Publications by authors named "Gregory Cooper"

439 Publications

Obesity prevalence in celiac disease in the United States from 2014 to 2018.

Int J Obes (Lond) 2021 Nov 6. Epub 2021 Nov 6.

Division of Gastroenterology and Hepatology, Department of Medicine, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

Celiac disease (CD) is not commonly associated with obesity; however, many patients are overweight or obese at time of diagnosis. As the number of people in the United States with obesity continues to rise, it is not known if the prevalence of obesity among patients with CD has also increased. This study utilized an electronic health record database incorporating over 360 individual hospitals in the United States (Explorys Incorporated, Cleveland, OH). Adult patients who had an esophagogastroduodenoscopy at least 1 day prior to reporting of CD from the years 2014 to 2018 formed the study population. From 2014 to 2018, 13,410 patients had a diagnosis of CD. The prevalence of obesity was 45,000/100,000 persons in this CD population. Prevalence of class I (BMI 30-34.9), II (BMI 35-39.9), and III (BMI > 40) obesity in patients with CD continued to rise over the 5-year span. Class I obesity had the highest prevalence and Class II the highest prevalence increase when obesity classes were compared. Clinicians should be aware of obesity as a comorbidity of increasing prevalence when providing longitudinal care for patients with CD.
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http://dx.doi.org/10.1038/s41366-021-01008-9DOI Listing
November 2021

Irritable bowel syndrome is strongly associated with the primary and idiopathic mast cell disorders.

Neurogastroenterol Motil 2021 Sep 17:e14265. Epub 2021 Sep 17.

University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.

Background: Mounting evidence supports a mechanistic association between irritable bowel syndrome (IBS) symptoms and mast cell hyperactivity. Yet, association between IBS and mast cell disorders (MCDs) has not been studied. We examined this association using two large databases and verified with manual chart review.

Methods: The IBM Watson Health Explorys database (Somers, NY), an aggregate of electronic health record (EHR) data from over two dozen US healthcare systems, and Epic's SlicerDicer tool, a self-service tool containing de-identified data from the Epic EHR, were used to identify patients with IBS and MCDs. Patients with organic gastrointestinal disease or diseases associated with secondary mast cell hyperproliferation were excluded. Results were verified with manual chart review from two academic centers.

Key Results: Up to 4% of IBS patients had a comorbid MCD. IBS was strongly associated with all MCDs. The strongest association was between IBS and mast cell activation syndrome (OR 16.3; 95% CI 13.1-20.3). Odds ratios for IBS+urticaria, IBS+idiopathic urticaria, IBS+non-malignant mastocytosis, and IBS+mast cell malignancy ranged from 4.5 to 9.9. Patients from each of these overlap cohorts were predominantly female, and the overlap occurred with all IBS subtypes. Thorough endoscopic evaluation and comorbid mood disorders and migraines are more common in the overlap cohorts than in IBS alone.

Conclusions/inferences: In a large US database encompassing >53 million patients over >20 years, patients with IBS are at least 4 times more likely to have a MCD than the general population. Further study of mast cell involvement in the pathogenesis of IBS is warranted.
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http://dx.doi.org/10.1111/nmo.14265DOI Listing
September 2021

Epidemiology of neuroendocrine tumors of the appendix in the USA: a population-based national study (2014-2019).

Ann Gastroenterol 2021 Sep-Oct;34(5):713-720. Epub 2021 Jun 14.

Gastroenterology and Hepatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (Emad Mansoor, Gregory Cooper), USA.

Background: The appendix is the third most common place for neuroendocrine tumors (NETs) along the digestive tract and NETs are the most common neoplasms of the appendix. However, there are limited population-based data on the epidemiology of this disease. Using a large database, we sought to describe the epidemiology and risk association of NETs of the appendix.

Method: We queried a multi-institutional database (Explorys Inc., Cleveland, OH, USA), comprising 360 hospitals in the United States (US), for patients with a diagnosis of NETs of the appendix from 2014-2019.

Results: Of the 30,324,050 individuals in the database, 2020 patients had an appendiceal NET diagnosis (0.007%). The most common presenting symptoms included abdominal pain, nausea, vomiting and diarrhea. Patients with appendiceal NETs were more likely to be female (odds ratio [OR] 1.36, 95% confidence interval [CI] 1.24-1.49), Caucasian (OR 2.71, 95%CI 2.40-3.07), with a history of smoking (OR 1.82, 95%CI 1.65-2.01), family history of primary gastrointestinal malignancy (OR 7.26, 95%CI 6.31-8.33), diagnosis of multiple endocrine tumor type 1 (OR 52.31, 95%CI 23.15-118.23), or neurofibromatosis type 1 (OR 16.37, 95%CI 7.24-37.01).

Conclusions: In a population-based study in the US, using the Explorys database, we found the overall prevalence of NETs of the appendix to be 7 per 100,000 persons. The incidence in the year January 2019-January 2020 was 0.4 per 100,000 individuals. These rates are higher than previously reported and may be more accurate, given the more comprehensive nature of the Explorys database.
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http://dx.doi.org/10.20524/aog.2021.0643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375642PMC
June 2021

Evaluation of eye tracking for a decision support application.

JAMIA Open 2021 Jul 2;4(3):ooab059. Epub 2021 Aug 2.

Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Eye tracking is used widely to investigate attention and cognitive processes while performing tasks in electronic medical record (EMR) systems. We explored a novel application of eye tracking to collect training data for a machine learning-based clinical decision support tool that predicts which patient data are likely to be relevant for a clinical task. Specifically, we investigated in a laboratory setting the accuracy of eye tracking compared to manual annotation for inferring which patient data in the EMR are judged to be relevant by physicians. We evaluated several methods for processing gaze points that were recorded using a low-cost eye-tracking device. Our results show that eye tracking achieves accuracy and precision of 69% and 53%, respectively compared to manual annotation and are promising for machine learning. The methods for processing gaze points and scripts that we developed offer a first step in developing novel uses for eye tracking for clinical decision support.
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http://dx.doi.org/10.1093/jamiaopen/ooab059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327376PMC
July 2021

A simple electronic medical record system designed for research.

