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Article ; Online: Comparison and validation of algorithms for asthma diagnosis in an electronic medical record system.

Howell, Daniel / Rogers, Linda / Kasarskis, Andrew / Twyman, Kathryn

Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

2022 Volume 128, Issue 6, Page(s) 677–681.e7

Abstract: Background: Asthma is one of the most common chronic health conditions, and to leverage the wealth of data in the electronic medical record (EMR), it is important to be able to accurately identify asthma diagnosis.: Objective: We aimed to determine ... ...

Abstract	Background: Asthma is one of the most common chronic health conditions, and to leverage the wealth of data in the electronic medical record (EMR), it is important to be able to accurately identify asthma diagnosis. Objective: We aimed to determine the rule-based algorithm with the most balanced performance for sensitivity and positive predictive value of asthma diagnosis. Methods: We performed a diagnostic accuracy study of multiple rule-based algorithms intended to identify asthma diagnosis in the EMR. Algorithm performance was validated by manual chart review of 795 charts of patients seen in a multisite, tertiary-level, pulmonary specialty clinic using explicit diagnostic criteria to distinguish asthma cases from controls. Results: An asthma diagnosis anywhere in the medical record had a 97% sensitivity and a 77% specificity for asthma (F-score 80) when tested on a validation set of asthma cases and nonasthma respiratory disease from a pulmonary specialty clinic. The most balanced performance was seen with asthma diagnosis restricted to an encounter, hospital problem, or problem list diagnosis with a sensitivity of 94% and specificity of 85% (F-score 84). High sensitivity was achieved with the modified Health Plan Employer Data and Information Set criteria and high specificity was achieved with the NUgene algorithm, an algorithm developed for identifying asthma cases by EMR for genome-wide association studies. Conclusion: Asthma diagnosis can be accurately identified for research purposes by restricting to encounter, hospital problem, or problem list diagnosis in a pulmonary specialty clinic. Additional rules lead to steep drop-offs in algorithm sensitivity in our population.
MeSH term(s)	Algorithms ; Asthma/diagnosis ; Asthma/epidemiology ; Electronic Health Records ; Genome-Wide Association Study ; Humans ; Software
Language	English
Publishing date	2022-03-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	1228189-x
ISSN	1534-4436 ; 0003-4738 ; 1081-1206
ISSN (online)	1534-4436
ISSN	0003-4738 ; 1081-1206
DOI	10.1016/j.anai.2022.03.025
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Article ; Online: Reply to Lesho.

Pak, Theodore R / Kasarskis, Andrew

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

2016 Volume 62, Issue 8, Page(s) 1053

MeSH term(s)	Communicable Diseases ; Computational Biology ; Disease Management ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; Meta-Analysis as Topic ; Sequence Analysis, DNA
Language	English
Publishing date	2016-04-15
Publishing country	United States
Document type	Comment ; Letter
ZDB-ID	1099781-7
ISSN	1537-6591 ; 1058-4838
ISSN (online)	1537-6591
ISSN	1058-4838
DOI	10.1093/cid/ciw010
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Article ; Online: NREM delta power and AD-relevant tauopathy are associated with shared cortical gene networks.

Scarpa, Joseph R / Jiang, Peng / Gao, Vance D / Vitaterna, Martha H / Turek, Fred W / Kasarskis, Andrew

Scientific reports

2021 Volume 11, Issue 1, Page(s) 7797

Abstract: Reduced NREM sleep in humans is associated with AD neuropathology. Recent work has demonstrated a reduction in NREM sleep in preclinical AD, pointing to its potential utility as an early marker of dementia. We test the hypothesis that reduced NREM delta ... ...

