System and method for disease diagnosis using optical spectroscopy

Abstract

Disclosed herein are systems and methods for diagnosing a medical disease using a sample receptacle configured to receive a sample acquired from a patient and an optical spectrometer, including a laser source, an optical cell, and a detector. An airflow pathway fluidly connects the sample receptacle and the optical cell to move air that interacted with the sample into the optical cell. A processor is configured to control the laser source to irradiate the optical cell when the air that interacted with the sample is in the optical cell and receive data from the detector in response to the laser irradiating the optical cell; and analyze the data and generate a report indicating whether the patient is suffering from the medical disease.

Description

SYSTEM AND METHOD FOR DISEASE DIAGNOSIS USING OPTICAL SPECTROSCOPYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 570,970 that was filed March 28, 2024, the entire contents of which are hereby incorporated by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This work was supported by the U.S. Department of Veterans Affairs, and the Federal government has certain rights in the invention.FIELD OF THE INVENTION

[0003] The disclosed technology is generally directed to systems and methods for medical disease diagnosis. More particularly, the technology is directed to medical disease diagnosis using optical spectroscopy.BACKGROUND OF THE INVENTION

[0004] Early detection of health issues offers numerous benefits, including improved treatment outcomes, enhanced quality of life, and the opportunity to enact proactive interventions. Non-invasive medical diagnostic testing and / or treatment methods offer many advantages over invasive diagnostic practices. For example, non-invasive approaches reduce the risk of complications, minimize patient discomfort, and shorten recovery times.

[0005] Unfortunately, some diseases have limited diagnostic approaches available and result in invasive procedures. For example, currently, there is no examination of symptoms or lab study that can predict or diagnose necrotizing enterocolitis (NEC) in infants. The gold standard for NEC diagnosis is abdominal x-ray showing pneumatosis and / or portal venous air, which indicates bowel infarction. These infants are then placed on a NEC protocol which usually involves cessation of enteral feedings, NG tube placement, and administration of total parenteral nutrition / antibiotics. If the infant does not get better with these measures, surgical excision of the infarcted bowel is performed. Early detection of NEC is paramount to reducing the morbidity and mortality from NEC.

[0006] Accordingly, there is a need for systems and methods for rapid, accurate, precise, and sensitive detection of diseases like NEC and others.BRIEF SUMMARY OF THE INVENTION

[0007] The present disclosure overcomes the aforementioned drawbacks by providing systems and methods for diagnosing a medical disease by scent. For example, the systems and may be manufactured to collect and prepare a scent from a patient-provided sample and interrogate the scent in an optical spectrometer for indicators of a medical disease.

[0008] In accordance with one aspect of the disclosure, a system is provided for diagnosing a medical disease may include a sample receptable, configured to receive a sample acquired from a patient, an optical spectrometer, and a processor. The optical spectrometer may include a laser source, an optical cell, and a detector. An airflow pathway may fluidly connect the sample receptacle and the optical cell to move air that interacted with the sample into the optical cell. The processor is configured to control the laser source to irradiate the optical cell when the air that interacted with the sample is in the optical cell and receive data from the detector in response to the laser irradiating the optical cell. The processor may further analyze the data and generate a report indicating whether the patient is suffering from the medical disease.

[0009] In accordance with one aspect of the disclosure, a method is provided for diagnosing a medical disease, including providing a sample comprising a scent, the scent comprising one or more indicators of the medical disease. The method further includes collecting the scent in an optical cell, illuminating the scent with a laser to produce a signal, detecting the signal, analyzing the signal for one or more indicators of the medical disease, and generating a report indicating the diagnosis of the medical disease.

[0010] The foregoing and other aspects and advantages of the invention will appear in the following description. In the description, reference is made to the accompanying drawings, which form a part hereof, and in which a preferred embodiment of the invention is shown by way of illustration. Such embodiment does not necessarily represent the full scope of the invention, however, and reference is made therefore to the claims and herein for interpreting the scope of the invention.BRIEF DESCRIPTION OF THE DRAWINGS[OOH] Non-limiting embodiments of the present invention will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the invention shownwhere illustration is not necessary to allow those of ordinaiy skill in the art to understand the invention.

[0012] FIG. 1 shows a schematic illustration of an exemplary analysis system in accordance with the present disclosure.

[0013] FIG. 2 shows a perspective illustration of an exemplary system for receiving a sample for processing of the same in accordance with a system such as illustrated in FIG. 1.

