212 results on '"Ginsburg GS"'
Search Results
2. A more rapid approach to systematically assessing published associations of genetic polymorphisms and disease risk: type 2 diabetes as a test case
- Author
-
Cho AH, Jiang X, Mann DM, Kawamoto K, Robinson TJ, Wang N, McCarthy JJ, Woodward M, and Ginsburg GS
- Subjects
lcsh:Public aspects of medicine ,lcsh:RA1-1270 - Abstract
Alex H Cho1, Xiaolei Jiang2, Devin M Mann3, Kensaku Kawamoto4, Timothy J Robinson5, Nancy Wang6, Jeanette J McCarthy2, Mark Woodward7, Geoffrey S Ginsburg1,21Center for Personalized Medicine and Department of Medicine, Duke University, Durham, NC, 2Institute for Genome Sciences and Policy, Duke University, Durham, NC, 3Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA, 4Department of Biomedical Informatics, University of Utah, Salt Lake City, UT, 5Medical College of Virginia, Richmond, VA, 6School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA; 7George Institute for Global Health and University of Sydney, AustraliaBackground: Comparative effectiveness research and research in genomic medicine are not orthogonal pursuits. Both require a robust evidence base, and each stands to benefit from applying the methods of the other. There is an exponentially growing literature reporting associations between single nucleotide polymorphisms (SNPs) and increased risk for diseases such as type 2 diabetes. Literature-based meta-analysis is an important method of assessing the validity of published gene-disease associations, but a traditional emphasis on exhaustiveness makes it difficult to study multiple polymorphisms efficiently. Here we describe a novel two-step search method for broadly yet systematically reviewing the literature to identify the "most-studied" gene-disease associations, thereby selecting those with a high possibility of replication on which to conduct abbreviated, simultaneous meta-analyses. This method was then applied to identify and evaluate the validity of SNPs reported to be associated with increased type 2 diabetes risk, to demonstrate proof of principle.Methods: A two-step MEDLINE search (1950 to present) was conducted in September 2007 for published genetic association data related to SNPs associated with risk of type 2 diabetes. The top 10 "most-studied" genes were selected for focused searches and final inclusion/exclusion determinations. To demonstrate the ability to efficiently update this two-step search for additions to the literature, an update of the second-step search was conducted 9 months later. Abstracted data were sorted based on study design, risk model, and specific SNPs. Meta-analyses were performed for individual SNPs, with separate analyses done for case-control and prospective studies, and were compared with the results of more recent genome-wide association studies.Results: The first-step search found 1116 articles covering 108 different genes. The top ten "most-studied" genes were: ABCC8 (or SUR1), ACE, CAPN10, KCNJ11 (or Kir6.2), HNF1 alpha, HNF4 alpha, IL-6, PGC-1 alpha, PPAR gamma 2, and TCF7L2. The second-step search found a total of 658 articles, yielding 124 articles for initial data abstraction and analysis. We also demonstrated the ability to update this search as newer studies appeared, using the same method almost a year later to find an additional 107 articles (77 were ultimately excluded), bringing the number of included studies to 154. From these studies, data on 90 different DNA variants within the ten genes were abstracted. Simultaneous meta-analyses found that higher-risk alleles for SNPs rs7903146 and rs12255372 in TCF7L2, rs1801282 in PPAR gamma 2, rs5219 in KCNJ11, rs3792267 in CAPN10, rs2144909 in HNF4 alpha, and rs1800795 in IL-6 appeared to be associated with increased type 2 diabetes risk. These findings were generally highly concordant with the results of traditional literature-based meta-analyses performed for individual genes.Conclusions: The methodology described in this manuscript represents a reasonable approach to more rapidly identifying and evaluating frequently studied genetic-risk markers for diseases such as type 2 diabetes. Comparison with results of traditional meta-analyses suggests that these gains in efficiency do not necessarily come at the price of reduced accuracy. Given the quickening pace of discovery of such markers, more efficient, unbiased, and readily updatable methods for systematically assessing and re-assessing a changing literature could prove valuable. Good methods for evidence evaluation are also important to the potential application of genetic markers to comparative effectiveness research, and vice versa.Keywords: meta-analyses, genes, inclusion/exclusion, data, genetic risk 
- Published
- 2012
3. Abstract P2-10-03: A cross-platform comparison of genomic signatures and OncotypeDx score to discover potential prognostic/predictive genes and pathways
- Author
-
Kuderer, NM, primary, Barry, WT, additional, Geradts, J, additional, Ginsburg, GS, additional, Lyman, GH, additional, Datto, M, additional, Liotcheva, V, additional, Isner, P, additional, Veldman, T, additional, Agarwal, P, additional, Hwang, S, additional, Ready, N, additional, and Marcom, PK, additional
- Published
- 2012
- Full Text
- View/download PDF
4. P3-14-04: Assessment of Genomic Prognostic Signatures as Predictors of Response to Neoadjuvant Chemotherapy in Patients with Early Stage Breast Cancer.
- Author
-
Culakova, E, primary, Poniewierski, MS, additional, Huang, M, additional, Kuderer, NM, additional, Ginsburg, GS, additional, Barry, W, additional, Marcom, PK, additional, Ready, N, additional, Abernethy, A, additional, and Lyman, GH, additional
- Published
- 2011
- Full Text
- View/download PDF
5. Identifying patients at high risk of a cardiovascular event in the near future: current status and future directions: report of a national heart, lung, and blood institute working group.
- Author
-
Eagle KA, Ginsburg GS, Musunuru K, Aird WC, Balaban RS, Bennett SK, Blumenthal RS, Coughlin SR, Davidson KW, Frohlich ED, Greenland P, Jarvik GP, Libby P, Pepine CJ, Ruskin JN, Stillman AE, Van Eyk JE, Tolunay HE, McDonald CL, and Smith SC Jr
- Published
- 2010
- Full Text
- View/download PDF
6. The long and winding road to warfarin pharmacogenetic testing.
- Author
-
Ginsburg GS, Voora D, Ginsburg, Geoffrey S, and Voora, Deepak
- Published
- 2010
- Full Text
- View/download PDF
7. Regression of atherosclerosis with therapeutic antibodies pipe cleaner or pipe dream?
- Author
-
Ginsburg GS
- Published
- 2007
- Full Text
- View/download PDF
8. Microarrays coming of age in cardiovascular medicine: standards, predictions, and biology.
- Author
-
Ginsburg GS, Seo D, and Frazier C
- Published
- 2006
- Full Text
- View/download PDF
9. Novel-and 'Neu'-Therapeutic Possibilities for Heart Failure.
- Author
-
Freedman NJ and Ginsburg GS
- Published
- 2006
- Full Text
- View/download PDF
10. All of Us Research Program year in review: 2023-2024.
- Author
-
Kozlowski E, Farrell MM, Faust EJ, Gallagher CS, Jones G, Landis E, Litwin TR, Lunt C, Mian SH, Mockrin SC, Musick A, Patten T, Sanchez J, Schully S, and Ginsburg GS
- Subjects
- Humans, United States, Biomedical Research
- Published
- 2024
- Full Text
- View/download PDF
11. A new annual feature of AJHG: All of Us Research Program year in review.
- Author
-
Kozlowski E, Ginsburg GS, and Korf BR
- Subjects
- Humans, United States, Periodicals as Topic, Human Genetics
- Published
- 2024
- Full Text
- View/download PDF
12. Predictive signature of murine and human host response to typical and atypical pneumonia.
- Author
-
McCravy M, O'Grady N, Khan K, Betancourt-Quiroz M, Zaas AK, Treece AE, Yang Z, Que L, Henao R, Suchindran S, Ginsburg GS, Woods CW, McClain MT, and Tsalik EL
- Subjects
- Animals, Humans, Mice, Female, Pneumonia, Pneumococcal microbiology, Orthomyxoviridae Infections immunology, ROC Curve, Gene Expression Profiling, Pneumonia, Viral diagnosis, Pneumonia, Viral immunology, Mice, Inbred C57BL, Pneumonia, Bacterial microbiology, Pneumonia, Bacterial diagnosis, Host-Pathogen Interactions, Streptococcus pneumoniae genetics, Streptococcus pneumoniae isolation & purification, Pneumonia, Mycoplasma diagnosis, Mycoplasma pneumoniae genetics, Mycoplasma pneumoniae isolation & purification, Disease Models, Animal
- Abstract
Background: Pneumonia due to typical bacterial, atypical bacterial and viral pathogens can be difficult to clinically differentiate. Host response-based diagnostics are emerging as a complementary diagnostic strategy to pathogen detection., Methods: We used murine models of typical bacterial, atypical bacterial and viral pneumonia to develop diagnostic signatures and understand the host's response to these types of infections. Mice were intranasally inoculated with Streptococcus pneumoniae , Mycoplasma pneumoniae , influenza or saline as a control. Peripheral blood gene expression analysis was performed at multiple time points. Differentially expressed genes were used to perform gene set enrichment analysis and generate diagnostic signatures. These murine-derived signatures were externally validated in silico using human gene expression data. The response to S. pneumoniae was the most rapid and robust., Results: Mice infected with M. pneumoniae had a delayed response more similar to influenza-infected animals. Diagnostic signatures for the three types of infection had 0.94-1.00 area under the receiver operator curve (auROC). Validation in five human gene expression datasets revealed auROC of 0.82-0.96., Discussion: This study identified discrete host responses to typical bacterial, atypical bacterial and viral aetiologies of pneumonia in mice. These signatures validated well in humans, highlighting the conserved nature of the host response to these pathogen classes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2024
- Full Text
- View/download PDF
13. Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators.