Abstract	Reduced NREM sleep in humans is associated with AD neuropathology. Recent work has demonstrated a reduction in NREM sleep in preclinical AD, pointing to its potential utility as an early marker of dementia. We test the hypothesis that reduced NREM delta power and increased tauopathy are associated with shared underlying cortical molecular networks in preclinical AD. We integrate multi-omics data from two extensive public resources, a human Alzheimer's disease cohort from the Mount Sinai Brain Bank (N = 125) reflecting AD progression and a (C57BL/6J × 129S1/SvImJ) F2 mouse population in which NREM delta power was measured (N = 98). Two cortical gene networks, including a CLOCK-dependent circadian network, are associated with NREM delta power and AD tauopathy progression. These networks were validated in independent mouse and human cohorts. Identifying gene networks related to preclinical AD elucidate possible mechanisms associated with the early disease phase and potential targets to alter the disease course.
MeSH term(s)	Alzheimer Disease/pathology ; Animals ; Cerebellar Cortex/metabolism ; Cohort Studies ; Gene Regulatory Networks ; Humans ; Mice ; Mice, Inbred C57BL ; Sleep Wake Disorders/pathology
Language	English
Publishing date	2021-04-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-86255-6
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Article ; Online: How next-generation sequencing and multiscale data analysis will transform infectious disease management.

Pak, Theodore R / Kasarskis, Andrew

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

2015 Volume 61, Issue 11, Page(s) 1695–1702

Abstract: Recent reviews have examined the extent to which routine next-generation sequencing (NGS) on clinical specimens will improve the capabilities of clinical microbiology laboratories in the short term, but do not explore integrating NGS with clinical data ... ...

Abstract	Recent reviews have examined the extent to which routine next-generation sequencing (NGS) on clinical specimens will improve the capabilities of clinical microbiology laboratories in the short term, but do not explore integrating NGS with clinical data from electronic medical records (EMRs), immune profiling data, and other rich datasets to create multiscale predictive models. This review introduces a range of "omics" and patient data sources relevant to managing infections and proposes 3 potentially disruptive applications for these data in the clinical workflow. The combined threats of healthcare-associated infections and multidrug-resistant organisms may be addressed by multiscale analysis of NGS and EMR data that is ideally updated and refined over time within each healthcare organization. Such data and analysis should form the cornerstone of future learning health systems for infectious disease.
MeSH term(s)	Communicable Diseases/diagnosis ; Communicable Diseases/microbiology ; Communicable Diseases/therapy ; Computational Biology/methods ; Disease Management ; Electronic Health Records ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; Meta-Analysis as Topic ; Sequence Analysis, DNA/methods ; Software
Language	English
Publishing date	2015-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1099781-7
ISSN	1537-6591 ; 1058-4838
ISSN (online)	1537-6591
ISSN	1058-4838
DOI	10.1093/cid/civ670
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Article ; Online: Parkinson's Disease is Associated with Dysregulations of a Dopamine-Modulated Gene Network Relevant to Sleep and Affective Neurobehaviors in the Striatum.

Jiang, Peng / Scarpa, Joseph R / Gao, Vance D / Vitaterna, Martha Hotz / Kasarskis, Andrew / Turek, Fred W

Scientific reports

2019 Volume 9, Issue 1, Page(s) 4808

Abstract: In addition to the characteristic motor symptoms, Parkinson's disease (PD) often involves a constellation of sleep and mood symptoms. However, the mechanisms underlying these comorbidities are largely unknown. We have previously reconstructed gene ... ...

