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MACHINE LEARNING TO RATE ATAXIC BREATHING SEVERITY
Opioid-induced respiratory depression is traditionally recognized by assessment of respiratory rate, arterial oxygen saturation, end-tidal CO2, and mental status. Although an irregular or ataxic breathing pattern is widely recognized as a manifestation of opioid effects, the presence of ataxic breathing is not routinely monitored or scored. A major obstacle to widespread monitoring for ataxic breathing is the necessity for manual, offline analysis.
University of Utah researchers have developed a machine learning algorithm that enables real-time, quantitative monitoring of patients’ breathing patterns. This algorithm determines the severity of ataxic breathing events and has been verified to classify those events in a manner consistent with manual analysis. Accordingly, the algorithm should enable detection of opioid-induced respiratory depression events and determine their severity.
SYSTEM FOR EVALUATING AND ASSESSING ABNORMAL CARDIAC CONDUCTION
Cardiac arrhythmias and abnormal heart conduction are common, with over 600,000 sudden cardiac deaths per year in the United States. Present methods for atrial assessment and atrial fibrillation ablation require expensive, high-risk, time-intensive procedures in hospital operating rooms and experimental MRI imaging techniques. Related technology for assessing ventricular conduction abnormalities is inexpensive and low-risk, but addresses only one part of ventricular abnormality.
In order to simplify and enhance the diagnosis of abnormal heart conduction, a novel approach has been created to quantify the number and character of P waves or QRS generated by the heart. This approach assesses both P and QRS signals during a 5-15 minute, continuous, high-resolution ECG recording to determine patient risk for cardiac arrhythmia.
SMALL MOLECULE DETECTION ASSAY IN BIOLOGICAL SYSTEMS
The demand to perform rapid and selective testing for small molecules in biological samples using inexpensive instrumentation is increasing. For example, current drug testing methods rely on antibody-based assays, which can produce false-positive results, requiring additional expensive mass spectrometry-based testing to establish if the illegal substance is present.
A University of Utah inventor developed a novel detection platform based on nucleic acid aptamers capable of selectively detecting small molecules such as drugs, toxins, or metabolites in complex biological systems. The key aspect of the platform is split aptamer ligation technology, which generates an aptamer-based, enzyme-linked detection system that is superior to existing antibody-based assays, as it allows for rapid and inexpensive detection at low concentrations. The new platform has the potential to distinguish between structurally similar analytes such as morphine and codeine. In addition, it will find broad application in the fields of forensics, medical diagnostics, and environmental research.
NOVEL QUANTITATIVE, ARRAY-BASED METHYLATION ANALYSIS
DNA methylation often reflects epigenetic changes that affect oncogenesis and normal cell functions. Current methods for assessing DNA methylation, however, are labor intensive, technically complicated, and often ambiguous.
A novel microarray-based technique for the quantification of DNA methylation has been developed. The microarray uses methyl binding domain proteins to recognize CpGs with high specificity both in vivo and in vitro. The two step process hybridizes the DNA to an array of oligonucleotide probes and then exposes the DNA to fluorescently labeled methyl binding proteins. Analysis of the binding kinetics provides information of the methylation level at each addressable spot with increased specificity. This technique dramatically simplifies quantification of methylated DNA, increases accuracy, and avoids limitations associated with prior methods.
BIOMARKERS FOR EARLY-STAGE PANCREATIC CANCER
Pancreatic ductal adenocarcinoma (PDAC) is diagnosed too late for treatments to be effective in approximately 80 percent of patients. Screening programs to detect early stage PDAC demonstrate low accuracy, limiting their use for diagnostics and disease monitoring. This leaves patients with only palliative care options and a less than five year prognosis.
University of Utah researchers have developed a biomarker panel supported by extensive studies across clinical samples to provide early screening for PDACs so that patients can receive early clinical intervention. The panel includes a key protein in the blood, basigin, which was found to be elevated in early stage pancreatic cancer patients, but not in late stage or healthy patients. A panel of biomarkers, including basigin, can discriminate between healthy subjects and patients with early stage cancer, with high sensitivity at 95 percent specificity thresholds.