[0014] FIG. 3 shows simulated infrared absorbance spectra, using reference spectral data from NIST and HITRAN databases, of select esters (including 2-ethylhexyl acetic ester, decanoic acid ethyl ester, dodecanoic acid ethyl ester, hexadecanoic acid ethyl ester, ethyl acetate, and ethyl benzoate) (top) and interfering species (H2O, CH4, and CO2) (bottom).

[0015] FIG. 4 shows a flow chart setting forth some exemplary steps of a method of diagnosing a medical disease according to some aspects of the present disclosure.DETAILED DESCRIPTION OF THE INVENTION

[0016] Disclosed herein are systems and methods for rapid, chemically specific, and sensitive detection of scent-based indicators for medical disease. In some cases, the medical disease may be a condition related to metabolism, digestion, or a cell, tissue, organ, or organ system related to metabolism or digestion. In some cases, the medical disease may be necrotizing enterocolitis (NEC).

[0017] The present disclosure recognizes that some studies have investigated using fecal smell to diagnose NEC. One mouse model used an electronic nose and found that the NEC mice had significantly more Escherichia coli and less Lactobacillus than the normal controls. Another group used an electronic nose to investigate if volatile organic compounds (VOC) profiles from fecal samples to predict which infants would develop NEC. This study demonstrated the ability to predict NEC 2-3 days before onset of clinical symptoms. A similar study corroborated these findings and was able to detect changes in fecal VOCs 4 days before clinical detection of NEC. Specifically, these studies found that the NEC infants did not have these esters: 2-ethylhexyl acetic ester, decanoic acid ethyl ester, dodecanoic acid ethyl ester, and hexadecanoic acid ethyl ester. Despite these earlier studies, the field still lacks a low-cost, portable system that can be used by untrained staff to detect NEC-specific metabolites.

[0018] The present disclosure provides systems and methods for diagnosing a medical disease. Referring now to FIG. 1, a system 100 is disclosed herein that may include an optical spectrometer 102 including a laser 104, an optical cell 106, and a detector 108. In one non-limiting example, the laser may be a roughly 9 pm laser. Additionally or alternatively, the laser 104 may include one or more excitation sources and, accordingly, one or more beam splitters 110 may be utilized to direct an excitation beam 112, for example, using one or more mirrors 114, to the spectrometer 102. As will be described, vapor from a sample may enter the spectrometer 102 through a first port 1 16 and out through a second port 118. A sample may refer to a material produced by a patient. In some cases, a sample may be one or more expressed materials such as feces, urine, vomit, menstrual blood, sweat, exhaled breath, tears, mucus, or sputum. In some cases, the sample is a biological waste product, such as a human waste product, including waste products of the digestive system or metabolism. In some cases, the sample may be a direct or indirect biological waste product or a human waste product of a cell, tissue, organ, or organ system which may be suspected of experiencing one or more medical diseases. In some cases, the sample may have one or more scents or vapors.

[0019] A scent may refer to a smell. A scent or vapor may be characterized by one or more molecular species present in, on, or being generate from a sample. In some cases, a scent or vapor may be detectable by a human nose or a canine nose. In some cases, the absence or presence of one or more molecular species characterizing a scent may be indicators of disease. In some cases, the molecular species characterizing a scent may be volatile or non-volatile. In some cases, the conditions created by the systems and methods disclosed herein may increase or decrease the volatility of the molecular species.

[0020] The first port of FIG. 1 may be coupled to a sample receptacle 200. Coupling may include a tube, conduit, duct, or other structure configured to transport gases. Referring to FIG. 2, the sample receptable may include a sample holder 201 configured to receive the sample. The sample receptable may be configured to receive a sample held within another container, such as a diaper, cup, dish, or plate. In some cases, the sample holder and / or the sample receptable may be disposable. The sample receptacle may be outfitted with additional features for conditioning the sample, or conditioning the air interacting with the sample, for later analysis. The sample receptacle may further comprise a source of heat. The source of heat may be controlled to maintain a desired temperature or temperature range using a temperature controller unit 202. In some cases, the sample receptacle may further include a dehumidifier, such as a chemical absorbent dehumidifier (e.g., desiccant) or a condensing dehumidifier. In some cases, dehumidification may be achieved by evaporation. In some cases, the sample receptable may be flushed with one or more gases (e.g., N2) between samples in order to prevent cross-contamination. Examples of suitable methods and systemsfor dehumidification are described in U.S. Patent Application Publication No. 2023 / 0136493, International Patent Application Publication WO 2021 / 243035, and Alshehri, A., Rothstein, J.P. & Kavehpour, H.P. Improving heat and mass transfer rates through continuous drop-wise condensation. Sci Rep 11, 19636 (2021), the entireties of which are incorporated, for any purpose, by reference herein.