- Author
-
Skaar TC, Myers RA, Fillingim RB, Callaghan JT, Cicali E, Eadon MT, Elwood EN, Ginsburg GS, Lynch S, Nguyen KA, Obeng AO, Park H, Pratt VM, Rosenman M, Sadeghpour A, Shuman S, Singh R, Tillman EM, Volpi S, Wiisanen K, Winterstein AG, Horowitz CR, Voora D, Orlando L, Chakraborty H, Van Driest S, Peterson JF, Cavallari LA, Johnson JA, and Dexter PR
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Pain Management methods, Pain Measurement, Pharmacogenomic Testing, Precision Medicine methods, Analgesics, Opioid therapeutic use, Analgesics, Opioid adverse effects, Chronic Pain drug therapy, Cytochrome P-450 CYP2D6 genetics, Cytochrome P-450 CYP2D6 metabolism
- Abstract
Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2024
- Full Text
- View/download PDF
14. Rationale and design for a pragmatic randomized trial to assess gene-based prescribing for SSRIs in the treatment of depression.
- Author
-
Hines LJ, Wilke RA, Myers R, Mathews CA, Liu M, Baye JF, Petry N, Cicali EJ, Duong BQ, Elwood E, Hulvershorn L, Nguyen K, Ramos M, Sadeghpour A, Wu RR, Williamson L, Wiisanen K, Voora D, Singh R, Blake KV, Murrough JW, Volpi S, Ginsburg GS, Horowitz CR, Orlando L, Chakraborty H, Dexter P, Johnson JA, Skaar TC, Cavallari LH, Van Driest SL, and Peterson JF
- Subjects
- Adult, Female, Humans, Male, Antidepressive Agents therapeutic use, Antidepressive Agents administration & dosage, Antidepressive Agents adverse effects, Pharmacogenomic Variants, Pragmatic Clinical Trials as Topic, Prospective Studies, Cytochrome P-450 CYP2C19 genetics, Cytochrome P-450 CYP2D6 genetics, Depression drug therapy, Depression genetics, Depression diagnosis, Pharmacogenomic Testing, Selective Serotonin Reuptake Inhibitors administration & dosage, Selective Serotonin Reuptake Inhibitors therapeutic use
- Abstract
Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2024
- Full Text
- View/download PDF
15. Lipoprotein subclasses are associated with Hepatic steatosis: insights from the prospective multicenter imaging study for the evaluation of chest pain (PROMISE) clinical trial.
- Author
-
Karady J, McGarrah RW, Nguyen M, Giamberardino SN, Meyersohn N, Lu MT, Staziaki PV, Puchner SB, Bittner DO, Foldyna B, Mayrhofer T, Connelly MA, Tchernof A, White PJ, Nasir K, Corey K, Voora D, Pagidipati N, Ginsburg GS, Kraus WE, Hoffmann U, Douglas PS, Shah SH, and Ferencik M
- Abstract
Objectives: To determine the relationship between lipoprotein particle size/number with hepatic steatosis (HS), given its association with traditional lipoproteins and coronary atherosclerosis., Methods: Individuals with available CT data and blood samples enrolled in the PROMISE trial were studied. HS was defined based on CT attenuation. Lipoprotein particle size/number were measured by nuclear magnetic resonance spectroscopy. Principal components analysis (PCA) was used for dimensionality reduction. The association of PCA factors and individual lipoprotein particle size/number with HS were assessed in multivariable regression models. Associations were validated in an independent cohort of 59 individuals with histopathology defined HS., Results: Individuals with HS (n=410/1,509) vs those without (n=1,099/1,509), were younger (59±8 vs 61±8 years) and less often females (47.6 % vs 55.9 %). All PCA factors were associated with HS: factor 1 (OR:1.36, 95 %CI:1.21-1.53), factor 3 (OR:1.75, 95 %CI:1.53-2.02) and factor 4 (OR:1.49; 95 %CI:1.32-1.68) were weighted heavily with small low density lipoprotein (LDL) and triglyceride-rich (TRL) particles, while factor 2 (OR:0.86, 95 %CI:0.77-0.97) and factor 5 (OR:0.74, 95 %CI:0.65-0.84) were heavily loaded with high density lipoprotein (HDL) and larger LDL particles. These observations were confirmed with the analysis of individual lipoprotein particles in PROMISE. In the validation cohort, association between HS and large TRL (OR: 8.16, 95 %CI:1.82-61.98), and mean sizes of TRL- (OR: 2.82, 95 %CI:1.14-9.29) and HDL (OR:0.35, 95 %CI:0.13-0.72) were confirmed., Conclusions: Large TRL, mean sizes of TRL-, and HDL were associated with radiographic and histopathologic HS. The use of lipoprotein particle size/number could improve cardiovascular risk assessment in HS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier B.V.)
- Published
- 2024
- Full Text
- View/download PDF
16. Remote digital health technologies for improving the care of people with respiratory disorders.
- Author
-
Dunn J, Coravos A, Fanarjian M, Ginsburg GS, and Steinhubl SR
- Subjects
- Humans, Digital Health, Respiratory Tract Diseases therapy
- Abstract
Respiratory diseases are a leading cause of morbidity and mortality globally. However, existing systems of care, built around scheduled appointments, are not well designed to support the needs of people with chronic and acute respiratory conditions that can change rapidly and unexpectedly. Home-based and personal digital health technologies (DHTs) allow implementation of new models of care catering to the unique needs of individuals. The high number of respiratory triggers and unique responses to them require a personalised solution for each patient. The real-world, repetitive monitoring capabilities of DHTs enable identification of the normal operating characteristics for each individual and, therefore, recognition of the earliest deviations from that state. However, despite this potential, the number of clinical efficacy studies of DHTs is quite small. Evaluation of clinical effectiveness of DHTs in improving health quality in real-world settings is urgently needed., Competing Interests: Declaration of interests JD reports personal fees as a Scientific Advisor to Veri and grant support from AstraZeneca. AC is the CEO, co-founder, and a shareholder of HumanFirst; and was a board member of the Digital Medical Society until 2023. MF is an advisor and shareholder of HumanFirst. SRS reports financial compensation as a consultant for physIQ; declares research grant support from Janssen Research & Development; and received reimbursement as an Executive Committee member for the Heartline Study, which is a trial on wearables to detect atrial fibrillation. GSG declared no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
17. Implementation of a Prospective Index-Cluster Sampling Strategy for the Detection of Presymptomatic Viral Respiratory Infection in Undergraduate Students.
- Author
-
Uthappa DM, McClain MT, Nicholson BP, Park LP, Zhbannikov I, Suchindran S, Jimenez M, Constantine FJ, Nichols M, Jones DC, Hudson LL, Jaggers LB, Veldman T, Burke TW, Tsalik EL, Ginsburg GS, and Woods CW
- Abstract
Background: Index-cluster studies may help characterize the spread of communicable infections in the presymptomatic state. We describe a prospective index-cluster sampling strategy (ICSS) to detect presymptomatic respiratory viral illness and its implementation in a college population., Methods: We enrolled an annual cohort of first-year undergraduates who completed daily electronic symptom diaries to identify index cases (ICs) with respiratory illness. Investigators then selected 5-10 potentially exposed, asymptomatic close contacts (CCs) who were geographically co-located to follow for infections. Symptoms and nasopharyngeal samples were collected for 5 days. Logistic regression model-based predictions for proportions of self-reported illness were compared graphically for the whole cohort sampling group and the CC group., Results: We enrolled 1379 participants between 2009 and 2015, including 288 ICs and 882 CCs. The median number of CCs per IC was 6 (interquartile range, 3-8). Among the 882 CCs, 111 (13%) developed acute respiratory illnesses. Viral etiology testing in 246 ICs (85%) and 719 CCs (82%) identified a pathogen in 57% of ICs and 15% of CCs. Among those with detectable virus, rhinovirus was the most common (IC: 18%; CC: 6%) followed by coxsackievirus/echovirus (IC: 11%; CC: 4%). Among 106 CCs with a detected virus, only 18% had the same virus as their associated IC. Graphically, CCs did not have a higher frequency of self-reported illness relative to the whole cohort sampling group., Conclusions: Establishing clusters by geographic proximity did not enrich for cases of viral transmission, suggesting that ICSS may be a less effective strategy to detect spread of respiratory infection., Competing Interests: Potential conflicts of interest. M. T. M. reports grants from the Defense Advanced Research Projects Agency (DARPA) and the National Institutes of Health (NIH), and has a patent pending on “Methods to diagnose and treat acute respiratory infections.” T. W. B. reports grants from DARPA and NIH; reports owning equity in and serving as a consultant for Biomeme; and has a patent pending on Methods to diagnose and treat acute respiratory infections. E. L. T. reports consultancy fees and equity from Biomeme; has patents pending on Biomarkers for the molecular classification of bacterial infection and Methods to diagnose and treat acute respiratory infections; and is currently an employee of Danaher Diagnostics. C. W. W. and G. S. G. have patents pending on Molecular classification of bacterial infection and gene expression signatures useful to predict or diagnose sepsis and methods of using the same, and have patents issued on Methods to diagnose and treat acute respiratory disease and Methods of identifying infectious disease and assays for identifying infectious disease. C. W. W. reports owning equity in and consulting for Biomeme; reports grants from DARPA, NIH, Antibacterial Resistance Leadership Group, and Sanofi; and has received consultancy fees from bioMérieux, Roche, Biofire, Giner, and Biomeme. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