MICROFLUIDIC CHIP FOR EXTREME PCR
Polymerase chain reaction (PCR) is an inexpensive and robust technique for amplifying specific segments of DNA for gene analysis, DNA sequencing, DNA profiling, and diagnostic tests. The speed at which PCR can be performed depends on the time required to cycle through temperature dependent steps.
The microfluidic chip for extreme PCR allows for a 1 to 2 second PCR cycle. The chip has one uniform channel through which a PCR mix flows, with a single port acting as both an inlet and outlet. A thermal gradient is introduced across the chip, where one end is at the melting temperature of a target and the other is at the annealing temperature of DNA. The target is amplified after two cycles through the chip and identified on a high resolution melting instrument in roughly one minute. This chip facilitates extreme PCR that is cheap, easy to manufacture, and simple to use.
SEROLOGIC ASSAYS TO DIRECT PERSONALIZED DEMYELINATING DISEASE TREATMENT
There are over 2 million people around the world who suffer from multiple sclerosis (MS). It can take a protracted period to identify the disease, and while there are more treatments to address MS than there were a decade ago, they often have serious side effects and none of the current treatments stop the disease.
University of Utah researchers have identified a series of bacteria whose presence is highly associated with demyelinating diseases, specifically MS. These bacteria have been used to create a set of microbial reagents for use in serologic assays to personalize antimicrobial treatment of MS. Treating MS with specific antibiotics to halt or prevent disease would significantly improve patient outcomes by treating the root cause with less serious side effects.
PERCH: ENHANCED GENETIC VARIANT PRIORITIZATION
There are multiple tools available to identify, score, and annotate genetic variants within a genome. However, the majority of these tools are restricted to high-penetrance genes for Mendelian diseases and can only analyze certain pedigree structures.
A University of Utah researcher has developed a framework for prioritizing genetic disease variants. This framework, Polymorphism Evaluation, Ranking, and Classification for Heritable traits (PERCH), predicts the pathogenicity of genetic variants better than competing methods. PERCH uses BayesDel, BayesSeg, BayesHLR, and BayesGBA to prioritize variants or gene sets. PERCH measures the biological relevance of each gene to the disease of interest, searching for disease susceptibility genes through whole-exome, whole-genome, or gene-panel sequencing data.
DIAGNOSTIC MARKER AND THERAPEUTIC TARGET FOR EWING’S SARCOMA
Ewing’s Sarcoma is an aggressive and highly metastatic bone or soft tissue associated tumor in children and young adults. These tumors frequently progress undetected until they metastasize, whereupon the mortality of the disease greatly increases. Identifying Ewing’s tumors typically involves detection of CD99 and EWS/FLI expression that have limited sensitivity and specificity.
Gene ontology (GO) analysis and subsequent studies in tumor tissues has verified NKX2.2 gene or protein expression as an important contributor to
the neural characteristics of the tumor. The invention describes a quantitative approach to measuring NKX2.2 expression as a sensitive approach to diagnosing Ewing’s tumors. Additional biology studies have shown that blocking NKX2.2 expression causes Ewing’s Sarcoma cells to lose their oncogenic phenotype, which suggests additional therapeutic applications.
SINGLE-STEP ANTI-TNF DRUG MONTIORING
Anti-TNF (tumor necrosis factor) therapeutics are top-grossing drugs that are a major treatment advancement for inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and Crohn’s disease. Patient blood levels of TNF blockers need routine monitoring to ensure effective therapeutic response and patient safety. The current clinical test for TNF blockers is expensive and time-consuming, requiring cell culturing.
University of Utah researchers have developed an immunoassay platform with customized antibody detection reagents that enables one-step anti-TNF drug monitoring. The immunoassay provides a fluorimetric readout in less than an hour.