[0021] Still referring to FIG. 2, the sample receptable may define or partially define an airflow pathway 203 coupled to the first port 116 of FIG. 1. The airflow pathway fluidly connects the sample receptacle and the optical cell 106 of FIG. 1 to move air that interacted with the sample into the optical cell and then out through the second port 118 of FIG. 1 . The airflow pathway 203 may include a conduit configured to move air from one location to another. In some cases, the airflow pathway may include a duct, tube, or otherwise defined volume of space configured to contain one or more fluids (e.g., gases, liquids). In some cases, the airflow pathway may further include a pump or fan to initiate the movement of air from one location to another. In some cases, the path of airflow from the sample receptacle 200 to first port 116 and second port 118 may be configured to recirculate the air that interacted with the sample. In some cases, the air that interacted with the sample a first time, may be recirculated past the sample for a second or more times. In some cases, the air that interacted with the sample is recirculated to pass through the optical cell 106 two or more times.

[0022] In some cases, the airflow pathway may further include a humidity sensor. In some cases, the humidity sensor may include a capacitive humidity sensor, a resistive humidity sensor, or a thermal humidity sensor. The humidity sensor may measure relative humidity or absolute humidity. As will be described, a processor 120 is configured to receive data from the detector 108 and may be configured to control operation of the system 100 and, in particular, the spectrometer 102 and / or laser 104.

[0023] The airflow pathway fluidly connects the sample receptacle to the optical cell of FIG. 1 to move air that interacted with the sample into the optical cell. In some cases, the optical cell is a multi-pass gas optical cell. In some cases, the multi-pass gas optical cell may have a pathlength of no less than 0.03 meters to no more than 200 meters. In some cases, the multi-pass cell has a pathlength of about 76 meters.

[0024] In some cases, the optical spectrometer may include two or more lasers. In some cases, the laser source can be configured to perform a pump-probe experiment. In some cases, the laser source may be an infrared (IR) laser source (e.g., near-IR, mid-IR, or far-IR), an ultraviolet laser source, or a terahertz laser source. In some cases, the laser source may have awavelength of about 0.10 gm to about 0.28 gm, about 0.28 gm to about 0.30 gm, about 0.315 gm to about 0.40 gm, about 0.78 gm to about 1.4 gm, about 1.5 gm to about 7.0 gm, about 8.0 gm to about 10 gm, about 9 gm to about 30 gm, or about 30 gm to about 3.0 mm. In some cases, the laser source wavelength may be tuned or scanned (e.g., wavelength modulation spectroscopy). The laser source wavelength may be scanned to generate detectable spectroscopic features (e.g., one or more spectral peaks, a lack of one or more spectral peaks, a ratio of spectral peak intensities, spectral peak widths or a ratio of spectral peak widths, a shift in location of one or more spectral peaks, etc) of one or more molecular species present or absent in the sample which may be indicative of disease. By way of example, it has been demonstrated by others that the lack of spectral features identifying 2-ethylhexyl acetic ester, decanoic acid ethyl ester, dodecanoic acid ethyl ester, and hexadecanoic acid ethyl ester in the feces of an infant may be used to diagnose necrotizing enterocolitis (NEC). With the diagnosis of NEC in mind, the laser source maybe scanned to interrogate the vibrational bands of esters, including the C-0 and C=O bands. In other cases, the laser source may be scanned to interrogate the vibrational bands of hydrocarbons. For example, Figure 3 shows infrared absorbance bands of 2-ethylhexyl acetic ester, decanoic acid ethyl ester, dodecanoic acid ethyl ester, hexadecanoic acid ethyl ester, ethyl acetate, and ethyl benzoate between about 900 cm1to about 1600 cm1.

[0025] The optical spectrometer includes a detector. Acceptable detectors are described elsewhere in the art. Acceptable infrared detectors such as a thermal detector (e.g., deuterated, L-alanine doped triglycine sulfate (DLaTGS)) or a quantum detector (e.g., mercuric cadmium telluride (MCT) detector). Other acceptable detectors may include germanium, silicon, InGaAs, InSb, LiTaOs, or Si bolometer. A detector may be selected based upon the spectral range of the vibrational bands or scattering of the molecular species of interest.

[0026] As illustrated in FIG. 1, the system 100 includes a processor 102. In some cases, the processor may be a computer having instructions (e.g., code) which direct at least part of the system. In some cases, the processor 120 is configured to control the laser 104 to irradiate the optical cell 106 when the air that interacted with the sample is in the optical cell 106. The processor 120 may receive data from the detector in response to the laser irra iating the optical cell and analyze the data and generate a report indicating whether the patient is suffering from the medical disease. A patient may refer to a person or animal. The person may be of any age including infancy, toddler, childhood, puberty, older adolescence, adulthood, middle age, and senior.