- Published
- 2024
- Full Text
- View/download PDF
18. The All of Us Research Program is an opportunity to enhance the diversity of US biomedical research.
- Author
-
Bianchi DW, Brennan PF, Chiang MF, Criswell LA, D'Souza RN, Gibbons GH, Gilman JK, Gordon JA, Green ED, Gregurick S, Hodes RJ, Kilmarx PH, Koob GF, Koroshetz WJ, Langevin HM, Lorsch JR, Marrazzo JM, Pérez-Stable EJ, Rathmell WK, Rodgers GP, Rutter JL, Simoni JM, Tromberg BJ, Tucci DL, Volkow ND, Woychik R, Zenk SN, Kozlowski E, Peterson RS, Ginsburg GS, and Denny JC
- Subjects
- Humans, Mentors, Population Health, Biomedical Research
- Published
- 2024
- Full Text
- View/download PDF
19. Host-response transcriptional biomarkers accurately discriminate bacterial and viral infections of global relevance.
- Author
-
Ko ER, Reller ME, Tillekeratne LG, Bodinayake CK, Miller C, Burke TW, Henao R, McClain MT, Suchindran S, Nicholson B, Blatt A, Petzold E, Tsalik EL, Nagahawatte A, Devasiri V, Rubach MP, Maro VP, Lwezaula BF, Kodikara-Arachichi W, Kurukulasooriya R, De Silva AD, Clark DV, Schully KL, Madut D, Dumler JS, Kato C, Galloway R, Crump JA, Ginsburg GS, Minogue TD, and Woods CW
- Subjects
- Humans, Biomarkers, Cambodia, Australia, Virus Diseases diagnosis, Virus Diseases genetics, Bacterial Infections diagnosis, Bacterial Infections genetics
- Abstract
Diagnostic limitations challenge management of clinically indistinguishable acute infectious illness globally. Gene expression classification models show great promise distinguishing causes of fever. We generated transcriptional data for a 294-participant (USA, Sri Lanka) discovery cohort with adjudicated viral or bacterial infections of diverse etiology or non-infectious disease mimics. We then derived and cross-validated gene expression classifiers including: 1) a single model to distinguish bacterial vs. viral (Global Fever-Bacterial/Viral [GF-B/V]) and 2) a two-model system to discriminate bacterial and viral in the context of noninfection (Global Fever-Bacterial/Viral/Non-infectious [GF-B/V/N]). We then translated to a multiplex RT-PCR assay and independent validation involved 101 participants (USA, Sri Lanka, Australia, Cambodia, Tanzania). The GF-B/V model discriminated bacterial from viral infection in the discovery cohort an area under the receiver operator curve (AUROC) of 0.93. Validation in an independent cohort demonstrated the GF-B/V model had an AUROC of 0.84 (95% CI 0.76-0.90) with overall accuracy of 81.6% (95% CI 72.7-88.5). Performance did not vary with age, demographics, or site. Host transcriptional response diagnostics distinguish bacterial and viral illness across global sites with diverse endemic pathogens., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
20. Genomic medicine year in review: 2023.
- Author
-
Manolio TA, Narula J, Bult CJ, Chisholm RL, Deverka PA, Ginsburg GS, Green ED, Hooker G, Jarvik GP, Mensah GA, Ramos EM, Roden DM, Rowley R, and Williams MS
- Published
- 2023
- Full Text
- View/download PDF
21. Branched-Chain Amino Acids in Computed Tomography-Defined Adipose Depots and Coronary Artery Disease: A PROMISE Trial Biomarker Substudy.
- Author
-
Zhao E, Giamberardino SN, Pagidipati NJ, Voora D, Ginsburg GS, Hoffmann U, Karády J, Ferencik M, Douglas PS, Foldyna B, and Shah SH
- Subjects
- Humans, Middle Aged, Adiposity, Amino Acids, Branched-Chain metabolism, Prospective Studies, Risk Factors, Biomarkers metabolism, Tomography, X-Ray Computed, Obesity complications, Chest Pain, Coronary Angiography methods, Adipose Tissue diagnostic imaging, Adipose Tissue metabolism, Coronary Artery Disease etiology
- Abstract
Background The interplay between branched-chain amino acid (BCAA) metabolism, an important pathway in adiposity and cardiometabolic disease, and visceral adipose depots such as hepatic steatosis (HS) and epicardial adipose tissue is unknown. We leveraged the PROMISE clinical trial with centrally adjudicated coronary computed tomography angiography imaging to determine relationships between adipose depots, BCAA dysregulation, and coronary artery disease (CAD). Methods and Results The PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial randomized 10 003 outpatients with stable chest pain to computed tomography angiography versus standard-of-care diagnostics. For this study, we included 1798 participants with available computed tomography angiography data and biospecimens. Linear and logistic regression were used to determine associations between a molar sum of BCAAs measured by nuclear magnetic resonance spectroscopy with body mass index, adipose traits, and obstructive CAD. Mendelian randomization was then used to determine if BCAAs are in the causal pathway for adipose depots or CAD. The study sample had a mean age of 60 years (SD, 8.0), body mass index of 30.6 (SD, 5.9), and epicardial adipose tissue volume of 57.3 (SD, 21.3) cm
3 /m2 ; 27% had HS, and 14% had obstructive CAD. BCAAs were associated with body mass index (multivariable beta 0.12 per SD increase in BCAA [95% CI, 0.08-0.17]; P =4×10-8 ). BCAAs were also associated with HS (multivariable odds ratio [OR], 1.46 per SD increase in BCAAs [95% CI, 1.28-1.67]; P =2×10-8 ), but BCAAs were associated only with epicardial adipose tissue volume (odds ratio, 1.18 [95% CI, 1.07-1.32]; P =0.002) and obstructive CAD (OR, 1.18 [95% CI, 1.04-1.34]; P =0.009) in univariable models. Two-sample Mendelian randomization did not support the role of BCAAs as within the causal pathways for HS or CAD. Conclusions BCAAs have been implicated in the pathogenesis of cardiometabolic diseases, and adipose depots have been associated with the risk of CAD. Leveraging a large clinical trial, we further establish the role of dysregulated BCAA catabolism in HS and CAD, although BCAAs did not appear to be in the causal pathway of either disease. This suggests that BCAAs may serve as an independent circulating biomarker of HS and CAD but that their association with these cardiometabolic diseases is mediated through other pathways.- Published
- 2023
- Full Text
- View/download PDF
22. Author Correction: Differential chromatin accessibility in peripheral blood mononuclear cells underlies COVID-19 disease severity prior to seroconversion.
- Author
-
Giroux NS, Ding S, McClain MT, Burke TW, Petzold E, Chung HA, Rivera GO, Wang E, Xi R, Bose S, Rotstein T, Nicholson BP, Chen T, Henao R, Sempowski GD, Denny TN, De Ussel MI, Satterwhite LL, Ko ER, Ginsburg GS, Kraft BD, Tsalik EL, Shen X, and Woods CW
- Published
- 2023
- Full Text
- View/download PDF
23. An antiplatelet response gene expression signature is associated with bleeding.
- Author
-
Friede KA, Myers RA, Gales J, Zhbannikov I, Ortel TL, Shah SH, Kraus WE, Ginsburg GS, and Voora D
- Subjects
- Humans, Ticagrelor adverse effects, Aspirin, Hemorrhage chemically induced, Hemorrhage genetics, Treatment Outcome, Platelet Aggregation Inhibitors, Transcriptome
- Abstract
Aims: Gene expression biosignatures may hold promise to individualize antiplatelet therapy in conjunction with current guidelines and risk scores. The Aspirin Response Signature (ARS) score is comprised of a weighted sum of correlated, pro-thrombotic gene transcripts measured in whole blood. In prior work where volunteers were exposed to aspirin 325 mg daily, higher ARS score was associated with lower platelet function; separately, in a clinical cohort of patients, higher ARS scores were associated with increased risk of adverse cardiovascular events. To better understand this apparent paradox, we measured ARS gene expression and score in volunteers to determine aspirin dose-response and ticagrelor relationships with ARS score and separately in patients to assess whether ARS is associated with incident bleeding., Methods and Results: Blood samples were collected from volunteers (N = 188) who were exposed to 4 weeks of daily aspirin 81 mg, daily aspirin 325 mg, and/or twice-daily ticagrelor 90 mg. ARS scores were calculated from whole blood RNA qPCR, and platelet function and protein expression were assessed in platelet-rich plasma. In mixed linear regression models, aspirin 81 mg exposure was not associated with changes in ARS gene expression or score. Aspirin 325 mg exposure resulted in a 6.0% increase in ARS gene expression (P = 7.5 × 10-9 vs. baseline, P = 2.1 × 10-4 vs. aspirin 81 mg) and an increase in expression of platelet proteins corresponding to ARS genes. Ticagrelor exposure resulted in a 30.7% increase in ARS gene expression (P < 1 × 10-10 vs. baseline and each aspirin dose) and ARS score (P = 7.0 × 10-7 vs. baseline, P = 3.6 × 10-6 and 5.59 × 10-4 vs. aspirin 81 and 325 mg, respectively). Increases in ARS gene expression or score were associated with the magnitude of platelet inhibition across agents. To assess the association between ARS scores and incident bleeding, ARS scores were calculated in patients undergoing cardiac catheterization (N = 1421), of whom 25.4% experienced bleeding events over a median 6.2 years of follow-up. In a Cox model adjusting for demographics and baseline antithrombotic medication use, patients with ARS scores above the median had a higher risk of incident bleeding [hazard ratio 1.26 (95% CI 1.01-1.56), P = 0.038]., Conclusions: The ARS is an Antiplatelet Response Signature that increases in response to greater platelet inhibition due to antiplatelet therapy and may represent a homeostatic mechanism to prevent bleeding. ARS scores could inform future strategies to prevent bleeding while maintaining antiplatelet therapy's benefit of ischaemic cardiovascular event protection., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2023
- Full Text
- View/download PDF
24. Lipoprotein Subclasses Associated With High-Risk Coronary Atherosclerotic Plaque: Insights From the PROMISE Clinical Trial.