JAMIA Open 2021 Jul 31;4(3):ooab040. Epub 2021 Jul 31.

Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

With the extensive deployment of electronic medical record (EMR) systems, EMR usability remains a significant source of frustration to clinicians. There is a significant research need for software that emulates EMR systems and enables investigators to conduct laboratory-based human-computer interaction studies. We developed an open-source software package that implements the display functions of an EMR system. The user interface emphasizes the temporal display of vital signs, medication administrations, and laboratory test results. It is well suited to support research about clinician information-seeking behaviors and adaptive user interfaces in terms of measures that include task accuracy, time to completion, and cognitive load. The Simple EMR System is freely available to the research community and is on GitHub.
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http://dx.doi.org/10.1093/jamiaopen/ooab040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325484PMC
July 2021

Identifying 'win-win-win' futures from inequitable value chain trade-offs: A system dynamics approach.

Agric Syst 2021 May;190:103096

Digital Green, East India Office, Patna, India.

Context: There is growing recognition that food systems must adapt to become more sustainable and equitable. Consequently, in developing country contexts, there is increasing momentum away from traditional producer-facing value chain upgrades towards efforts to increase both the availability and affordability of nutritious foods at the consumer level. However, such goals must navigate the inherent complexities of agricultural value chains, which involve multiple interactions, feedbacks and unintended consequences, including important but often surprising trade-offs between producers and consumers.

Objective And Methods: Based around the 'Loop' horticultural aggregation scheme of Digital Green in Bihar, India, we develop a system dynamics modelling framework to survey the value chain trade-offs emerging from upgrades that aim to improve the availability of fruits and vegetables in small retail-oriented markets. We model the processes of horticultural production, aggregation, marketing, and retailing - searching for futures that are 'win-win-win' for: (i) the availability of fruits and vegetables in small retail markets, (ii) the profits of farmers participating in aggregation, and (iii) the sustainability of the initial scheme for Digital Green as an organisation. We simulate two internal upgrades to aggregation and two upgrades to the wider enabling environment through a series of 5000 Monte Carlo trajectories - designed to explore the plausible future dynamics of the three outcome dimensions relative to the baseline.

Results: We find that 'win-win-win' futures cannot be achieved by internal changes to the aggregation scheme alone, emerging under a narrow range of scenarios that boost supplies to the small retail market whilst simultaneously supporting the financial takeaways of farmers. In contrast, undesirable producer versus consumer trade-offs emerge as unintended consequences of scaling-up aggregation and the introduction of market-based cold storage.

Significance: This approach furthers ongoing efforts to capture complex value chain processes, outcomes and upgrades within system dynamics modelling frameworks, before scanning the horizon of plausible external scenarios, internal dynamics and unintended trade-offs to identify 'win-win-win' futures for all.
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http://dx.doi.org/10.1016/j.agsy.2021.103096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121761PMC
May 2021

Letter to the Editor: Characteristics of Liver Transplant Patients Admitted with COVID-19.

Gastroenterology 2021 09 18;161(3):1069-1070. Epub 2021 May 18.

Division of Gastroenterology and Liver Disease, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio.

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http://dx.doi.org/10.1053/j.gastro.2021.05.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129782PMC
September 2021

Infliximab-Induced Acute Liver Failure in a Patient With Crohn's Disease Requiring Orthotopic Liver Transplantation.

ACG Case Rep J 2021 May 14;8(5):e00586. Epub 2021 May 14.

Division of Gastroenterology and Liver Disease, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH.

Tumor necrosis factor-alpha inhibitors are not known to have significant liver toxicity; however, a few case reports state otherwise. We report the case of a 25-year-old man with Crohn's disease who was initiated on infliximab. The patient developed severe mixed hepatocellular and cholestatic liver injury that progressed into acute liver failure. Based on clinical history, laboratory findings, and histology, this was presumed because of the development of autoimmune hepatitis secondary to infliximab. He underwent liver transplantation. The mainstay of treatment in this rare condition involves steroid therapy and possible transplantation. Patients must then avoid anti-tumor necrosis factor-alpha therapy for life.
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http://dx.doi.org/10.14309/crj.0000000000000586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126550PMC
May 2021

Bayesian network models with decision tree analysis for management of childhood malaria in Malawi.

BMC Med Inform Decis Mak 2021 05 17;21(1):158. Epub 2021 May 17.

Intelligent Systems Program, University of Pittsburgh, 5108 Sennott Square, 210 South Bouquet Street, Pittsburgh, PA, 15260, USA.

Background: Malaria is a major cause of death in children under five years old in low- and middle-income countries such as Malawi. Accurate diagnosis and management of malaria can help reduce the global burden of childhood morbidity and mortality. Trained healthcare workers in rural health centers manage malaria with limited supplies of malarial diagnostic tests and drugs for treatment. A clinical decision support system that integrates predictive models to provide an accurate prediction of malaria based on clinical features could aid healthcare workers in the judicious use of testing and treatment. We developed Bayesian network (BN) models to predict the probability of malaria from clinical features and an illustrative decision tree to model the decision to use or not use a malaria rapid diagnostic test (mRDT).

Methods: We developed two BN models to predict malaria from a dataset of outpatient encounters of children in Malawi. The first BN model was created manually with expert knowledge, and the second model was derived using an automated method. The performance of the BN models was compared to other statistical models on a range of performance metrics at multiple thresholds. We developed a decision tree that integrates predictions with the costs of mRDT and a course of recommended treatment.