Abstract	In addition to the characteristic motor symptoms, Parkinson's disease (PD) often involves a constellation of sleep and mood symptoms. However, the mechanisms underlying these comorbidities are largely unknown. We have previously reconstructed gene networks in the striatum of a population of (C57BL/6J x A/J) F2 mice and associated the networks to sleep and affective phenotypes, providing a resource for integrated analyses to investigate perturbed sleep and affective functions at the gene network level. Combining this resource with PD-relevant transcriptomic datasets from humans and mice, we identified four networks that showed elevated gene expression in PD patients, including a circadian clock and mitotic network that was altered similarly in mouse models of PD. We then utilized multiple types of omics data from public databases and linked this gene network to postsynaptic dopamine signaling in the striatum, CDK1-modulated transcriptional regulation, and the genetic susceptibility of PD. These findings suggest that dopamine deficiency, a key aspect of PD pathology, perturbs a circadian/mitotic gene network in striatal neurons. Since the normal functions of this network were relevant to sleep and affective behaviors, these findings implicate that dysregulation of functional gene networks may be involved in the emergence of non-motor symptoms in PD. Our analyses present a framework for integrating multi-omics data from diverse sources in mice and humans to reveal insights into comorbid symptoms of complex diseases.
MeSH term(s)	Affective Symptoms/genetics ; Affective Symptoms/pathology ; Affective Symptoms/physiopathology ; Animals ; CDC2 Protein Kinase/metabolism ; Circadian Clocks/genetics ; Corpus Striatum/cytology ; Corpus Striatum/pathology ; Corpus Striatum/physiopathology ; Datasets as Topic ; Disease Models, Animal ; Dopamine/deficiency ; Dopaminergic Neurons/pathology ; Gene Expression Profiling ; Gene Expression Regulation/physiology ; Gene Regulatory Networks/physiology ; Genetic Predisposition to Disease ; Humans ; Male ; Mice ; Parkinson Disease/genetics ; Parkinson Disease/pathology ; Parkinson Disease/physiopathology ; Sleep/genetics ; Transcription, Genetic
Chemical Substances	CDC2 Protein Kinase (EC 2.7.11.22) ; CDK1 protein, human (EC 2.7.11.22) ; Cdk1 protein, mouse (EC 2.7.11.22) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2019-03-18
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-41248-4
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Article ; Online: Polygenic risk score for alcohol drinking behavior improves prediction of inflammatory bowel disease risk.

Di Narzo, Antonio F / Hart, Amy / Kosoy, Roman / Peters, Lauren / Stojmirovic, Aleksandar / Cheng, Haoxiang / Zhang, Zhongyang / Shan, Mingxu / Cho, Judy / Kasarskis, Andrew / Argmann, Carmen / Peter, Inga / Schadt, Eric E / Hao, Ke

Human molecular genetics

2021 Volume 30, Issue 6, Page(s) 514–523

Abstract: Epidemiological studies have long recognized risky behaviors as potentially modifiable factors for the onset and flares of inflammatory bowel disease (IBD); yet, the underlying mechanisms are largely unknown. Recently, the genetic susceptibilities to ... ...

Abstract	Epidemiological studies have long recognized risky behaviors as potentially modifiable factors for the onset and flares of inflammatory bowel disease (IBD); yet, the underlying mechanisms are largely unknown. Recently, the genetic susceptibilities to cigarette smoking, alcohol and cannabis use [i.e. substance use (SU)] have been characterized by well-powered genome-wide association studies (GWASs). We aimed to assess the impact of genetic determinants of SU on IBD risk. Using Mount Sinai Crohn's and Colitis Registry (MSCCR) cohort of 1058 IBD cases and 188 healthy controls, we computed the polygenic risk score (PRS) for SU and correlated them with the observed IBD diagnoses, while adjusting for genetic ancestry, PRS for IBD and SU behavior at enrollment. The results were validated in a pediatric cohort with no SU exposure. PRS of alcohol consumption (DrnkWk), smoking cessation and age of smoking initiation, were associated with IBD risk in MSCCR even after adjustment for PRSIBD and actual smoking status. One interquartile range decrease in PRSDrnkWk was significantly associated to higher IBD risk (i.e. inverse association) (with odds ratio = 1.65 and 95% confidence interval: 1.32, 2.06). The association was replicated in a pediatric Crohn's disease cohort. Colocalization analysis identified a locus on chromosome 16 with polymorphisms in IL27, SULT1A2 and SH2B1, which reached genome-wide statistical significance in GWAS (P < 7.7e-9) for both alcohol consumption and IBD risk. This study demonstrated that the genetic predisposition to SU was associated with IBD risk, independent of PRSIBD and in the absence of SU behaviors. Our study may help further stratify individuals at risk of IBD.
MeSH term(s)	Adolescent ; Alcohol Drinking/adverse effects ; Biomarkers/metabolism ; Case-Control Studies ; Child ; Child, Preschool ; Cohort Studies ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Infant ; Inflammatory Bowel Diseases/diagnosis ; Inflammatory Bowel Diseases/etiology ; Inflammatory Bowel Diseases/metabolism ; Male ; Polymorphism, Single Nucleotide ; Risk Factors
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-02-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddab045
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Article ; Online: Meta-analysis of sample-level dbGaP data reveals novel shared genetic link between body height and Crohn's disease.