[0027] In some cases, the processor 120, in analyzing the data, is configured to interact with or operate according to an artificial intelligence module. In some cases, the artificial intelligence module includes a neural network or a machine learning system. The artificial intelligence module may have undergone supervised training with a training data set. In some cases, the training data set may be trained using data collected with one or more controlled variables, such as humidity, temperature, positive diagnosis of disease, negative diagnosis of disease, presence of one or more interfering species, absence of one or more interfering species, or samples from patients having comorbidities.|0028] Also disclosed herein are methods for diagnosing a medical disease. Referring to FIG. 4, one non-limiting example of a method 400 in accordance with the present disclosure includes, at process block 402, providing a sample configured to provide vapor or comprising a scent in a sample receptacle, such as described above. At process block 404, the vapor or the scent is directed to an optical cell 404. The vapor is illuminated or excited at process block 406 with a laser to produce a signal. At process block 408, the signal is detected and, at process block 410, the signal is analyzed for one or more indicators of the medical disease. At process block 412, a report is generated that includes an indication of a presence or absence or probability of the medical disease. The methods disclosed herein may be performed in batches or in a continuous (i.e., in-line or near-line) fashion.

[0029] In some cases, providing a sample comprising a scent may include providing an article of clothing having the scent. For example, a soiled diaper may be provided. Collecting the scent in an optical cell may further include conditioning the scent (e.g., conditioning the air carrying the scent). In some cases, the scent may be heated or cooled to a temperature or a temperature range. The scent may be separated from one or more components of ambient air. In some cases, the scent may be dehumidified. In some cases, the scent may be mixed with a carrier gas. In some cases, collecting the scent in an optical cell may further include flushing the optical cell with one or more gases (e.g., N2) between samples to prevent crosscontamination.

[0030] The methods disclosed herein include illuminating the scent with a laser to produce a signal (e.g., spectroscopic features) and detecting the signal. These methods may be achieved with the optical spectrometer components as described above. In some cases, the optical spectrometer may be configured to conduct laser absorption spectroscopy. In some cases, they may be configured to conduct infrared laser absorption spectroscopy. In some cases, they may be configured to conduct mid-infrared laser absorption spectroscopy. The laser sourcewavelength may be scanned to generate detectable spectroscopic features (e.g., one or more spectral peaks, a lack of one or more spectral peaks, a ratio of spectral peak intensities, spectral peak widths or a ratio of spectral peak widths, a shift in location of one or more spectral peaks, etc) of one or more molecular species present or absent in the sample which may be indicative of disease. By way of example, it has been demonstrated by others that the lack of spectral features identifying 2-ethylhexyl acetic ester, decanoic acid ethyl ester, dodecanoic acid ethyl ester, and hexadecanoic acid ethyl ester in the feces of an infant may be used to diagnose necrotizing enterocolitis (NEC). With the diagnosis of NEC in mind, the laser source maybe scanned to interrogate the vibrational bands of esters, including the C-0 and C=O bands. In other cases, the laser source may be scanned to interrogate the vibrational bands of hydrocarbons. For example, Figure 3 shows infrared absorbance bands of 2-ethylhexyl acetic ester, decanoic acid ethyl ester, dodecanoic acid ethyl ester, hexadecanoic acid ethyl ester, ethyl acetate, and ethyl benzoate between about 900 cm'1to about 1600 cm'1.

[0031] The methods disclosed herein further include analyzing the signal for one or more indicators of the medical disease, and generating a report indicating the diagnosis of the medical disease. An indicator of disease may refer to one or more metrics corresponding or correlating to one or more medical diseases. In some cases, indicators of disease can include biomarkers (i.e., a measurable substance in a patient whose presence or absence is indicative of some phenomenon such as disease, infection, or environmental exposure). In some cases, a processor may be used to analyze the data. In some cases, the data is provided to an artificial intelligence module. In some cases, the artificial intelligence module includes a neural network or a machine learning system. The artificial intelligence module may have undergone supervised training with a training data set. Tn some cases, the training data set may be trained using data collected with one or more controlled variables, such as humidity, temperature, positive diagnosis of disease, negative diagnosis of disease, presence of one or more interfering species, absence of one or more interfering species, or samples from patients having comorbidities.