IMPROVEMENT IN DETECTION SENSITIVITY OF RARE DISEASE VARIANTS FOR LIQUID BIOPSY TESTING
Circulating tumor DNA and tumor-derived exosomes are becoming popular as non-invasive cancer diagnostic tools, termed “liquid” biopsy. Standard next-generation sequencing (NGS) DNA processing approaches enable broad identification of both known and unknown tumor-associated variants, including single nucleotide variants. However, even with the highest fidelity sequencing platforms, errors introduced at >0.1% limit identification of disease associated variants that occur at <1% frequency. This increases the risk of over-representation of false variants and diminishes the clinical relevance of such tests.
University of Utah researchers have developed a droplet digital PCR (ddPCR) approach for enhancing detection sensitivity. This ddPCR approach has the following proprietary intervening steps to enrich circulating tumor DNA: (1) high-throughput automated gel extraction to isolate subfractions of the mononucleosomal peak, and (2) specific adapter sequences or molecular identifiers that allow grouping of PCR duplicates into “family sizes.”
DIAGNOSTIC FOR EPILEPSY AND FEBRILE CONVULSIONS
Febrile seizures are the most common seizure disorder in infants, with a prevalence of 2-5 percent in Europe and North America. Complications of febrile convulsions include the development of afebrile seizures and epilepsy later in life. The current standard of care involves Phenobarbital or Valproate with significant risks and potential adverse effects. Yet, simple febrile seizures have no proven risks. On the basis of risk/benefit analysis, neither long-term nor intermittent anticonvulsant therapy is indicated for children who have experienced one or more simple febrile seizures.
University of Utah researchers have created a rapid PCR-based test to determine patients’ risk for neurological disorders such as seizures and epilepsy. The test compares the subject’s Nav1.7 haplotype to a reference haplotype. Each haplotype can be correlated with specific neurological disorders and the severity of those disorders. This approach enables patient stratification according to risk of seizure and development of curated treatment plans that mitigate unnecessary adverse events in patients with low risk for seizure.
RAPID qPCR TEST FOR COLON CANCER
Colon cancer is the second leading cause of cancer-related deaths in the United States, causing over 50,000 deaths each year. Sessile serrate colon adenoma/polyps (SSA/Ps) cause 20 to 30 percent of colon cancers. Routine screening colonoscopies help diagnose colon cancer by detecting polyps, but overlapping features make differentiating between malignant (SSA/P) and benign hyperplastic (HP) polyps difficult. In effect, patients falsely diagnosed with hyperplastic polyps fail to undergo necessary follow-on surveillance for colon cancer.
A newly derived panel of expressed genes distinguishes between SSA/Ps and HPs, and detects which polyps produce a higher risk of colon cancer. The seven gene panel includes twenty-eight markers associated with cancerous SSA/Ps, resulting in lower detection limits and higher sensitivity. The panel also acts as a more effective colon cancer screening method by identifying colon cancer inducing genes that were discovered via RNA-seq analysis. Improved polyp classification has immediate clinical and research significance, with the potential to become a gold standard diagnostic.
ACTIVATION PATTERN PERMUTATION COMPUTED TOMOGRAPHY OF CARDIAC CONDUCTION
Sudden cardiac death is often associated with arrhythmia, which affects over three million people each year in the United States. These patients are at increased risk of stroke, heart attack, heart failure, and sudden cardiac death. Risk of developing an arrhythmia can be determined through the identification of cardiac conduction abnormalities, but that method falls short of monitoring the health of the cardiac tissue itself.
Measuring the conduction velocity of electrical impulses through heart tissue determines the health of that tissue. A standard clinical loop catheter is used to extract longitudinal and transverse conduction velocities. These velocities are indicative of various disease states, providing clinicians with the exact location of diseased tissue to improve patient treatment plans. A map of where the diseased tissue resides in the heart is generated for reference during the procedures, enhancing the treatment of heart defects, such as atrial fibrillation.