Results: The manually created BN model achieved an area under the ROC curve (AUC) equal to 0.60 which was statistically significantly higher than the other models. At the optimal threshold for classification, the manual BN model had sensitivity and specificity of 0.74 and 0.42 respectively, and the automated BN model had sensitivity and specificity of 0.45 and 0.68 respectively. The balanced accuracy values were similar across all the models. Sensitivity analysis of the decision tree showed that for values of probability of malaria below 0.04 and above 0.40, the preferred decision that minimizes expected costs is not to perform mRDT.

Conclusion: In resource-constrained settings, judicious use of mRDT is important. Predictive models in combination with decision analysis can provide personalized guidance on when to use mRDT in the management of childhood malaria. BN models can be efficiently derived from data to support clinical decision making.
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http://dx.doi.org/10.1186/s12911-021-01514-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130361PMC
May 2021

Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.

Am J Hum Genet 2021 05;108(5):857-873

GeneDx, Gaithersburg, MD 20877, USA.

The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206167PMC
May 2021

Long-read genome sequencing for the molecular diagnosis of neurodevelopmental disorders.

HGG Adv 2021 Apr 16;2(2). Epub 2021 Jan 16.

HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.

Exome and genome sequencing have proven to be effective tools for the diagnosis of neurodevelopmental disorders (NDDs), but large fractions of NDDs cannot be attributed to currently detectable genetic variation. This is likely, at least in part, a result of the fact that many genetic variants are difficult or impossible to detect through typical short-read sequencing approaches. Here, we describe a genomic analysis using Pacific Biosciences circular consensus sequencing (CCS) reads, which are both long (>10 kb) and accurate (>99% bp accuracy). We used CCS on six proband-parent trios with NDDs that were unexplained despite extensive testing, including genome sequencing with short reads. We identified variants and created assemblies in each trio, with global metrics indicating these datasets are more accurate and comprehensive than those provided by short-read data. In one proband, we identified a likely pathogenic (LP), L1-mediated insertion in that results in duplication of exon 3, leading to a frameshift. In a second proband, we identified multiple large structural variants, including insertion-translocations affecting and , which we show disrupt transcript levels. We consider this extensive structural variation likely pathogenic. The breadth and quality of variant detection, coupled to finding variants of clinical and research interest in two of six probands with unexplained NDDs, support the hypothesis that long-read genome sequencing can substantially improve rare disease genetic discovery rates.
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http://dx.doi.org/10.1016/j.xhgg.2021.100023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087252PMC
April 2021

Patient-Specific Modeling with Personalized Decision Paths.

AMIA Annu Symp Proc 2020 25;2020:602-611. Epub 2021 Jan 25.

Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA.

Predictive models can be useful in predicting patient outcomes under uncertainty. Many algorithms employ "population" methods, which optimize a single model to perform well on average over an entire population, but the model may perform poorly on some patients. Personalized methods optimize predictive performance for each patient by tailoring the model to the individual. We present a new personalized method based on decision trees: the Personalized Decision Path using a Bayesian score (PDP-Bay). Performance on eight synthetic, genomic, and clinical datasets was compared to that of decision trees and a previously described personalized decision path method in terms of area under the ROC curve (AUC) and expected calibration error (ECE). Model complexity was measured by average path length. The PDP-Bay model outperformed the decision tree in terms of both AUC and ECE. The results support the conclusion that personalization may achieve better predictive performance and produce simpler models than population approaches.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075540PMC
June 2021

Dietary inflammatory index and risk of colorectal adenoma: effect measure modification by race, nonsteroidal anti-inflammatory drugs, cigarette smoking and body mass index?

Cancer Causes Control 2021 Aug 29;32(8):837-847. Epub 2021 Apr 29.

Department of Family Medicine, University of Virginia School of Medicine, McKim Hall Rm 3156, Charlottesville, VA, 22908, USA.

Purpose: To investigate if the association between dietary inflammatory potential and colorectal adenoma (CRA) is modified by race and factors known to modulate inflammation.

Methods: We examined effect measure modification of race, nonsteroidal anti-inflammatory drugs (NSAIDs), cigarette smoking and body mass index (BMI) on the diet-CRA association by employing energy-adjusted dietary inflammatory index (E-DII™) to characterize dietary inflammatory potential among 587 cases and 1,313 controls participating in a colonoscopy screening-based cross-sectional study of CRA. Participants completed a food frequency questionnaire from which E-DII score was derived. E-DII score was calculated from 34 food parameters (constituents), utilizing an energy-adjusted global comparative database to compute z scores from which centered proportions were summed to create the score. CRA cases were defined as individuals whose colonoscopy detected at least one pathologically confirmed adenomatous polyp. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: A pro-inflammatory diet was not statistically significantly associated with elevated CRA risk (OR 1.07; 95% CI 0.97-1.19; p value = 0.18) in the multivariate regression model. NSAIDs use (OR 1.19; 95% CI 1.03-1.38; OR 0.96; 95% CI 0.83-1.12; P = 0.04) and race (OR 1.22; 95% CI 1.03-1.44; OR 0.99; 95% CI 0.86-1.14; P = 0.14) appeared to modify the association, whereas cigarette smoking and BMI did not (P = 0.40 and 0.78, respectively).

Conclusion: NSAIDs use and race may modify the diet-CRA association. Further investigation in prospective cohort studies is warranted to confirm these findings.
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http://dx.doi.org/10.1007/s10552-021-01436-yDOI Listing
August 2021

Receipt of Serial Endoscopy Procedures Prior to Esophageal Adenocarcinoma Diagnosis Is Associated with Better Survival.

Dig Dis Sci 2021 Apr 21. Epub 2021 Apr 21.

Division of Gastroenterology and Liver Disease, Department of Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue Mailstop 5066, Cleveland, OH, 44106-5066, USA.