- Author
-
McGarrah RW, Ferencik M, Giamberardino SN, Hoffmann U, Foldyna B, Karady J, Ginsburg GS, Kraus WE, Douglas PS, and Shah SH
- Subjects
- Humans, Prospective Studies, Lipoproteins, Lipoproteins, HDL, Coronary Angiography, Biomarkers, Chest Pain, Risk Factors, Coronary Artery Disease diagnostic imaging, Plaque, Atherosclerotic
- Abstract
BACKGROUND More than half of major adverse cardiovascular events (MACE) occur in the absence of obstructive coronary artery disease and are often attributed to the rupture of high-risk coronary atherosclerotic plaque (HRP). Blood-based biomarkers that associate with imaging-defined HRP and predict MACE are lacking. METHODS AND RESULTS Nuclear magnetic resonance-based lipoprotein particle profiling was performed in the biomarker substudy of the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial (N=4019) in participants who had stable symptoms suspicious for coronary artery disease. Principal components analysis was used to reduce the number of correlated lipoproteins into uncorrelated lipoprotein factors. The association of lipoprotein factors and individual lipoproteins of significantly associated factors with core laboratory determined coronary computed tomographic angiography features of HRP was determined using logistic regression models. The association of HRP-associated lipoproteins with MACE was assessed in the PROMISE trial and validated in an independent coronary angiography biorepository (CATHGEN [Catheterization Genetics]) using Cox proportional hazards models. Lipoprotein factors composed of high-density lipoprotein (HDL) subclasses were associated with HRP. In these factors, large HDL (odds ratio [OR], 0.70 [95% CI, 0.56-0.85]; P <0.001) and medium HDL (OR, 0.84 [95% CI, 0.72-0.98]; P =0.028) and HDL size (OR, 0.82 [95% CI, 0.69-0.96]; P =0.018) were associated with HRP in multivariable models. Medium HDL was associated with MACE in PROMISE (hazard ratio [HR], 0.76 [95% CI, 0.63-0.92]; P =0.004), which was validated in the CATHGEN biorepository (HR, 0.91 [95% CI, 0.88-0.94]; P <0.001). CONCLUSIONS Large and medium HDL subclasses and HDL size inversely associate with HRP features, and medium HDL subclasses inversely associate with MACE in PROMISE trial participants. These findings may aid in the risk stratification of individuals with chest pain and provide insight into the pathobiology of HRP. REGISTRATION URL: https://clinicaltrials.gov; Unique identifier: NCT01174550.
- Published
- 2023
- Full Text
- View/download PDF
25. Development of Competency-based Online Genomic Medicine Training (COGENT).
- Author
-
Haga SB, Chung WK, Cubano LA, Curry TB, Empey PE, Ginsburg GS, Mangold K, Miyake CY, Prakash SK, Ramsey LB, Rowley R, Rohrer Vitek CR, Skaar TC, Wynn J, and Manolio TA
- Subjects
- Humans, Genomic Medicine, Genomics education, Health Personnel education, Education, Distance, Medicine
- Abstract
The fields of genetics and genomics have greatly expanded across medicine through the development of new technologies that have revealed genetic contributions to a wide array of traits and diseases. Thus, the development of widely available educational resources for all healthcare providers is essential to ensure the timely and appropriate utilization of genetics and genomics patient care. In 2020, the National Human Genome Research Institute released a call for new proposals to develop accessible, sustainable online education for health providers. This paper describes the efforts of the six teams awarded to reach the goal of providing genetic and genomic training modules that are broadly available for busy clinicians.
- Published
- 2023
- Full Text
- View/download PDF
26. Pre-exposure cognitive performance variability is associated with severity of respiratory infection.
- Author
-
Zhai Y, Doraiswamy PM, Woods CW, Turner RB, Burke TW, Ginsburg GS, and Hero AO
- Subjects
- Humans, Pandemics, Cognition, Reaction Time, COVID-19, Respiratory Tract Infections
- Abstract
Using data from a longitudinal viral challenge study, we find that the post-exposure viral shedding and symptom severity are associated with a novel measure of pre-exposure cognitive performance variability (CPV), defined before viral exposure occurs. Each individual's CPV score is computed from data collected from a repeated NeuroCognitive Performance Test (NCPT) over a 3 day pre-exposure period. Of the 18 NCPT measures reported by the tests, 6 contribute materially to the CPV score, prospectively differentiating the high from the low shedders. Among these 6 are the 4 clinical measures digSym-time, digSym-correct, trail-time, and reaction-time, commonly used for assessing cognitive executive functioning. CPV is found to be correlated with stress and also with several genes previously reported to be associated with cognitive development and dysfunction. A perturbation study over the number and timing of NCPT sessions indicates that as few as 5 sessions is sufficient to maintain high association between the CPV score and viral shedding, as long as the timing of these sessions is balanced over the three pre-exposure days. Our results suggest that variations in cognitive function are closely related to immunity and susceptibility to severe infection. Further studying these relationships may help us better understand the links between neurocognitive and neuroimmune systems which is timely in this COVID-19 pandemic era., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
27. Implementation-effectiveness trial of systematic family health history based risk assessment and impact on clinical disease prevention and surveillance activities.
- Author
-
Wu RR, Myers RA, Neuner J, McCarty C, Haller IV, Harry M, Fulda KG, Dimmock D, Rakhra-Burris T, Buchanan A, Ginsburg GS, and Orlando LA
- Subjects
- Humans, Female, Middle Aged, Male, Medical History Taking, Risk Assessment, Genetic Counseling, Delivery of Health Care
- Abstract
Background: Systematically assessing disease risk can improve population health by identifying those eligible for enhanced prevention/screening strategies. This study aims to determine the clinical impact of a systematic risk assessment in diverse primary care populations., Methods: Hybrid implementation-effectiveness trial of a family health history-based health risk assessment (HRA) tied to risk-based guideline recommendations enrolling from 2014-2017 with 12 months of post-intervention survey data and 24 months of electronic medical record (EMR) data capture., Setting: 19 primary care clinics at four geographically and culturally diverse U.S. healthcare systems., Participants: any English or Spanish-speaking adult with an upcoming appointment at an enrolling clinic., Methods: A personal and family health history based HRA with integrated guideline-based clinical decision support (CDS) was completed by each participant prior to their appointment. Risk reports were provided to patients and providers to discuss at their clinical encounter., Outcomes: provider and patient discussion and provider uptake (i.e. ordering) and patient uptake (i.e. recommendation completion) of CDS recommendations., Measures: patient and provider surveys and EMR data., Results: One thousand eight hundred twenty nine participants (mean age 56.2 [SD13.9], 69.6% female) completed the HRA and had EMR data available for analysis. 762 (41.6%) received a recommendation (29.7% for genetic counseling (GC); 15.2% for enhanced breast/colon cancer screening). Those with recommendations frequently discussed disease risk with their provider (8.7%-38.2% varied by recommendation, p-values ≤ 0.004). In the GC subgroup, provider discussions increased referrals to counseling (44.4% with vs. 5.9% without, P < 0.001). Recommendation uptake was highest for colon cancer screening (provider = 67.9%; patient = 86.8%) and lowest for breast cancer chemoprevention (0%)., Conclusions: Systematic health risk assessment revealed that almost half the population were at increased disease risk based on guidelines. Risk identification resulted in shared discussions between participants and providers but variable clinical action uptake depending upon the recommendation. Understanding the barriers and facilitators to uptake by both patients and providers will be essential for optimizing HRA tools and achieving their promise of improving population health., Trial Registration: Clinicaltrials.gov number NCT01956773 , registered 10/8/2013., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