PRACTICAL SMALL MOLECULE IMMUNOASSAY
Biomarker assays provide early detection and identification of disease, which enables timely delivery of individualized treatment strategies to patients. These assays also have the potential to track progression, regression, and recurrence of disease. Detection is typically achieved using an enzyme-linked immunosorbent assay platform, but such assays suffer from poor detection limits and a restricted dynamic range.
The small molecule immunoassay facilitates label-free analyte detection with antibodies. It utilizes two non-linear methods – enhanced second harmonic correlation spectroscopy and enhanced second harmonic imaging – for detection and identification of small molecules. Surface immobilized antibody arrays detect the small molecules, eliminating the need for a second antibody. The assay can be used for diagnostic testing, environmental screening, and drug screening.
DYE CARRIER FOR DIAGNOSTIC IMAGING OF BODY TISSUES
Fluorescence microscopy enables the study of molecular and morphologic changes in biological specimens with micrometer resolution, providing valuable diagnostic information. Fluorescence microscopy is difficult to use for examination of living tissue, however, because of the need for close association between microscope instrumentation and the imaged tissue, as well as the high concentration of fluorescent dyes required for microscopy.
A disposal dye carrier attached to imaging instruments allows physicians to diagnose tissue without extracting tissue from the body. The carrier consists of a foam-hydrogel composite filled with fluorescent dye. The carrier releases the dye to diffuse throughout the tissue to a depth of 1 mm. Dye release is controlled by the composition of the carrier. The carriers are designed to be used with in vivo imaging instruments which send and receive light to and from the dye to enable live tissue imaging during diagnostic and surgical procedures. The images provide clinicians with a map of the tissue microstructure.
ULTRASOUND-DRIVEN VESTIBULAR-EVOKED MYOGENIC DIAGNOSTIC TEST
The vestibular system is vital part of a person’s ability to balance. Almost 69 million Americans have experienced vestibular dysfunction. An additional 8 million American adults report a chronic problem with balance, while 2.5 million report a chronic problem with dizziness. Diagnosing vestibular dysfunction requires a series of expensive and invasive tests, such as vestibular evoked myogenic testing. These tests are often inaccurate and can cause patient discomfort.
The ultrasound driven vestibular-evoked myogenic diagnostic test uses focused ultrasound and infrared pulses to stimulate vestibular organs. These thermal pulses activate vestibular-evoked myogenic potentials in the neck and ocular muscles. The myogenic potentials are averaged over time to generate a waveform that represents vestibular organ function. The magnitude and latency of the stimulus-response is then used to diagnosis vestibular otolith function.
SENSITIVE ASSAY FOR 5α-DIHYDROTESTOSTERONE
Circulating androgen 5a-dihydrotestosterone (DHT) is a major indicator of benign prostatic hyperplasia, which affects over three million men each year in the United States and can lead to prostate cancer. Additionally, polycystic ovarian syndrome (PCOS), which affects 8-10 percent of women, is caused by elevated androgen concentrations. PCOS causes conditions ranging from type 2 diabetes to obesity and heart disease. Immunoassays for testosterone and other androgens, however, are often inaccurate due to analytical interference and inaccurate results at low concentrations.
A simple, high-throughput assay uses specific derivitizing agents to improve detection of keto-steroids, such as DHT. This method has enhanced ionization efficiency and can detect analytes at low concentration levels.
DIAGNOSTIC, PROGNOSTIC, AND THERAPEUTIC BIOMARKER FOR EWING’S SARCOMA
Ewing’s Sarcoma is an aggressive and highly metastatic bone or soft tissue associated tumor in children and young adults. These tumors frequently progress undetected until they metastasize, whereupon the mortality of the disease greatly increases. Many tumors develop resistance to current first-line treatments, yet no tool exists that distinguishes prior to treatment between resistant and sensitive tumors.