Background: The poor prognosis of esophageal adenocarcinoma (EAC) has focused efforts on early detection by serial endoscopic surveillance of Barrett's esophagus (BE). Previously, we reported that receipt of endoscopy before EAC diagnosis was associated with improved survival.

Aim: We aimed to refine our previous analysis, assessing surveillance as measured by performance of serial endoscopy before EAC diagnosis and evaluating its association with stage and survival.

Methods: A retrospective cohort study was performed using the Surveillance, Epidemiology and End Results-Medicare database. Patients aged ≥ 70 years with EAC diagnosed during 1998-2009 were identified. Diagnosis with BE and receipt of ≥ 2 upper endoscopic procedures within 5 years before cancer diagnosis were identified. We compared a reference group not receiving serial endoscopy to 3 patterns based on ≥ 2 endoscopy dates relative to a timepoint 2 years before cancer diagnosis: "remote," "recent," and "sustained."

Results: Among 5532 patients, 28% (n = 1,575) had localized stage. Thirteen percent (n = 703) received ≥ 2 endoscopic procedures before cancer diagnosis: 224, 298, and 181 in the "recent," "remote," and "sustained" groups. Serial endoscopy and prior BE were associated with localized stage ("sustained" group OR 2.95, 95% confidence interval [CI] 2.07, 4.19; prior BE OR 2.68, 95% CI 2.03, 3.56). Serial endoscopy was associated with improved survival even with adjustment for lead time bias ("sustained" group HR 0.45, 95% CI 0.37, 0.55) and length time bias.

Conclusions: Sustained endoscopy was associated with earlier stage and improved survival. These results support the role of sustained surveillance in early detection of EAC.
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http://dx.doi.org/10.1007/s10620-021-06927-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528889PMC
April 2021

Genome-wide strand asymmetry in massively parallel reporter activity favors genic strands.

Genome Res 2021 May 20;31(5):866-876. Epub 2021 Apr 20.

HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA.

Massively parallel reporter assays (MPRAs) are useful tools to characterize regulatory elements in human genomes. An aspect of MPRAs that is not typically the focus of analysis is their intrinsic ability to differentiate activity levels for a given sequence element when placed in both of its possible orientations relative to the reporter construct. Here, we describe pervasive strand asymmetry of MPRA signals in data sets from multiple reporter configurations in both published and newly reported data. These effects are reproducible across different cell types and in different treatments within a cell type and are observed both within and outside of annotated regulatory elements. From elements in gene bodies, MPRA strand asymmetry favors the sense strand, suggesting that function related to endogenous transcription is driving the phenomenon. Similarly, we find that within mobile element insertions, strand asymmetry favors the transcribed strand of the ancestral retrotransposon. The effect is consistent across the multiplicity of elements in human genomes and is more pronounced in less diverged elements. We find sequence features driving MPRA strand asymmetry and show its prediction from sequence alone. We see some evidence for RNA stabilization and transcriptional activation mechanisms and hypothesize that the effect is driven by natural selection favoring efficient transcription. Our results indicate that strand asymmetry is a pervasive and reproducible feature in MPRA data. More importantly, the fact that MPRA asymmetry favors naturally transcribed strands suggests that it stems from preserved biological functions that have a substantial, global impact on gene and genome evolution.
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http://dx.doi.org/10.1101/gr.270751.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092006PMC
May 2021

Impact of the Coronavirus Disease 2019 Pandemic on Gastrointestinal Procedures and Cancers in the United States: A Multicenter Research Network Study.

Gastroenterology 2021 06 1;160(7):2602-2604.e5. Epub 2021 Mar 1.

Division of Gastroenterology & Hepatology, West Virginia University, Morgantown, West Virginia. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2021.02.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919513PMC
June 2021

Modeling physician variability to prioritize relevant medical record information.

JAMIA Open 2020 Dec 31;3(4):602-610. Epub 2020 Dec 31.

Intelligent Systems Program, School of Computing and Information, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Objective: Patient information can be retrieved more efficiently in electronic medical record (EMR) systems by using machine learning models that predict which information a physician will seek in a clinical context. However, information-seeking behavior varies across EMR users. To explicitly account for this variability, we derived hierarchical models and compared their performance to nonhierarchical models in identifying relevant patient information in intensive care unit (ICU) cases.

Materials And Methods: Critical care physicians reviewed ICU patient cases and selected data items relevant for presenting at morning rounds. Using patient EMR data as predictors, we derived hierarchical logistic regression (HLR) and standard logistic regression (LR) models to predict their relevance.

Results: In 73 pairs of HLR and LR models, the HLR models achieved an area under the receiver operating characteristic curve of 0.81, 95% confidence interval (CI) [0.80-0.82], which was statistically significantly higher than that of LR models (0.75, 95% CI [0.74-0.76]). Further, the HLR models achieved statistically significantly lower expected calibration error (0.07, 95% CI [0.06-0.08]) than LR models (0.16, 95% CI [0.14-0.17]).

Discussion: The physician reviewers demonstrated variability in selecting relevant data. Our results show that HLR models perform significantly better than LR models with respect to both discrimination and calibration. This is likely due to explicitly modeling physician-related variability.

Conclusion: Hierarchical models can yield better performance when there is physician-related variability as in the case of identifying relevant information in the EMR.
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http://dx.doi.org/10.1093/jamiaopen/ooaa058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886572PMC
December 2020

Barriers to Follow-Up Colonoscopy After Positive FIT or Multitarget Stool DNA Testing.

J Am Board Fam Med 2021 Jan-Feb;34(1):61-69

From the Division of Gastroenterology, University Hospitals Cleveland Medical Center, Cleveland OH (GSC, AG); Center for Community Health Integration and Department of Family Medicine, Case Western Reserve University, Cleveland OH (JW, KCS); Department of Population and Quantitative Health, Case Western Reserve University, Cleveland OH (SC, PF); and the Case Comprehensive Cancer Center, Cleveland OH (GSC, JW, PF, KCS).