28. Risk factors for cardiovascular disease among individuals with hepatic steatosis.
- Author
-
Karády J, Ferencik M, Mayrhofer T, Meyersohn NM, Bittner DO, Staziaki PV, Szilveszter B, Hallett TR, Lu MT, Puchner SB, Simon TG, Foldyna B, Ginsburg GS, McGarrah RW, Voora D, Shah SH, Douglas PS, Hoffmann U, and Corey KE
- Subjects
- Humans, Male, Middle Aged, Female, Coronary Angiography methods, Cohort Studies, Prospective Studies, Risk Factors, Heart Disease Risk Factors, Cardiovascular Diseases epidemiology, Coronary Artery Disease epidemiology
- Abstract
Cardiovascular disease (CVD) is the leading cause of mortality in adults with hepatic steatosis (HS). However, risk factors for CVD in HS are unknown. We aimed to identify factors associated with coronary artery disease (CAD) and incident major adverse cardiovascular events (MACE) in individuals with HS. We performed a nested cohort study of adults with HS detected on coronary computed tomography in the PROspective Multicenter Imaging Study for Evaluation of chest pain (PROMISE) trial. Obstructive CAD was defined as ≥50% coronary stenosis. MACE included hospitalization for unstable angina, nonfatal myocardial infarction, or all-cause death. Multivariate modeling, adjusted for age, sex, atherosclerotic CVD (ASCVD) risk score and body mass index, identified factors associated with obstructive CAD. Cox regression, adjusted for ASCVD risk score, determined the predictors of MACE. A total of 959 of 3,756 (mean age 59.4 years, 55.0% men) had HS. Obstructive CAD was present in 15.2% (145 of 959). Male sex (adjusted odds ratio [aOR] = 1.83, 95% confidence interval [CI] 1.18-1.2.84; p = 0.007), ASCVD risk score (aOR = 1.05, 95% CI 1.03-1.07; p < 0.001), and n-terminal pro-b-type natriuretic peptide (NT-proBNP; aOR = 1.90, 95% CI 1.38-2.62; p < 0.001) were independently associated with obstructive CAD. In the 25-months median follow-up, MACE occurred in 4.4% (42 of 959). Sedentary lifestyle (adjusted hazard ratio [aHR] = 2.53, 95% CI 1.27-5.03; p = 0.008) and NT-proBNP (aOR = 1.50, 95% CI 1.01-2.25; p = 0.046) independently predicted MACE. Furthermore, the risk of MACE increased by 3% for every 1% increase in ASCVD risk score (aHR = 1.03, 95% CI 1.01-1.05; p = 0.02). Conclusion: In individuals with HS, male sex, NT-pro-BNP, and ASCVD risk score are associated with obstructive CAD. Furthermore, ASCVD, NT-proBNP, and sedentary lifestyle are independent predictors of MACE. These factors, with further validation, may help risk-stratify adults with HS for incident CAD and MACE., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)
- Published
- 2022
- Full Text
- View/download PDF
29. Genomic Medicine Year in Review: 2022.
- Author
-
Manolio TA, Narula J, Bult CJ, Chisholm RL, Deverka PA, Ginsburg GS, Goldrich M, Green ED, Jarvik GP, Mensah GA, Ramos EM, Relling MV, Roden DM, Rowley R, and Williams MS
- Subjects
- Humans, Genomic Medicine
- Published
- 2022
- Full Text
- View/download PDF
30. A method for intelligent allocation of diagnostic testing by leveraging data from commercial wearable devices: a case study on COVID-19.
- Author
-
Shandhi MMH, Cho PJ, Roghanizad AR, Singh K, Wang W, Enache OM, Stern A, Sbahi R, Tatar B, Fiscus S, Khoo QX, Kuo Y, Lu X, Hsieh J, Kalodzitsa A, Bahmani A, Alavi A, Ray U, Snyder MP, Ginsburg GS, Pasquale DK, Woods CW, Shaw RJ, and Dunn JP
- Abstract
Mass surveillance testing can help control outbreaks of infectious diseases such as COVID-19. However, diagnostic test shortages are prevalent globally and continue to occur in the US with the onset of new COVID-19 variants and emerging diseases like monkeypox, demonstrating an unprecedented need for improving our current methods for mass surveillance testing. By targeting surveillance testing toward individuals who are most likely to be infected and, thus, increasing the testing positivity rate (i.e., percent positive in the surveillance group), fewer tests are needed to capture the same number of positive cases. Here, we developed an Intelligent Testing Allocation (ITA) method by leveraging data from the CovIdentify study (6765 participants) and the MyPHD study (8580 participants), including smartwatch data from 1265 individuals of whom 126 tested positive for COVID-19. Our rigorous model and parameter search uncovered the optimal time periods and aggregate metrics for monitoring continuous digital biomarkers to increase the positivity rate of COVID-19 diagnostic testing. We found that resting heart rate (RHR) features distinguished between COVID-19-positive and -negative cases earlier in the course of the infection than steps features, as early as 10 and 5 days prior to the diagnostic test, respectively. We also found that including steps features increased the area under the receiver operating characteristic curve (AUC-ROC) by 7-11% when compared with RHR features alone, while including RHR features improved the AUC of the ITA model's precision-recall curve (AUC-PR) by 38-50% when compared with steps features alone. The best AUC-ROC (0.73 ± 0.14 and 0.77 on the cross-validated training set and independent test set, respectively) and AUC-PR (0.55 ± 0.21 and 0.24) were achieved by using data from a single device type (Fitbit) with high-resolution (minute-level) data. Finally, we show that ITA generates up to a 6.5-fold increase in the positivity rate in the cross-validated training set and up to a 4.5-fold increase in the positivity rate in the independent test set, including both symptomatic and asymptomatic (up to 27%) individuals. Our findings suggest that, if deployed on a large scale and without needing self-reported symptoms, the ITA method could improve the allocation of diagnostic testing resources and reduce the burden of test shortages., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
31. Coronary Atherosclerosis, Cardiac Troponin, and Interleukin-6 in Patients With Chest Pain: The PROMISE Trial Results.
- Author
-
Ferencik M, Mayrhofer T, Lu MT, Bittner DO, Emami H, Puchner SB, Meyersohn NM, Ivanov AV, Adami EC, Voora D, Ginsburg GS, Januzzi JL, Douglas PS, and Hoffmann U
- Subjects
- Aged, Chest Pain, Constriction, Pathologic complications, Coronary Angiography methods, Female, Humans, Inflammation complications, Interleukin-6, Male, Middle Aged, Predictive Value of Tests, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, Troponin, Troponin I, Coronary Artery Disease complications, Coronary Artery Disease diagnostic imaging, Coronary Stenosis complications, Coronary Stenosis diagnostic imaging, Coronary Stenosis therapy, Myocardial Infarction complications, Plaque, Atherosclerotic
- Abstract
Background: Increased inflammation and myocardial injury can be observed in the absence of myocardial infarction or obstructive coronary artery disease (CAD)., Objectives: The authors determined whether biomarkers of inflammation and myocardial injury-interleukin (IL)-6 and high-sensitivity cardiac troponin (hs-cTn)-were associated with the presence and extent of CAD and were independent predictors of major adverse cardiovascular events (MACEs) in stable chest pain., Methods: Using participants from the PROMISE trial, the authors measured hs-cTn I and IL-6 concentrations and analyzed computed tomography angiography (CTA) images in the core laboratory for CAD characteristics: significant stenosis (≥70%), high-risk plaque (HRP), Coronary Artery Disease Reporting and Data System (CAD-RADS) categories, segment involvement score (SIS), and coronary artery calcium (CAC) score. The primary endpoint was a composite MACE (death, myocardial infarction, or unstable angina)., Results: The authors included 1,796 participants (age 60.2 ± 8.0 years; 47.5% men, median follow-up 25 months). In multivariable linear regression adjusted for atherosclerotic cardiovascular disease (ASCVD) risk, hs-cTn was associated with HRP, stenosis, CAD-RADS, and SIS. IL-6 was only associated with stenosis and CAD-RADS. hs-cTn above median (1.5 ng/L) was associated with MACEs in univariable analysis (HR: 2.1 [95% CI: 1.3-3.6]; P = 0.006), but not in multivariable analysis adjusted for ASCVD and CAD. IL-6 above median (1.8 ng/L) was associated with MACEs in multivariable analysis adjusted for ASCVD and HRP (HR: 1.9 [95% CI: 1.1-3.3]; P = 0.03), CAC (HR: 1.9 [95% CI: 1.0-3.4]; P = 0.04), and SIS (HR: 1.8 [95% CI: 1.0-3.2]; P = 0.04), but not for stenosis or CAD-RADS. In participants with nonobstructive CAD (stenosis 1%-69%), the presence of both hs-cTn and IL-6 above median was strongly associated with MACEs (HR: 2.5-2.7 after adjustment for CAD characteristics)., Conclusions: Concentrations of hs-cTn and IL-6 were associated with CAD characteristics and MACEs, indicating that myocardial injury and inflammation may each contribute to pathways in CAD pathophysiology. This association was most pronounced among participants with nonobstructive CAD representing an opportunity to tailor treatment in this at-risk group. (PROspective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]; NCT01174550)., Competing Interests: Funding Support and Author Disclosures The PROMISE trial was funded by grants R01HL098237, R01HL098236, R01HL98305, and R01HL098235 from the National Heart, Lung, and Blood Institute (NHLBI). The funding source had no role in the design and conduct of this study, study analyses and interpretation of the data, the drafting and editing of the manuscript and its final contents, approval of the manuscript, and the decision to submit the manuscript for publication. The views expressed in this article do not necessarily represent the official views of the NHLBI. This article was prepared while Dr Ginsburg was employed at Duke University. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. Dr Ferencik has received a grant from the American Heart Association, National Institutes of Health; and has received consulting fees from Biograph, Inc. Dr Bittner was supported by a grant from the National Institutes of Health/NHLBI (5K24HL113128). Dr Lu has received grant support from the American Roentgen Ray Society Scholarship during the conduct of the study; and has received personal fees from PQBypass outside of the submitted work. Dr Meyersohn was supported by National Institutes of Health/NHLBI (T32 HL076136). Dr Douglas has received grant support from HeartFlow; and has served on a data and safety monitoring board for GE HealthCare outside of the submitted work. Dr Hoffmann has received grants from the American College of Radiology Imaging Network and HeartFlow during the conduct of the study, and from Siemens Healthcare outside of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
32. A research agenda to support the development and implementation of genomics-based clinical informatics tools and resources.