[0032] In another aspect, also disclosed herein are methods, systems, and devices for detecting a scent. The methods for scent detection include providing a sample comprising a scent. The scent includes one or more indicators of a condition. The method further includes collecting the scent in an optical cell, illuminating the scent with a laser to produce a signal, detecting the signal, and analyzing the signal for one or more indicators of the condition. Insome cases, the methods further include generating a report indicating the presence of the condition.Miscellaneous

[0033] Unless otherwise specified or indicated by context, the terms “a”, “an”, and “the” mean “one or more.” For example, “a molecule” should be interpreted to mean “one or more molecules.”

[0034] As used herein, “about”, “approximately,” “substantially,” and “significantly” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which they are used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” and “approximately” will mean plus or minus <10% of the particular term and “substantially” and “significantly” will mean plus or minus >10% of the particular term.

[0035] As used herein, the terms “include” and “including” have the same meaning as the terms “comprise” and “comprising.” The terms “comprise” and “comprising” should be interpreted as being “open” transitional terms that permit the inclusion of additional components further to those components recited in the claims. The terms “consist” and “consisting of’ should be interpreted as being “closed” transitional terms that do not permit the inclusion additional components other than the components recited in the claims. The term “consisting essentially of’ should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter.

[0036] In those instances where a convention analogous to “at least one of A, B and C, etc.” is used, in general such a construction is intended in the sense of one having ordinary skill in the art would understand the convention (e.g., “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.). 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 or figures, 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.”

[0037] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any nonclaimed element as essential to the practice of the invention.

[0038] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.|0039| Preferred aspects of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred aspects may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect a person having ordinary skill in the art to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMSWhat is claimed is:

1. A system for diagnosing a medical disease, comprising: a sample receptacle configured to receive a sample acquired from a patient; an optical spectrometer comprising: a laser source, an optical cell, and a detector; an airflow pathway fluidly connecting the sample receptacle and the optical cell to move air that interacted with the sample into the optical cell; a processor configured to: control the laser source to irradiate the optical cell when the air that interacted with the sample is in the optical cell and receive data from the detector in response to the laser irradiating the optical cell; and analyze the data and generate a report indicating whether the patient is suffering from the medical disease.

2. The system of claim 1, wherein the sample is human waste.

3. The system of any one of claims 1-2, wherein the sample receptacle further comprises a source of heat.

4. The system of any one of claims 1-3, wherein the sample receptacle further comprises a dehumidifier.

5. The system of any one of claims 1-4, wherein the airflow pathway further comprises a humidity sensor.

6. The system of any one of claims 1-5, wherein, to analyze the data, the processor is configured to provide the data to an artificial intelligence module.

7. The system of claim 6, wherein the artificial intelligence module includes a neural network or a machine learning system.

8. The system of any one of claims 1-7, wherein the medical disease is a condition of a digestive tract.

9. The system of any one of claims 1-8, wherein the sample comprises one or more indicators of disease.

10. The system of claim 9, wherein an indicator of disease is a presence of one or more biomarkers or an absence of one or more biomarkers.

11. The system of claim 10, wherein the report indicates the sample is substantially free of 2- ethylhexyl acetic ester, decanoic acid ethyl ester, dodecanoic acid ethyl ester, and hexadecanoic acid ethyl ester.

12. The system of claim 11, wherein the medical disease is necrotizing enterocolitis.

13. A method for diagnosing a medical disease, comprising: providing a sample comprising a scent, the scent comprising one or more indicators of the medical disease; collecting the scent in an optical cell; illuminating the scent with a laser to produce a signal; detecting the signal; analyzing the signal for one or more indicators of the medical disease; and generating a report indicating the diagnosis of the medical disease.

14. The method of claim 13, wherein the sample is biological waste.

15. The method of any one of claims 13-14, wherein analyzing the signal for one or more indicators of the medical disease comprises a trained neural network.

16. The method of claim 15, wherein an indicator of disease is the presence of one or more biomarkers or the absence of one or more biomarkers.

17. The method of any one of claims 13-16, wherein the one or more indicators of disease is the sample being substantially free of 2-ethylhexyl acetic ester, decanoic acid ethyl ester, dodecanoic acid ethyl ester, and hexadecanoic acid ethyl ester.

18. The method of claim 17, wherein the generating a report indicating the diagnosis of the medical disease further comprises: generating a report indicating the medical disease is necrotizing enterocolitis.

19. The method of claim 13. wherein collecting the scent in an optical cell further comprises dehumidifying the scent.

20. A method for generating a report comprising: providing a sample comprising a scent, the scent comprising one or more indicators of a condition; collecting the scent in an optical cell; illuminating the scent with a laser to produce a signal; detecting the signal; analyzing the signal for one or more indicators of the condition; and generating a report indicating the presence of the condition.

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