Background: Fecal immunochemical testing (FIT) and multi-target stool DNA testing (mt-sDNA) are recommended colorectal cancer screening options but require follow-up with colonoscopy to determine the source of a positive result. We performed a retrospective analysis in an academic health system to determine adherence to colonoscopy in these patients.

Methods: We identified all patients aged 40 years and older with at least 1 primary care visit who had a positive FIT or mt-sDNA between January 2016 and June 2018. We identified receipt of colonoscopy within 6 months of the positive test and reviewed medical records to determine reasons for lack of colonoscopy.

Results: We identified 308 eligible patients with positive FIT and 323 with positive mt-sDNA. Some patients with positive FIT (46.7%) and patients with positive mt-sDNA (71.5%) underwent colonoscopy within 6 months, and time to colonoscopy was also shorter with mt-sDNA (hazard ratio, 1.83; 95% CI, 1.48-2.25). These differences remained in a multivariable model adjusting for patient characteristics. Among patients without colonoscopy after positive FIT, 1 or more system, provider, and patient-related barriers were identified in 32.1%, 57.6%, and 36.3%, respectively. Among patients without colonoscopy after positive mt-sDNA, corresponding frequencies were 30.4%, 43.5%, and 57.6%, respectively.

Conclusions: Follow-up colonoscopy was higher for mt-sDNA than FIT, which could be due in part to preselection by clinicians and/or patients. Among patients who did not follow-up, provider and system factors were as frequently encountered as patient factors. These findings reinforce the need for multi-level interventions to improve follow-up.
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http://dx.doi.org/10.3122/jabfm.2021.01.200345DOI Listing
August 2021

Aberrant regulation of a poison exon caused by a non-coding variant in a mouse model of Scn1a-associated epileptic encephalopathy.

PLoS Genet 2021 01 7;17(1):e1009195. Epub 2021 Jan 7.

HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States of America.

Dravet syndrome (DS) is a developmental and epileptic encephalopathy that results from mutations in the Nav1.1 sodium channel encoded by SCN1A. Most known DS-causing mutations are in coding regions of SCN1A, but we recently identified several disease-associated SCN1A mutations in intron 20 that are within or near to a cryptic and evolutionarily conserved "poison" exon, 20N, whose inclusion is predicted to lead to transcript degradation. However, it is not clear how these intron 20 variants alter SCN1A expression or DS pathophysiology in an organismal context, nor is it clear how exon 20N is regulated in a tissue-specific and developmental context. We address those questions here by generating an animal model of our index case, NM_006920.4(SCN1A):c.3969+2451G>C, using gene editing to create the orthologous mutation in laboratory mice. Scn1a heterozygous knock-in (+/KI) mice exhibited an ~50% reduction in brain Scn1a mRNA and Nav1.1 protein levels, together with characteristics observed in other DS mouse models, including premature mortality, seizures, and hyperactivity. In brain tissue from adult Scn1a +/+ animals, quantitative RT-PCR assays indicated that ~1% of Scn1a mRNA included exon 20N, while brain tissue from Scn1a +/KI mice exhibited an ~5-fold increase in the extent of exon 20N inclusion. We investigated the extent of exon 20N inclusion in brain during normal fetal development in RNA-seq data and discovered that levels of inclusion were ~70% at E14.5, declining progressively to ~10% postnatally. A similar pattern exists for the homologous sodium channel Nav1.6, encoded by Scn8a. For both genes, there is an inverse relationship between the level of functional transcript and the extent of poison exon inclusion. Taken together, our findings suggest that poison exon usage by Scn1a and Scn8a is a strategy to regulate channel expression during normal brain development, and that mutations recapitulating a fetal-like pattern of splicing cause reduced channel expression and epileptic encephalopathy.
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http://dx.doi.org/10.1371/journal.pgen.1009195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790302PMC
January 2021

Racial Disparities in Epigenetic Aging of the Right vs Left Colon.

J Natl Cancer Inst 2020 Dec 30. Epub 2020 Dec 30.

Department of Family Medicine, University of Virginia, Charlottesville, VA.

There are well-documented racial differences in age-of-onset and laterality of colorectal cancer. Epigenetic age acceleration is postulated to be an underlying factor. However, comparative studies of side-specific colonic tissue epigenetic aging are lacking. Here, we performed DNA methylation analysis of matched right and left biopsies of normal colon from 128 individuals. Among African Americans (n = 88), the right colon showed accelerated epigenetic aging as compared to individual-matched left colon (1.51 years; 95% CI = 0.62 to 2.40 years; two-sided P = .001). In contrast, among European Americans (n = 40), the right colon shows remarkable age deceleration (1.93 years; 95% CI = 0.65 to 3.21 years; two-sided P = .004). Further, epigenome-wide analysis of DNA methylation identifies a unique pattern of hypermethylation in African American right colon. Our study is the first to report such race and side-specific differences in epigenetic aging of normal colon, providing novel insight into the observed younger age-of-onset and relative preponderance of right-side colon neoplasia in African Americans.
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http://dx.doi.org/10.1093/jnci/djaa206DOI Listing
December 2020

A state-based approach to genomics for rare disease and population screening.

Genet Med 2021 04 27;23(4):777-781. Epub 2020 Nov 27.

School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Purpose: The Alabama Genomic Health Initiative (AGHI) is a state-funded effort to provide genomic testing. AGHI engages two distinct cohorts across the state of Alabama. One cohort includes children and adults with undiagnosed rare disease; a second includes an unselected adult population. Here we describe findings from the first 176 rare disease and 5369 population cohort AGHI participants.