- Author
-
Wiley K, Findley L, Goldrich M, Rakhra-Burris TK, Stevens A, Williams P, Bult CJ, Chisholm R, Deverka P, Ginsburg GS, Green ED, Jarvik G, Mensah GA, Ramos E, Relling MV, Roden DM, Rowley R, Alterovitz G, Aronson S, Bastarache L, Cimino JJ, Crowgey EL, Del Fiol G, Freimuth RR, Hoffman MA, Jeff J, Johnson K, Kawamoto K, Madhavan S, Mendonca EA, Ohno-Machado L, Pratap S, Taylor CO, Ritchie MD, Walton N, Weng C, Zayas-Cabán T, Manolio TA, and Williams MS
- Subjects
- Electronic Health Records, Genome, Human, Genomics, Humans, Research Design, Medical Informatics
- Abstract
Objective: The Genomic Medicine Working Group of the National Advisory Council for Human Genome Research virtually hosted its 13th genomic medicine meeting titled "Developing a Clinical Genomic Informatics Research Agenda". The meeting's goal was to articulate a research strategy to develop Genomics-based Clinical Informatics Tools and Resources (GCIT) to improve the detection, treatment, and reporting of genetic disorders in clinical settings., Materials and Methods: Experts from government agencies, the private sector, and academia in genomic medicine and clinical informatics were invited to address the meeting's goals. Invitees were also asked to complete a survey to assess important considerations needed to develop a genomic-based clinical informatics research strategy., Results: Outcomes from the meeting included identifying short-term research needs, such as designing and implementing standards-based interfaces between laboratory information systems and electronic health records, as well as long-term projects, such as identifying and addressing barriers related to the establishment and implementation of genomic data exchange systems that, in turn, the research community could help address., Discussion: Discussions centered on identifying gaps and barriers that impede the use of GCIT in genomic medicine. Emergent themes from the meeting included developing an implementation science framework, defining a value proposition for all stakeholders, fostering engagement with patients and partners to develop applications under patient control, promoting the use of relevant clinical workflows in research, and lowering related barriers to regulatory processes. Another key theme was recognizing pervasive biases in data and information systems, algorithms, access, value, and knowledge repositories and identifying ways to resolve them., (Published by Oxford University Press on behalf of the American Medical Informatics Association 2022. This work is written by US Government employees and is in the public domain in the US.)
- Published
- 2022
- Full Text
- View/download PDF
33. Differential chromatin accessibility in peripheral blood mononuclear cells underlies COVID-19 disease severity prior to seroconversion.
- Author
-
Giroux NS, Ding S, McClain MT, Burke TW, Petzold E, Chung HA, Rivera GO, Wang E, Xi R, Bose S, Rotstein T, Nicholson BP, Chen T, Henao R, Sempowski GD, Denny TN, De Ussel MI, Satterwhite LL, Ko ER, Ginsburg GS, Kraft BD, Tsalik EL, Shen X, and Woods CW
- Subjects
- Antiviral Agents, Humans, Immunoglobulin G genetics, Leukocytes, Mononuclear, SARS-CoV-2, Seroconversion, Severity of Illness Index, COVID-19 genetics, Chromatin genetics
- Abstract
SARS-CoV-2 infection triggers profound and variable immune responses in human hosts. Chromatin remodeling has been observed in individuals severely ill or convalescing with COVID-19, but chromatin remodeling early in disease prior to anti-spike protein IgG seroconversion has not been defined. We performed the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and RNA-seq on peripheral blood mononuclear cells (PBMCs) from outpatients with mild or moderate symptom severity at different stages of clinical illness. Early in the disease course prior to IgG seroconversion, modifications in chromatin accessibility associated with mild or moderate symptoms were already robust and included severity-associated changes in accessibility of genes in interleukin signaling, regulation of cell differentiation and cell morphology. Furthermore, single-cell analyses revealed evolution of the chromatin accessibility landscape and transcription factor motif accessibility for individual PBMC cell types over time. The most extensive remodeling occurred in CD14+ monocytes, where sub-populations with distinct chromatin accessibility profiles were observed prior to seroconversion. Mild symptom severity was marked by upregulation of classical antiviral pathways, including those regulating IRF1 and IRF7, whereas in moderate disease, these classical antiviral signals diminished, suggesting dysregulated and less effective responses. Together, these observations offer novel insight into the epigenome of early mild SARS-CoV-2 infection and suggest that detection of chromatin remodeling in early disease may offer promise for a new class of diagnostic tools for COVID-19., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
34. Digital health-enabled genomics: Opportunities and challenges.
- Author
-
Bombard Y, Ginsburg GS, Sturm AC, Zhou AY, and Lemke AA
- Subjects
- Delivery of Health Care, Electronic Health Records, Genomics, Humans, COVID-19 genetics, Pandemics
- Abstract
Digital health solutions, with apps, virtual care, and electronic medical records, are gaining momentum across all medical disciplines, and their adoption has been accelerated, in part, by the COVID-19 pandemic. Personal wearables, sensors, and mobile technologies are increasingly being used to identify health risks and assist in diagnosis, treatment, and monitoring of health and disease. Genomics is a vanguard of digital healthcare as we witness a convergence of the fields of genomic and digital medicine. Spurred by the acute need to increase health literacy, empower patients' preference-sensitive decisions, or integrate vast amounts of complex genomic data into the clinical workflow, there has been an emergence of digital support tools in genomics-enabled care. We present three use cases that demonstrate the application of these converging technologies: digital genomics decision support tools, conversational chatbots to scale the genetic counseling process, and the digital delivery of comprehensive genetic services. These digital solutions are important to facilitate patient-centered care delivery, improve patient outcomes, and increase healthcare efficiencies in genomic medicine. Yet the development of these innovative digital genomic technologies also reveals strategic challenges that need to be addressed before genomic digital health can be broadly adopted. Alongside key evidentiary gaps in clinical and cost-effectiveness, there is a paucity of clinical guidelines, policy, and regulatory frameworks that incorporate digital health. We propose a research agenda, guided by learning healthcare systems, to realize the vision of digital health-enabled genomics to ensure its sustainable and equitable deployment in clinical care., Competing Interests: Declaration of interests G.S.G. is an employee of the National Institutes of Health, the Department of Health and Human Services, and the United States government. The opinions expressed in this article are the author’s own and do not reflect the view of these organizations. This article was prepared while G.S.G. was employed at Duke University. At that time, G.S.G. was a consultant for KonicaMinolta and Fabric Genomics. G.S.G. was an owner of Peer Medical, Origin Commercial Advisors, Predigen, MeTree&You, and Coprata. G.S.G. received royalties from Elsevier. A.Y.Z. is a full-time employee and shareholder of Color Health, Inc. A.C.S. is an employee of 23andMe. The article was prepared while A.C.S. was employed at Geisinger. At that time, A.C.S. was a consultant for Invitae and 23andMe., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
35. A precision medicine approach to stress testing using metabolomics and microribonucleic acids.
- Author
-
Limkakeng AT, Rowlette LL, Hatch A, Nixon AB, Ilkayeva O, Corcoran D, Modliszewski J, Griffin SM, Ginsburg GS, and Voora D
- Subjects
- Biomarkers, Humans, Pilot Projects, Precision Medicine, MicroRNAs genetics, Myocardial Ischemia
- Abstract
Both transcriptomics and metabolomics hold promise for identifying acute coronary syndrome (ACS) but they have not been used in combination, nor have dynamic changes in levels been assessed as a diagnostic tool. We assessed integrated analysis of peripheral blood miRNA and metabolite analytes to distinguish patients with myocardial ischemia on cardiac stress testing. We isolated and quantified miRNA and metabolites before and after stress testing from seven patients with myocardial ischemia and 1:1 matched controls. The combined miRNA and metabolomic data were analyzed jointly in a supervised, dimension-reducing discriminant analysis. We implemented a baseline model (T0) and a stress-delta model. This novel integrative analysis of the baseline levels of metabolites and miRNA expression showed modest performance for distinguishing cases from controls. The stress-delta model showed worse performance. This pilot study shows potential for an integrated precision medicine approach to cardiac stress testing.