Glutathione-S-transferase M4 (GSTM4) has been identified as a major contributor to tumorigenesis and drug resistance in Ewing’s Sarcoma. Patients with higher levels of GSTM4 typically have worse treatment outcomes, meaning determination of GSTM4 expression levels should enable earlier diagnosis and serve as a predictor for patient outcomes. Furthermore, reduction of GSTM4 levels increases sensitivity of Ewing’s Sarcoma cells to chemotherapeutic agents and reduces oncogenic transformation.
MEASUREMENT OF TOTAL, FREE, AND AUTOANTIBODY-BOUND BIOMARKERS
The presence or absence of specific biomarkers can be predictive in the diagnosis of various conditions. The majority of diagnostic tests for quantitative measurement of biomarkers use immune-based techniques, which utilize detection antibodies. In individuals with autoimmune disorders, however, patient autoantibodies affect the immunoassay and cause inaccurate results or misdiagnosis.
The proposed method binds antibodies to specific analytes, converting all target analytes in the sample to antibody-bound form. This creates enriched fractions that facilitate more accurate measurement of biomarker concentration. This method has been used for quantification of total thyroglobulin in serum and plasma samples to detect recurrence of thyroid carcinoma. This approach can also be applied to other biomarkers where autoantibodies can adversely affect the assay used to detect the biomarker.
CORRECTING NONLINEAR CALIBRATION IN MASS SPECTROMETRY
Stable isotope labeled internal standards are widely used in mass spectrometry. Isotopic interference between signals of the internal standard and the analyte, however, causes nonlinear calibration, which limits the dynamic range and produces inaccurate assessments of analyte concentration.
Application of two equations to mass spectrometry expands the range of analysis by generating a more accurate fit and correcting the inherent bias for many analyte/internal standard pairs. This process allows for corrections to nonlinear data, enabling the use of analyte/internal standard combinations that would otherwise be impractical. This approach removes much of the difficulty associated with use of stable labeled internal standards, such as labeling, isotope effects, and cost.
TWO-ZONE FLOW-THROUGH PCR USING THIN FILMS
PCR is an inexpensive and robust technique for amplifying specific segments of DNA for gene analysis, DNA sequencing, DNA profiling, and diagnostic tests. The speed at which PCR can be performed depends on the time required to cycle through temperature dependent steps.
A novel PCR machine that combines a microfluidic card and simple thermal cycler performs PCR at extreme speeds by reducing cycling time to less than a second. Copper blocks surround the microfluidic consumable card to improve heat transfer and temperature control. This interaction reduces overall PCR time by enabling temperature equilibration in under 0.3 seconds. The device is more affordable than existing solutions and portable, facilitating use in point-of-care settings.
MYC-DRIVEN DIAGNOSTIC FOR SMALL CELL LUNG CANCER
Small cell lung cancer (SCLC) accounts for almost 30,000 deaths each year in the United States, with a two-year survival rate of less than six percent. Almost 40 percent of SCLC patients develop resistance to platinum-based chemotherapy, the current first-line treatment. Studies indicate that MYC amplification is associated with treatment resistance and poor outcomes, but little was known regarding how MYC impacts SCLC. Researchers at Huntsman Cancer Institute and the University of Utah have discovered that roughly 20 percent of SCLC patients develop a variant form of the disease, characterized by certain MYC-related biomarkers. The proposed technology detects variant SCLC by identifying the concentration of specific biomarkers in a patient. The technology can also be used to predict patient response to chemotherapy to help guide clinician decisions and improve patient outcomes.
FUNCTIONAL PROFILING OF THE MICROBIOME
Human gut microbiota play an important role in the immune system and de novo synthesis of essential vitamins. Little is known, however, about how gut microbiota influence overall health and disease. Functional Profiling of the Microbiome will aid researchers, physicians, and patients in understanding the role of gut microbiota in human health and wellness. The proposed technology provides a way to quickly and easily identify the enzyme activity present in a sample. Coupled with existing metagenomics, this functional profile will provide insight into the effect of diet and medication use on the gut and the relationships between microbial functionality and disease progression.