Methods: AGHI participants enroll in one of two arms of a research protocol that provides access to genomic testing results and biobank participation. Rare disease cohort participants receive genome sequencing to identify primary and secondary findings. Population cohort participants receive genotyping to identify pathogenic and likely pathogenic variants for actionable conditions.

Results: Within the rare disease cohort, genome sequencing identified likely pathogenic or pathogenic variation in 20% of affected individuals. Within the population cohort, 1.5% of individuals received a positive genotyping result. The rate of genotyping results corroborated by reported personal or family history varied by gene.

Conclusions: AGHI demonstrates the ability to provide useful health information in two contexts: rare undiagnosed disease and population screening. This utility should motivate continued exploration of ways in which emerging genomic technologies might benefit broad populations.
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http://dx.doi.org/10.1038/s41436-020-01034-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311654PMC
April 2021

Epidemiology of Autoimmune Hepatitis (AIH) in the United States Between 2014 and 2019: A Population-based National Study.

J Clin Gastroenterol 2021 Nov-Dec 01;55(10):903-910

Department of Internal Medicine and Division of Gastroenterology and Liver Disease, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, OH.

Background And Aims: Autoimmune hepatitis (AIH) is a chronic, inflammatory disease of the liver with increasing prevalence. However, limited epidemiological data exist for the prevalence of AIH in the United States. We used a large database to describe the prevalence of AIH in the United States and the autoimmune diseases associated with it.

Approach And Results: Data was collected from a commercial database (Explorys Inc., Cleveland, OH), an aggregate of Electronic Health Record data from 26 major integrated health care systems in the United States. We identified a cohort of patients with a diagnosis of AIH from April 2014 to April 2019 based on a Systemized Nomenclature of Medicine-Clinical Terms and calculated the prevalence of AIH. Of the 37,161,280 individuals active in the database from April 2014 to 2019, we identified 11,600 individuals with a diagnosis of AIH with an overall prevalence rate of 31.2/100,000. The prevalence of AIH was increased in females compared with males [odds ratio (OR)=3.21, P<0.0001], elderly (aged above 65 y) compared with adults (aged 18 to 65 y) and children (aged below 18 y) (OR=2.51, P<0.0001) and whites compared with African Americans, Asians, and Hispanics (OR=1.12, P<0.0001). Moreover, patients with AIH were more likely to have Sjögren syndrome, systemic lupus erythematosus, ulcerative colitis, celiac disease, rheumatoid arthritis, Crohn's disease, and autoimmune thyroiditis as compared with patients without AIH.

Conclusions: We found that the estimated prevalence of AIH in the United States is 31.2/100,000, which is comparable to the reported prevalence of AIH in Europe. We confirmed that AIH has a strong association with other autoimmune diseases studied in the literature.
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http://dx.doi.org/10.1097/MCG.0000000000001449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050120PMC
October 2021

Rates of Intestinal Resection and Colectomy in Inflammatory Bowel Disease Patients After Initiation of Biologics: A Cohort Study.

Clin Gastroenterol Hepatol 2020 Oct 14. Epub 2020 Oct 14.

Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic Foundation, Cleveland, Ohio. Electronic address:

Background & Aims: 50% to 80% Crohn's disease (CD) and 10% to 30% ulcerative colitis (UC) patients require surgery over their lifetime. Biologic therapies may alter this natural history, but data on the effect of biologics on surgery rates in this patient population are mixed. We sought to investigate the influence of biologics on surgery prevalence in CD and UC.

Methods: We used a commercial database (Explorys Inc, Cleveland, OH), which includes electronic health record data from 26 major integrated US healthcare systems. We identified all patients who were diagnosed with CD or UC that were treated with any biologics between 2015 and 2020. The primary outcome was to examine the association between biologics therapy and the prevalence of bowel resection. Also, we identified the factors associated with surgery in IBD patients on biologics.

Results: Of 32,904,480 patients in the database, we identified 140,540 patients with CD and 115,260 patients with UC, of whom 25,840 (18%) and 9,050 (7.8%) patients received biologics, respectively. The prevalence of intestinal resection was significantly lower in biologics-treated CD patients (9.3%) compared to those who did not receive biologics (12.1%) (p < .001). Similarly, biologic-treated UC patients were significantly less likely to undergo colectomy (7.3%) compared to UC patients who did not receive biologic therapy (11.0%) (p < .001). Tobacco use, Clostridium difficile infection, and perianal disease were associated with intestinal resection in CD. Colon neoplasm and Clostridium difficile infection were associated with colectomy in UC.

Conclusions: In this study of a large healthcare administrative database, inflammatory bowel disease (IBD) patients treated with biologics were significantly less likely to undergo bowel resection when compared to those who never received biologics. This data suggests that biologics may impact surgical rates in IBD.
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http://dx.doi.org/10.1016/j.cgh.2020.10.008DOI Listing
October 2020

Graphical Presentations of Clinical Data in a Learning Electronic Medical Record.

Appl Clin Inform 2020 08 14;11(4):680-691. Epub 2020 Oct 14.

Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.

Background: Complex electronic medical records (EMRs) presenting large amounts of data create risks of cognitive overload. We are designing a Learning EMR (LEMR) system that utilizes models of intensive care unit (ICU) physicians' data access patterns to identify and then highlight the most relevant data for each patient.

Objectives: We used insights from literature and feedback from potential users to inform the design of an EMR display capable of highlighting relevant information.

Methods: We used a review of relevant literature to guide the design of preliminary paper prototypes of the LEMR user interface. We observed five ICU physicians using their current EMR systems in preparation for morning rounds. Participants were interviewed and asked to explain their interactions and challenges with the EMR systems. Findings informed the revision of our prototypes. Finally, we conducted a focus group with five ICU physicians to elicit feedback on our designs and to generate ideas for our final prototypes using participatory design methods.

