameter makes it possible to obtain a "total", or score, or prediction value of a MICI.
• a total greater than 204 ⁇ 1 10 defines the individual as having IBD. Conversely, a score below 204 allows the individual to be classified as not having a chronic inflammatory bowel disease.
• the number 204 ⁇ 1 10 is defined in particular by the maximal score observed in a healthy population comprising about ten healthy patients, particularly as illustrated in Example 1 below.
• Another subject of the invention relates to an ex vivo method for the differential diagnosis of Crohn's disease with respect to ulcerative colitis in an individual, said method comprising the steps previously defined for the diagnosis of IBD, followed, in the individual defines as having IBD, a comparison of the value average of FF and the average of the "higher extreme" values of the parameter PO and Feret at a differential threshold defined as follows:
• the individual is defined as suffering from ulcerative colitis if, for each of the parameters FF, PO and Feret, a value greater than the corresponding differential threshold is reached, or
• the individual is defined as suffering from Crohn's disease in the opposite case.
• the Applicant has managed, after major research, to define a "differential threshold" for each of the parameters FF, PO and Feret, this threshold allowing a diagnosis, in individuals defined as suffering from IBD, either CD or the RCH.
• FF, PO and Feret have indeed been selected at this stage by the Applicant because he has, surprisingly, observed a significant difference between individuals with MC and those with UC.
• the "differential threshold” is defined, for each parameter FF, PO and Feret, as being the value allowing at least one of the IBD populations, in other words at least one population selected from the MC population and the RCH population, is represented at 100% and the second, that is to say that which is not represented at 100%, if any, is represented at least 80%.
• the total number of crypts analyzed in the endomicroscopic images of the colonic mucosa may be at least 32 ⁇ 10 crypts for a confidence level of 0.05 and at least 53 ⁇ 10 crypts for a confidence level of 0.01. This may be for example at least about 20 crytpes, or 40 crypts, or about 80 crypts, or about 90 crypts, or about 100 crypts, or about 120 crypts, analyzed on randomly selected colonic areas.
• the steps of measurement, selection of values, comparison and allocation of notes can be automated by means of a computer program for a posteriori analysis of endomicroscopy images, for example with IC-viewer (IronCAD), or with an integrated solution to the existing endomicroscopy software for real-time analysis, for example with Cellzero (Mauna Kea Technologies).
• Another subject of the invention relates to a computer program product downloadable from a communication network and / or recorded on a computer readable medium and / or executable by a processor, comprising program code instructions for setting one of the methods of the invention.
• Another subject of the invention relates to a system comprising an endomicroscope, visualization means and calculation means, for implementing a previously defined method.
• Another subject of the invention relates to a system comprising a confocal endomicroscope connected to display means and a computer comprising image analysis means for measuring on a confocal endomicroscopic image of the digestive mucosa of an individual, at least one of the parameters of the crypt well profiles (PPC) selected from FF, PO, Roto, Round, Feret, FE, Ma / ma and Dens, and a comparator adapted to compare the measurements made with the corresponding values of a healthy individual.
• PPC crypt well profiles
• the analysis means of this system can be adapted to select "higher extreme" values, higher than the thresholds defined below for each parameter:
• the comparator is adapted to compare, for each parameter, the average of the "higher extreme” values and the average value of FF at a defined pathological threshold, for each parameter, as follows:
• the computer further comprising a note generator connected to the comparator and adapted to assign the following notes:
• the score of 0 is assigned to the corresponding parameter
• the calculator further comprising a multiplier adapted to multiply the sum of the notes by the sum of the number of values of each parameter.
• the comparator of the system may furthermore be adapted to compare the average value of FF and the average of the higher extreme values.
• FF the average value of FF
• a differential threshold defined as follows:
• the system may comprise a confocal endomicroscope, display means and calculation means, in which said calculation means comprise:
• B1 means for measuring the parameters FF, PO, Roto, Round, Feret, FE, Ma / ma and Dens,
• FIG. 1 represents the diagram of the principle of laser confocal endomicroscopy.
• the vertical rectangle at the top represents the laser light source and the confocal system detector.
• the horizontal rectangle represents the pinhole through which light rays pass.
• the horizontal oval represents a focusing lens.
• Laser radiation passes through the center of the lens and reaches the tissue.