- Published
- 2022
- Full Text
- View/download PDF
36. A hands-free stool sampling system for monitoring intestinal health and disease.
- Author
-
Grego S, Welling CM, Miller GH, Coggan PF, Sellgren KL, Hawkins BT, Ginsburg GS, Ruiz JR, Fisher DA, and Stoner BR
- Subjects
- Feces, Humans, RNA, Ribosomal, 16S genetics, Specimen Handling methods, Gastrointestinal Microbiome genetics, Occult Blood
- Abstract
Analysis of stool offers simple, non-invasive monitoring for many gastrointestinal (GI) diseases and access to the gut microbiome, however adherence to stool sampling protocols remains a major challenge because of the prevalent dislike of handling one's feces. We present a technology that enables individual stool specimen collection from toilet wastewater for fecal protein and molecular assay. Human stool specimens and a benchtop test platform integrated with a commercial toilet were used to demonstrate reliable specimen collection over a wide range of stool consistencies by solid/liquid separation followed by spray-erosion. The obtained fecal suspensions were used to perform occult blood tests for GI cancer screening and for microbiome 16S rRNA analysis. Using occult blood home test kits, we found overall 90% agreement with standard sampling, 96% sensitivity and 86% specificity. Microbiome analysis revealed no significant difference in within-sample species diversity compared to standard sampling and specimen cross-contamination was below the detection limit of the assay. Furthermore, we report on the use of an analogue turbidity sensor to assess in real time loose stools for tracking of diarrhea. Implementation of this technology in residential settings will improve the quality of GI healthcare by facilitating increased adherence to routine stool monitoring., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
37. Global priorities for large-scale biomarker-based prospective cohorts.
- Author
-
Collins R, Balaconis MK, Brunak S, Chen Z, De Silva M, Gaziano JM, Ginsburg GS, Jha P, Kuri P, Metspalu A, Mulder N, and Risch N
- Abstract
The focus of this paper is on strategic approaches for establishing population-based prospective cohorts that collect and store biological samples from very large numbers of participants to help identify the determinants of common health outcomes. In particular, it aims to address key issues related to investigation of genetic, as well as social, environmental, and ancestral, diversity; generation of detailed genetic and other types of assay data; collection of detailed lifestyle and environmental exposure information; follow-up and characterization of incident health outcomes; and overcoming obstacles to data sharing and access (including capacity building). It concludes that there is a need for strategic planning at an international level (rather than the current ad hoc approach) toward the development of a carefully selected set of deeply characterized large-scale prospective cohorts that are readily accessible by researchers around the world., Competing Interests: R.C. is the principal investigator (PI) and CEO of UK Biobank; Z.C. is the co-PI of the China Kadoorie Biobank; M.G. is the PI of the Million Veteran Program; G.G. is the chief medical and scientific officer of the All of Us Program; P.K.. is the director of Proyecto OriGen; A.M. is the head of the Estonian Biobank; and N.M. is on the advisory board of Cell Genomics., (© 2022 The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
38. Harnessing the Power of Artificial Intelligence in Otolaryngology and the Communication Sciences.
- Author
-
Wilson BS, Tucci DL, Moses DA, Chang EF, Young NM, Zeng FG, Lesica NA, Bur AM, Kavookjian H, Mussatto C, Penn J, Goodwin S, Kraft S, Wang G, Cohen JM, Ginsburg GS, Dawson G, and Francis HW
- Subjects
- Communication, Humans, Artificial Intelligence, Otolaryngology
- Abstract
Use of artificial intelligence (AI) is a burgeoning field in otolaryngology and the communication sciences. A virtual symposium on the topic was convened from Duke University on October 26, 2020, and was attended by more than 170 participants worldwide. This review presents summaries of all but one of the talks presented during the symposium; recordings of all the talks, along with the discussions for the talks, are available at https://www.youtube.com/watch?v=ktfewrXvEFg and https://www.youtube.com/watch?v=-gQ5qX2v3rg . Each of the summaries is about 2500 words in length and each summary includes two figures. This level of detail far exceeds the brief summaries presented in traditional reviews and thus provides a more-informed glimpse into the power and diversity of current AI applications in otolaryngology and the communication sciences and how to harness that power for future applications., (© 2022. The Author(s) under exclusive licence to Association for Research in Otolaryngology.)
- Published
- 2022
- Full Text
- View/download PDF
39. Aspirin effects on platelet gene expression are associated with a paradoxical, increase in platelet function.
- Author
-
Myers RA, Ortel TL, Waldrop A, Dave S, Ginsburg GS, and Voora D
- Subjects
- Adult, Cross-Over Studies, Gene Expression, Humans, Platelet Aggregation, Platelet Aggregation Inhibitors pharmacology, RNA, Messenger metabolism, Aspirin adverse effects, Blood Platelets
- Abstract
Aspirin has known effects beyond inhibiting platelet cyclooxygenase-1 (COX-1) that have been incompletely characterized. Transcriptomics can comprehensively characterize the on- and off-target effects of medications. We used a systems pharmacogenomics approach of aspirin exposure in volunteers coupled with serial platelet function and purified platelet mRNA sequencing to test the hypothesis that aspirin's effects on the platelet transcriptome are associated with platelet function. We prospectively recruited 74 adult volunteers for a randomized crossover study of 81- vs. 325 mg/day, each for 4 weeks. Using mRNA sequencing of purified platelets collected before and after each 4-week exposure, we identified 208 aspirin-responsive genes with no evidence for dosage effects. In independent cohorts of healthy volunteers and patients with diabetes, we validated aspirin's effects on five genes: EIF2S3, CHRNB1, EPAS1, SLC9A3R2 and HLA-DRA. Functional characterization of the effects of aspirin on mRNA as well as platelet ribosomal RNA demonstrated that aspirin may act as an inhibitor of protein synthesis. Database searches for small molecules that mimicked the effects of aspirin on platelet gene expression in vitro identified aspirin but no other molecules that share aspirin's known mechanisms of action. The effects of aspirin on platelet mRNA were correlated with higher levels of platelet function both at baseline and after aspirin exposure-an effect that counteracts aspirin's known antiplatelet effect. In summary, this work collectively demonstrates a dose-independent effect of aspirin on the platelet transcriptome that counteracts the well-known antiplatelet effects of aspirin., (© 2021 British Pharmacological Society.)
- Published
- 2022
- Full Text
- View/download PDF
40. Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection.
- Author
-
Ko ER, Henao R, Frankey K, Petzold EA, Isner PD, Jaehne AK, Allen N, Gardner-Gray J, Hurst G, Pflaum-Carlson J, Jayaprakash N, Rivers EP, Wang H, Ugalde I, Amanullah S, Mercurio L, Chun TH, May L, Hickey RW, Lazarus JE, Gunaratne SH, Pallin DJ, Jambaulikar G, Huckins DS, Ampofo K, Jhaveri R, Jiang Y, Komarow L, Evans SR, Ginsburg GS, Tillekeratne LG, McClain MT, Burke TW, Woods CW, and Tsalik EL
- Subjects
- Adult, Bacteria, Child, Female, Fever diagnosis, Gene Expression, Humans, Male, Procalcitonin, Bacterial Infections drug therapy, COVID-19 diagnosis, Virus Diseases diagnosis
- Abstract
Importance: Bacterial and viral causes of acute respiratory illness (ARI) are difficult to clinically distinguish, resulting in the inappropriate use of antibacterial therapy. The use of a host gene expression-based test that is able to discriminate bacterial from viral infection in less than 1 hour may improve care and antimicrobial stewardship., Objective: To validate the host response bacterial/viral (HR-B/V) test and assess its ability to accurately differentiate bacterial from viral infection among patients with ARI., Design, Setting, and Participants: This prospective multicenter diagnostic study enrolled 755 children and adults with febrile ARI of 7 or fewer days' duration from 10 US emergency departments. Participants were enrolled from October 3, 2014, to September 1, 2019, followed by additional enrollment of patients with COVID-19 from March 20 to December 3, 2020. Clinical adjudication of enrolled participants identified 616 individuals as having bacterial or viral infection. The primary analysis cohort included 334 participants with high-confidence reference adjudications (based on adjudicator concordance and the presence of an identified pathogen confirmed by microbiological testing). A secondary analysis of the entire cohort of 616 participants included cases with low-confidence reference adjudications (based on adjudicator discordance or the absence of an identified pathogen in microbiological testing). Thirty-three participants with COVID-19 were included post hoc., Interventions: The HR-B/V test quantified the expression of 45 host messenger RNAs in approximately 45 minutes to derive a probability of bacterial infection., Main Outcomes and Measures: Performance characteristics for the HR-B/V test compared with clinical adjudication were reported as either bacterial or viral infection or categorized into 4 likelihood groups (viral very likely [probability score <0.19], viral likely [probability score of 0.19-0.40], bacterial likely [probability score of 0.41-0.73], and bacterial very likely [probability score >0.73]) and compared with procalcitonin measurement., Results: Among 755 enrolled participants, the median age was 26 years (IQR, 16-52 years); 360 participants (47.7%) were female, and 395 (52.3%) were male. A total of 13 participants (1.7%) were American Indian, 13 (1.7%) were Asian, 368 (48.7%) were Black, 131 (17.4%) were Hispanic, 3 (0.4%) were Native Hawaiian or Pacific Islander, 297 (39.3%) were White, and 60 (7.9%) were of unspecified race and/or ethnicity. In the primary analysis involving 334 participants, the HR-B/V test had sensitivity of 89.8% (95% CI, 77.8%-96.2%), specificity of 82.1% (95% CI, 77.4%-86.6%), and a negative predictive value (NPV) of 97.9% (95% CI, 95.3%-99.1%) for bacterial infection. In comparison, the sensitivity of procalcitonin measurement was 28.6% (95% CI, 16.2%-40.9%; P < .001), the specificity was 87.0% (95% CI, 82.7%-90.7%; P = .006), and the NPV was 87.6% (95% CI, 85.5%-89.5%; P < .001). When stratified into likelihood groups, the HR-B/V test had an NPV of 98.9% (95% CI, 96.1%-100%) for bacterial infection in the viral very likely group and a positive predictive value of 63.4% (95% CI, 47.2%-77.9%) for bacterial infection in the bacterial very likely group. The HR-B/V test correctly identified 30 of 33 participants (90.9%) with acute COVID-19 as having a viral infection., Conclusions and Relevance: In this study, the HR-B/V test accurately discriminated bacterial from viral infection among patients with febrile ARI and was superior to procalcitonin measurement. The findings suggest that an accurate point-of-need host response test with high NPV may offer an opportunity to improve antibiotic stewardship and patient outcomes.