PERSONALIZED ALLELE-SPECIFIC EXPRESSION PROFILING RNA PROBE REAGENTS & ALGORITHMS
Understanding the allele-specific expression effects helps determine how inherited mutations may impact carriers and their offspring. Existing allele expression diagnostics, such as bacterial artificial chromosome (BAC) probes, only work on cultured cells, which increases the time required for testing.
The proposed invention uses in situ hybridization probes to detect allele specific expression in cells and tissues. Nuclear whole transcriptome RNA sequencing is used to provide an intron retention score from samples to resolve expression of target alleles. These tools can resolve epigenetic allelic effects, genomic imprinting and random X-inactivation to monitor health and disease progression, and detect disorders by profiling RNASeq data.
DIAGNOSTIC TOOL FOR MAJOR DEPRESSIVE DISORDER AND BIPOLAR DISORDER
Similar presenting symptoms make it difficult to distinguish between Bipolar Disorder (BD) and Major Depressive Disorder (MDD) leading nearly 70 percent of patients to be misdiagnosed initially. Incorrect diagnoses results in delays in appropriate treatment and increased costs to the healthcare system. Adolescents experience higher choline levels in the anterior cingulate cortex when suffering from MDD than BD. Magnetic Resonance Spectroscopy (MRS) provides information regarding the biochemistry of specific regions in the brain.
A novel algorithm, developed by researchers at the University of Utah, processes spectroscopic data to provide total choline levels, which can then differentiate between the two diseases. Additional scans can be used to assess efficacy of prescribed treatments for both diseases by comparing current choline levels to the patient’s initial scan and levels of healthy patients.
PERSONALIZED CANCER DIAGNOSTICS AND PROGNOSTICS
Diagnosis, prognosis, and treatment of solid tumors, such as glioblastoma (GBM) and ovarian serous cystadenocarcinoma (OV), has remained largely unchanged for decades, despite the increased availability of patient genomic data. Many tumors develop resistance to platinum-based drugs, the current first-line treatment, yet no tool exists that distinguishes between resistant and sensitive tumors prior to treatment.
This technology provides a computational assessment of cancer genomic profiles for personalized prognostics and drug companion diagnostics. Comparing patient data to proprietary signatures, the algorithm predicts patient response to chemotherapy. Predicting patient response to treatment helps guide clinician decisions and ultimately improves patient outcomes.
NOVEL SUBSTRATE FOR BLOOD-BASED METHYLATED DNA DIAGNOSTIC KITS
Use of blood-based methylated DNA biomarkers for screening of cancer and other diseases is growing. For example, screening for Septin 9 (SEPT9) methylated DNA in blood plasma facilitates the detection of colorectal cancer, since specific cytosine residues in SEPT9 are methylated in cancerous tissue but not in normal colon tissue. Accurately assessing methylation levels for methylated DNA biomarkers, however, requires a robust positive control. Typical screening assays rely on completely methylated genomic DNA from cell line sources that fail to represent naturally occurring patterns of methylated DNA accurately.
This novel biomarker assay uses the pooled plasma of pregnant women as a positive control substrate for SEPT9 biomarker assays. Pooled plasma of pregnant women can also potentially be used as a positive control substrate for other methylated oncofetal biomarkers.
DIAGNOSING BIPOLAR DISORDER USING MAGNETIC RESONANCE SPECTROSCOPY
Bipolar Disorder (BD) is the fourth leading cause of disability among young people ages 10 to 24 globally. BD severely impacts quality of life by causing shifts in mood, energy, behavior, and ability to function. Many people suffer for years before obtaining an accurate diagnosis. New evidence links mitochondrial dysfunction in the brain to Bipolar Disorder.
Indicators of mitochondrial function in the brain can be measured using 31- Phosphorus Magnetic Resonance Spectroscopy (31P-MRS). A novel algorithm that compares mitochondrial function, as determined by 31P- MRS scans, to normal levels provides objective and reliable diagnoses. Additional scans could assess efficacy of prescribed treatments by comparing current mitochondrial function to patients’ initial levels.