Di Narzo, Antonio / Frades, Itziar / Crane, Heidi M / Crane, Paul K / Hulot, Jean-Sebastian / Kasarskis, Andrew / Hart, Amy / Argmann, Carmen / Dubinsky, Marla / Peter, Inga / Hao, Ke

Human genetics

2021 Volume 140, Issue 6, Page(s) 865–877

Abstract: To further explore genetic links between complex traits, we developed a comprehensive framework to harmonize and integrate extensive genotype and phenotype data from the four well-characterized cohorts with the focus on cardiometabolic diseases deposited ...

Abstract	To further explore genetic links between complex traits, we developed a comprehensive framework to harmonize and integrate extensive genotype and phenotype data from the four well-characterized cohorts with the focus on cardiometabolic diseases deposited to the database of Genotypes and Phenotypes (dbGaP). We generated a series of polygenic risk scores (PRS) to investigate pleiotropic effects of loci that confer genetic risk for 19 common diseases and traits on body height, type 2 diabetes (T2D), and myocardial infarction (MI). In a meta-analysis of 20,021 subjects, we identified shared genetic determinants of Crohn's Disease (CD), a type of inflammatory bowel disease, and body height (p = 5.5 × 10
MeSH term(s)	Adult ; Body Height/genetics ; Body Height/immunology ; Child ; Crohn Disease/genetics ; Crohn Disease/immunology ; Crohn Disease/pathology ; Databases, Genetic ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/immunology ; Diabetes Mellitus, Type 2/pathology ; Female ; Gene Expression Regulation ; Genetic Predisposition to Disease ; Humans ; Immune Checkpoint Proteins/genetics ; Immune Checkpoint Proteins/immunology ; Immunity, Innate ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/immunology ; Male ; Multifactorial Inheritance/immunology ; Myocardial Infarction/genetics ; Myocardial Infarction/immunology ; Myocardial Infarction/pathology ; Phenotype ; Risk Factors
Chemical Substances	Immune Checkpoint Proteins ; Intercellular Signaling Peptides and Proteins
Language	English
Publishing date	2021-01-16
Publishing country	Germany
Document type	Journal Article ; Meta-Analysis
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-020-02250-3
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Article ; Online: Comprehensive Immunoprofiling of Pediatric Zika Reveals Key Role for Monocytes in the Acute Phase and No Effect of Prior Dengue Virus Infection.

Michlmayr, Daniela / Kim, Eun-Young / Rahman, Adeeb H / Raghunathan, Rohit / Kim-Schulze, Seunghee / Che, Yan / Kalayci, Selim / Gümüş, Zeynep H / Kuan, Guillermina / Balmaseda, Angel / Kasarskis, Andrew / Wolinsky, Steven M / Suaréz-Fariñas, Mayte / Harris, Eva

Cell reports

2020 Volume 31, Issue 4, Page(s) 107569

Abstract: Zika virus (ZIKV) is an emerging, mosquito-borne flavivirus responsible for recent epidemics across the Americas, and it is closely related to dengue virus (DENV). Here, we study samples from 46 DENV-naive and 43 DENV-immune patients with RT-PCR- ... ...