Results: Participating physicians expressed support for the LEMR system. Identified design requirements included the display of data essential for every patient together with diagnosis-specific data and new or significantly changed information. Respondents expressed preferences for fishbones to organize labs, mouseovers to access additional details, and unobtrusive alerts minimizing color-coding. To address the concern about possible physician overreliance on highlighting, participants suggested that non-highlighted data should remain accessible. Study findings led to revised prototypes, which will inform the development of a functional user interface.

Conclusion: In the feedback we received, physicians supported pursuing the concept of a LEMR system. By introducing novel ways to support physicians' cognitive abilities, such a system has the potential to enhance physician EMR use and lead to better patient outcomes. Future plans include laboratory studies of both the utility of the proposed designs on decision-making, and the possible impact of any automation bias.
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http://dx.doi.org/10.1055/s-0040-1709707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560537PMC
August 2020

Epidemiology of Diverticulitis and Prevalence of First-Ever Colorectal Cancer Postdiverticulitis in Adults in the United States: A Population-Based National Study.

Dis Colon Rectum 2021 02;64(2):181-189

Division of Gastroenterology and Liver Disease, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio.

Background: The incidence of acute diverticulitis is increasing, and previous studies showed a wide range of prevalence of colorectal cancer after diverticulitis. There is a lack of high-quality evidence to support performing colonoscopy after diverticulitis.

Objective: We aimed to describe the incidence of first-ever diverticulitis and prevalence of first-ever colorectal cancer postdiverticulitis in the United States.

Design: This is a retrospective cohort study.

Settings: We queried a national database that contains data from 26 major integrated healthcare systems in the United States.

Patients: We identified an aggregated patient cohort aged ≥18 years with a diagnosis of first-ever diverticulitis from February 2015 to February 2020, followed by first-ever colorectal cancer diagnosis, at least 1 day after and within 1 year of diverticulitis.

Main Outcome Measures: The incidence of first-ever diverticulitis was calculated. The prevalence and OR of first-ever colorectal cancer after diverticulitis were analyzed.

Results: Among 31,778,290 individuals, we found the incidence of first-ever acute diverticulitis to be 2.9%. The prevalence of colorectal cancer within 1 year of first-ever acute diverticulitis was 0.57%, whereas the prevalence of colorectal cancer without a history of diverticulitis was 0.31% (OR = 1.8 (95% CI, 1.76-1.86)). The majority (92.3%) of the postdiverticulitis colorectal cancer were diagnosed within the first 6 months. The risk of colorectal cancer postdiverticulitis was higher in women (OR = 1.9), African Americans (OR = 2.0), and adults aged 18 to 65 years (OR = 2.3).

Limitations: We are unable to validate the diagnostic code because patient information in our database is deidentified.

Conclusions: Individuals are twice as likely to be diagnosed with colorectal cancer within 1 year of their first episode of acute diverticulitis compared with individuals without diverticulitis. We advocate for colonoscopy after the first occurrence of acute diverticulitis to screen for colorectal cancer, particularly for patients without a recent colonoscopy. See Video Abstract at http://links.lww.com/DCR/B412.

Epidemiologa De La Diverticulitis Y Prevalencia Del Cncer Colorrectal Posterior A La Diverticulitis En Adultos En Los Estados Unidos Un Estudio Nacional Basado En La Poblacin: ANTECEDENTES:La incidencia de diverticulitis aguda está aumentando y los estudios anteriores mostraron una amplia gama de prevalencia de cáncer colorrectal después de diverticulitis. Hay una falta de evidencia de alta calidad para apoyar la realización de una colonoscopia después de la diverticulitis.OBJETIVOS:Nuestro objetivo fue describir la incidencia de la primera diverticulitis y la prevalencia del cáncer colorrectal posterior a la primera diverticulitis en los Estados Unidos.DISEÑO:Este es un estudio de cohorte retrospectivo.AJUSTES:Consultamos una base de datos nacional que contiene datos de 26 sistemas de salud integrados importantes en los Estados Unidos.PACIENTES:Identificamos una cohorte agregada de pacientes mayores de 18 años con un diagnóstico de diverticulitis por primera vez entre febrero de 2015 y febrero de 2020, seguido de un diagnóstico de cáncer colorrectal por primera vez, al menos 1 día después y dentro de 1 año de diverticulitis.PRINCIPALES MEDIDAS DE RESULTADO:Se calculó la incidencia de la primer diverticulitis. Se analizaron la prevalencia y el odds ratio del primer CCR después de la diverticulitis.RESULTADOS:Entre 31,778,290 individuos, encontramos que la incidencia de la primera diverticulitis aguda fue del 2.9%. La prevalencia de cáncer colorrectal dentro de 1 año de la primera diverticulitis aguda fue del 0,57%, mientras que la prevalencia del cáncer colorrectal sin antecedentes de diverticulitis fue del 0,31% (OR 1,8; IC del 95%: 1,76-1,86). La mayoría (92,3%) de los pacientes con cáncer colorrectal posterior a diverticulitis se diagnosticaron dentro de los primeros 6 meses. El riesgo de CCR después de diverticulitis fue mayor en mujeres (OR 1,9), afroamericanos (OR 2,0) y adultos de 18 a 65 años (OR 2,3).LIMITACIONES:No podemos validar el código de diagnóstico debido a que la información del paciente en nuestra base de datos no está identificada.CONCLUSIONES:Las personas tienen el doble de probabilidades de ser diagnosticadas con cáncer colorrectal dentro del primer año de su primer episodio de diverticulitis aguda en comparación con las personas sin diverticulitis. Abogamos por la colonoscopia después de la primera aparición de diverticulitis aguda para detectar cáncer colorrectal, particularmente en pacientes sin una colonoscopia reciente. Consulte Video Resumenhttp://links.lww.com/DCR/B412. (Traducción-Dr Gonzalo Hagerman).
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http://dx.doi.org/10.1097/DCR.0000000000001837DOI Listing
February 2021

NCCN Guidelines Insights: Colorectal Cancer Screening, Version 2.2020.