• the fluorescent molecule present in the tissue then emits light upwards.
• the light rays outside the focal plane are diverged by the lens and do not pass through the pinhole.
• the light rays emitted by the focal plane are converged by the lens towards the pinhole and the detector.
• Figure 2 shows the architectural parameters considered crypts.
• Figure 2A shows the opening perimeter of the crypt.
• Figure 2B shows the Elongation Factor.
• Figure 2C shows Rotundity.
• Figure 2D shows the Ma / ma ratio of the opening of the crypt.
• Figure 2E shows the Roundness.
• Figure 2F shows the Ferret Diameter.
• Figure 2G shows the density of crypts per field.
• A Scope of opening of the crypt (expressed in ⁇ )
• B Roundness (in%)
• C Roundness (expressed in%)
• D Diameter of
• FIG. 4 represents the comparison of the average of the fluorescence leakage values (FF), expressed in LUT. sec -1 , in 5 healthy individuals ("S”), 10 individuals with Crohn's disease (“CD”) and 1 1 individuals with ulcerative colitis (“UC”).
• FF fluorescence leakage values
• FF Fluorescence leakage
• OP opening perimeter
• Round roundness
• Roto rotundity
• FE elongation factor
• Feret diameter Feret
• Ma / ma small axis long axis ratio
• Dens density
• the average values above the 90 th percentile of healthy patients from the perimeter of opening (PO) (p ⁇ 0.05), rotundity (Roto) (p ⁇ 0.01), diameter of Feret (Feret) ( p ⁇ 0.01), the elongation factor (FE) (p ⁇ 0.01), the Ma / ma ratio (p ⁇ 0.01) and the density (Dens) of the crypt image (p ⁇ 0.05) are significantly higher for the RCH group compared to healthy patients (see Figure 3).
• FF Fluorescence leakage
• OP opening perimeter
• Round roundness
• Roto rotundity
• FE elongation factor
• Feret diameter Feret
• Ma / ma small axis long axis ratio
• Dens density
• the diagnostic score of IBD is defined by:
• the average of the "extreme superior" values, that is to say above the 90 th percentile of the healthy patients, and the mean value of FF are compared to a pathological threshold defined by a consensus of experts.
• the pathological threshold, for each parameter is thus defined by the following values:
• the value of 0 is assigned to the parameter. If this value is greater than the pathological threshold, the score of 1 is given for FF, PO, Round, Feret, Dens and the score of 2 is given for Roto, FE and Ma / ma.
• the average FF value and the average of the "higher extreme" values of PO and Feret are compared to a differential threshold defined by an expert consensus.
• the differential threshold, for each of these parameters, is thus defined by the following values: - FF> 19.86 LUT.sec "1 ,
• the patient is defined as having an RCH.
• the patient is defined as having an MC.
• the values of the 90th percentile of the healthy population are: Opening Perimeter (> 474.62 ⁇ ) roundness (> 98.96%), roundness (> 68.43%), Feret diameter (> 169.88 ⁇ ), Elongation factor (> 1, 745), Ma / ma (> 1, 653) and density (> 0.2837).
• the specificity is 100%, the sensitivity of 81.8%, the VPP 100% and the VPN 88.2%.
• Example 2 4 healthy patients, 13 patients with clinical inflammatory remission (CDAI ⁇ 150) and 16 patients with ulcerative colitis been included in this retrospective study.
• the parameters described in Example 2 were quantified by measurement or calculation of these parameters using confocal endomicroscopy images (ColoFlex UHD, CellVolo, Mauna Kea Technologies).
• the diagnostic score is constructed as previously described.
• the differential diagnosis is constructed from FF (> 19.86 ⁇ 5.70 LUT.sec-1), PO (> 618.32 ⁇ 98.95 ⁇ ) and Feret (> 204.68 ⁇ 29.65 ⁇ ) as previously described.
• the sensitivity of the diagnosis of IBD is 96.55% for a specificity of 75%.
• the sensitivity of the differential diagnosis RCH / MC is 68.75% for a specificity of 61.54%.
• Example 2 The entire study population (Example 2 and Example 3) demonstrates that the diagnostic score allows the identification of IBD with a sensitivity of 98% and a specificity of 89%.
• the differential diagnosis is 65.4% sensitive and 75% specific.

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