Abstract	Zika virus (ZIKV) is an emerging, mosquito-borne flavivirus responsible for recent epidemics across the Americas, and it is closely related to dengue virus (DENV). Here, we study samples from 46 DENV-naive and 43 DENV-immune patients with RT-PCR-confirmed ZIKV infection at early-acute, late-acute, and convalescent time points from our pediatric cohort study in Nicaragua. We analyze the samples via RNA sequencing (RNA-seq), CyTOF, and multiplex cytokine/chemokine Luminex to generate a comprehensive, innate immune profile during ZIKV infection. Immunophenotyping and analysis of cytokines/chemokines reveal that CD14
MeSH term(s)	Acute Disease ; Child ; Dengue Virus/pathogenicity ; Female ; Humans ; Immunity, Innate/immunology ; Male ; Monocytes/virology ; Zika Virus/pathogenicity
Language	English
Publishing date	2020-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.107569
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Article ; Online: Integrative genomics strategies to elucidate the complexity of drug response.

Kasarskis, Andrew / Yang, Xia / Schadt, Eric

Pharmacogenomics

2011 Volume 12, Issue 12, Page(s) 1695–1715

Abstract: Pharmacogenomic investigation from both genome-wide association studies and experiments focused on candidate loci involved in drug mechanism and metabolism has yielded a substantial and increasing list of robust genetic effects on drug therapy in humans. ...

Abstract	Pharmacogenomic investigation from both genome-wide association studies and experiments focused on candidate loci involved in drug mechanism and metabolism has yielded a substantial and increasing list of robust genetic effects on drug therapy in humans. At the same time, reasonably comprehensive molecular data such as gene expression, proteomic and metabolomic data are now available for collections of hundreds to thousands of individuals. If these data are structured in a statistically robust and computationally tractable way, such as a network model, they can aid in the analysis of new pharmacogenomics studies by suggesting novel hypotheses for the regulation of genes involved in drug metabolism and response. Similarly, hypotheses taken from these same models can direct genome-wide association studies by focusing the genome-wide association studies analysis on a number of specific hypotheses informed by the relationships customarily seen between a gene's expression or protein activity and genetic variation at a particular locus. Network models based on other sorts of systematic biological data such as cell-based surveys of drug effect on gene expression and mining of literature and electronic medical records for associations between clinical and molecular phenotypes also promise similar utility. Although surely primitive in comparison with what will be developed, these model-based approaches to leveraging the increasing volume of data generated in the course of patient care and medical research nevertheless suggest a huge opportunity to improve our understanding of biological systems involved in pharmacogenomics and apply them to questions of medical relevance.
MeSH term(s)	Biomarkers, Pharmacological ; Electronic Health Records ; Gene Expression ; Genetic Variation ; Genome, Human ; Genome-Wide Association Study ; Humans ; Phenotype ; Proteomics
Chemical Substances	Biomarkers, Pharmacological
Language	English
Publishing date	2011-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2019513-8
ISSN	1744-8042 ; 1462-2416
ISSN (online)	1744-8042
ISSN	1462-2416
DOI	10.2217/pgs.11.115
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Article ; Online: A window into third-generation sequencing.

Schadt, Eric E / Turner, Steve / Kasarskis, Andrew

Human molecular genetics

2010 Volume 19, Issue R2, Page(s) R227–40

Abstract: First- and second-generation sequencing technologies have led the way in revolutionizing the field of genomics and beyond, motivating an astonishing number of scientific advances, including enabling a more complete understanding of whole genome sequences ...

Abstract	First- and second-generation sequencing technologies have led the way in revolutionizing the field of genomics and beyond, motivating an astonishing number of scientific advances, including enabling a more complete understanding of whole genome sequences and the information encoded therein, a more complete characterization of the methylome and transcriptome and a better understanding of interactions between proteins and DNA. Nevertheless, there are sequencing applications and aspects of genome biology that are presently beyond the reach of current sequencing technologies, leaving fertile ground for additional innovation in this space. In this review, we describe a new generation of single-molecule sequencing technologies (third-generation sequencing) that is emerging to fill this space, with the potential for dramatically longer read lengths, shorter time to result and lower overall cost.
MeSH term(s)	High-Throughput Nucleotide Sequencing/methods ; Humans ; Models, Biological ; Sequence Analysis, DNA/methods
Language	English
Publishing date	2010-10-15
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddq416
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