J Natl Compr Canc Netw 2020 10 1;18(10):1312-1320. Epub 2020 Oct 1.

National Comprehensive Cancer Network.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age to initiate screening in average risk individuals and follow-up for low-risk adenomas.
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http://dx.doi.org/10.6004/jnccn.2020.0048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311627PMC
October 2020

Identifying rare, medically relevant variation via population-based genomic screening in Alabama: opportunities and pitfalls.

Genet Med 2021 02 29;23(2):280-288. Epub 2020 Sep 29.

HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.

Purpose: To evaluate the effectiveness and specificity of population-based genomic screening in Alabama.

Methods: The Alabama Genomic Health Initiative (AGHI) has enrolled and evaluated 5369 participants for the presence of pathogenic/likely pathogenic (P/LP) variants using the Illumina Global Screening Array (GSA), with validation of all P/LP variants via Sanger sequencing in a CLIA-certified laboratory before return of results.

Results: Among 131 variants identified by the GSA that were evaluated by Sanger sequencing, 67 (51%) were false positives (FP). For 39 of the 67 FP variants, a benign/likely benign variant was present at or near the targeted P/LP variant. Variants detected within African American individuals were significantly enriched for FPs, likely due to a higher rate of nontargeted alternative alleles close to array-targeted P/LP variants.

Conclusion: In AGHI, we have implemented an array-based process to screen for highly penetrant genetic variants in actionable disease genes. We demonstrate the need for clinical validation of array-identified variants in direct-to-consumer or population testing, especially for diverse populations.
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http://dx.doi.org/10.1038/s41436-020-00976-zDOI Listing
February 2021

Colorectal Cancer, Age, and Obesity-Related Comorbidities: A Large Database Study.

Dig Dis Sci 2021 09 21;66(9):3156-3163. Epub 2020 Sep 21.

Division of Gastroenterology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Wearn 244, Cleveland, OH, 44106-5066, USA.

Background And Aims: The association between obesity and colorectal cancer (CRC) is well established in older individuals, but evidence is limited in the younger population. The study aims to analyze the relationship of obesity and its related comorbidities in early-onset CRC (E-CRC) and compare it to late-onset CRC (L-CRC).

Methods: A retrospective, cross-sectional study was performed on average-risk individuals ≥ 20 years who were active patients in the commercial database, IBM Watson Health Explorys in the last 5 years. Individuals with CRC were compared to those without CRC across different age groups (20-39, 40-49, and 50-74 years). Individuals with CRC diagnosed < 50 years (E-CRC) were compared to those with CRC between 50 and 74 years (L-CRC). Variables included sex, smoking, obese BMI, diabetes mellitus type 2 (DM2), hypertension (HTN), and hyperlipidemia (HLD). Since Explorys aggregates population-level, de-identified data, approval from institutional review board was not required.

Results: Among 37,483,140 individuals, 162,150 cases of sporadic CRC were identified. Compared to the general population, obesity and HLD were independent risk factors for CRC across all age groups; DM2, HTN, and smoking were independent risk factors for CRC in men of all age groups and women with L-CRC. Compared to L-CRC, individuals with E-CRC had lower percentages of obesity-related comorbidities.

Conclusion: In E-CRC, obesity, DM2, HTN, HLD, and smoking are independent risk factors for CRC among men; obesity and HLD are independent risk factors for CRC in women. These subgroups may benefit from a personalized screening approach to detect early-onset CRC.
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http://dx.doi.org/10.1007/s10620-020-06602-xDOI Listing
September 2021

Explicit representation of protein activity states significantly improves causal discovery of protein phosphorylation networks.

BMC Bioinformatics 2020 Sep 17;21(Suppl 13):379. Epub 2020 Sep 17.

Department of Biomedical Informatics, University of Pittsburgh, 5607 Baum Blvd, Suite 500, Pittsburgh, PA, 15206, USA.

Background: Protein phosphorylation networks play an important role in cell signaling. In these networks, phosphorylation of a protein kinase usually leads to its activation, which in turn will phosphorylate its downstream target proteins. A phosphorylation network is essentially a causal network, which can be learned by causal inference algorithms. Prior efforts have applied such algorithms to data measuring protein phosphorylation levels, assuming that the phosphorylation levels represent protein activity states. However, the phosphorylation status of a kinase does not always reflect its activity state, because interventions such as inhibitors or mutations can directly affect its activity state without changing its phosphorylation status. Thus, when cellular systems are subjected to extensive perturbations, the statistical relationships between phosphorylation states of proteins may be disrupted, making it difficult to reconstruct the true protein phosphorylation network. Here, we describe a novel framework to address this challenge.

Results: We have developed a causal discovery framework that explicitly represents the activity state of each protein kinase as an unmeasured variable and developed a novel algorithm called "InferA" to infer the protein activity states, which allows us to incorporate the protein phosphorylation level, pharmacological interventions and prior knowledge. We applied our framework to simulated datasets and to a real-world dataset. The simulation experiments demonstrated that explicit representation of activity states of protein kinases allows one to effectively represent the impact of interventions and thus enabled our framework to accurately recover the ground-truth causal network. Results from the real-world dataset showed that the explicit representation of protein activity states allowed an effective and data-driven integration of the prior knowledge by InferA, which further leads to the recovery of a phosphorylation network that is more consistent with experiment results.

Conclusions: Explicit representation of the protein activity states by our novel framework significantly enhances causal discovery of protein phosphorylation networks.
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http://dx.doi.org/10.1186/s12859-020-03676-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496209PMC
September 2020
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