- Published
- 2022
- Full Text
- View/download PDF
41. Systematic comparison of published host gene expression signatures for bacterial/viral discrimination.
- Author
-
Bodkin N, Ross M, McClain MT, Ko ER, Woods CW, Ginsburg GS, Henao R, and Tsalik EL
- Subjects
- Adult, Bacterial Infections epidemiology, Bacterial Infections genetics, Biomarkers analysis, COVID-19 diagnosis, COVID-19 genetics, Child, Cohort Studies, Diagnosis, Differential, Gene Expression Profiling statistics & numerical data, Genetic Association Studies statistics & numerical data, Humans, Publications statistics & numerical data, SARS-CoV-2 pathogenicity, Validation Studies as Topic, Virus Diseases epidemiology, Virus Diseases genetics, Bacterial Infections diagnosis, Datasets as Topic statistics & numerical data, Host-Pathogen Interactions genetics, Transcriptome, Virus Diseases diagnosis
- Abstract
Background: Measuring host gene expression is a promising diagnostic strategy to discriminate bacterial and viral infections. Multiple signatures of varying size, complexity, and target populations have been described. However, there is little information to indicate how the performance of various published signatures compare to one another., Methods: This systematic comparison of host gene expression signatures evaluated the performance of 28 signatures, validating them in 4589 subjects from 51 publicly available datasets. Thirteen COVID-specific datasets with 1416 subjects were included in a separate analysis. Individual signature performance was evaluated using the area under the receiving operating characteristic curve (AUC) value. Overall signature performance was evaluated using median AUCs and accuracies., Results: Signature performance varied widely, with median AUCs ranging from 0.55 to 0.96 for bacterial classification and 0.69-0.97 for viral classification. Signature size varied (1-398 genes), with smaller signatures generally performing more poorly (P < 0.04). Viral infection was easier to diagnose than bacterial infection (84% vs. 79% overall accuracy, respectively; P < .001). Host gene expression classifiers performed more poorly in some pediatric populations (3 months-1 year and 2-11 years) compared to the adult population for both bacterial infection (73% and 70% vs. 82%, respectively; P < .001) and viral infection (80% and 79% vs. 88%, respectively; P < .001). We did not observe classification differences based on illness severity as defined by ICU admission for bacterial or viral infections. The median AUC across all signatures for COVID-19 classification was 0.80 compared to 0.83 for viral classification in the same datasets., Conclusions: In this systematic comparison of 28 host gene expression signatures, we observed differences based on a signature's size and characteristics of the validation population, including age and infection type. However, populations used for signature discovery did not impact performance, underscoring the redundancy among many of these signatures. Furthermore, differential performance in specific populations may only be observable through this type of large-scale validation., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
42. A comparison of host response strategies to distinguish bacterial and viral infection.
- Author
-
Ross M, Henao R, Burke TW, Ko ER, McClain MT, Ginsburg GS, Woods CW, and Tsalik EL
- Subjects
- Adult, Bacterial Infections complications, Bacterial Infections metabolism, Bacterial Infections microbiology, Biomarkers metabolism, C-Reactive Protein genetics, C-Reactive Protein metabolism, Case-Control Studies, Chemokine CXCL10 genetics, Chemokine CXCL10 metabolism, Diagnosis, Differential, Emergency Service, Hospital, Female, Follow-Up Studies, Humans, Male, Middle Aged, Procalcitonin genetics, Procalcitonin metabolism, Prognosis, ROC Curve, Receptors, Immunologic genetics, Receptors, Immunologic metabolism, Respiratory Tract Infections etiology, Respiratory Tract Infections metabolism, Respiratory Tract Infections pathology, Retrospective Studies, TNF-Related Apoptosis-Inducing Ligand genetics, TNF-Related Apoptosis-Inducing Ligand metabolism, United States epidemiology, Virus Diseases complications, Virus Diseases virology, Bacteria isolation & purification, Bacterial Infections diagnosis, Respiratory Tract Infections epidemiology, Virus Diseases diagnosis, Viruses isolation & purification
- Abstract
Objectives: Compare three host response strategies to distinguish bacterial and viral etiologies of acute respiratory illness (ARI)., Methods: In this observational cohort study, procalcitonin, a 3-protein panel (CRP, IP-10, TRAIL), and a host gene expression mRNA panel were measured in 286 subjects with ARI from four emergency departments. Multinomial logistic regression and leave-one-out cross validation were used to evaluate the protein and mRNA tests., Results: The mRNA panel performed better than alternative strategies to identify bacterial infection: AUC 0.93 vs. 0.83 for the protein panel and 0.84 for procalcitonin (P<0.02 for each comparison). This corresponded to a sensitivity and specificity of 92% and 83% for the mRNA panel, 81% and 73% for the protein panel, and 68% and 87% for procalcitonin, respectively. A model utilizing all three strategies was the same as mRNA alone. For the diagnosis of viral infection, the AUC was 0.93 for mRNA and 0.84 for the protein panel (p<0.05). This corresponded to a sensitivity and specificity of 89% and 82% for the mRNA panel, and 85% and 62% for the protein panel, respectively., Conclusions: A gene expression signature was the most accurate host response strategy for classifying subjects with bacterial, viral, or non-infectious ARI., Competing Interests: ELT, RH, MTM, GSG, TWB, and CWW have filed for a patent for Methods to Diagnose and Treat Acute Respiratory Infections (WO 2017/004390 A1).
- Published
- 2021
- Full Text
- View/download PDF
43. Genomic medicine year in review: 2021.
- Author
-
Manolio TA, Bult CJ, Chisholm RL, Deverka PA, Ginsburg GS, Goldrich M, Jarvik GP, Mensah GA, Ramos EM, Relling MV, Roden DM, Rowley R, Williams MS, and Green ED
- Published
- 2021
- Full Text
- View/download PDF
44. Comparing the Diagnostic Accuracy of Clinician Judgment to a Novel Host Response Diagnostic for Acute Respiratory Illness.
- Author
-
Jaffe IS, Jaehne AK, Quackenbush E, Ko ER, Rivers EP, McClain MT, Ginsburg GS, Woods CW, and Tsalik EL
- Abstract
Background: Difficulty discriminating bacterial from viral infections drives antibacterial misuse. Host gene expression tests discriminate bacterial and viral etiologies, but their clinical utility has not been evaluated., Methods: Host gene expression and procalcitonin levels were measured in 582 emergency department participants with suspected infection. We also recorded clinician diagnosis and clinician-recommended treatment. These 4 diagnostic strategies were compared with clinical adjudication as the reference. To estimate the clinical impact of host gene expression, we calculated the change in overall Net Benefit (∆NB; the difference in Net Benefit comparing 1 diagnostic strategy with a reference) across a range of prevalence estimates while factoring in the clinical significance of false-positive and -negative errors., Results: Gene expression correctly classified bacterial, viral, or noninfectious illness in 74.1% of subjects, similar to the other strategies. Clinical diagnosis and clinician-recommended treatment revealed a bias toward overdiagnosis of bacterial infection resulting in high sensitivity (92.6% and 94.5%, respectively) but poor specificity (67.2% and 58.8%, respectively), resulting in a 33.3% rate of inappropriate antibacterial use. Gene expression offered a more balanced sensitivity (79.0%) and specificity (80.7%), which corresponded to a statistically significant improvement in average weighted accuracy (79.9% vs 71.5% for procalcitonin and 76.3% for clinician-recommended treatment; P <.0001 for both). Consequently, host gene expression had greater Net Benefit in diagnosing bacterial infection than clinician-recommended treatment (∆NB=6.4%) and procalcitonin (∆NB=17.4%)., Conclusions: Host gene expression-based tests to distinguish bacterial and viral infection can facilitate appropriate treatment, improving patient outcomes and mitigating the antibacterial resistance crisis., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2021.)
- Published
- 2021
- Full Text
- View/download PDF
45. The Host Response to Viral Infections Reveals Common and Virus-Specific Signatures in the Peripheral Blood.
- Author
-
Tsalik EL, Fiorino C, Aqeel A, Liu Y, Henao R, Ko ER, Burke TW, Reller ME, Bodinayake CK, Nagahawatte A, Arachchi WK, Devasiri V, Kurukulasooriya R, McClain MT, Woods CW, Ginsburg GS, Tillekeratne LG, and Schughart K
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, Complement Activation, Female, Humans, Immunity genetics, Interferons metabolism, MAP Kinase Signaling System, Male, Middle Aged, Oxidative Stress, Transcriptome, Young Adult, Interferons genetics, Respiratory Tract Infections immunology, T-Lymphocytes physiology, Virus Diseases genetics, Viruses immunology
- Abstract
Viruses cause a wide spectrum of clinical disease, the majority being acute respiratory infections (ARI). In most cases, ARI symptoms are similar for different viruses although severity can be variable. The objective of this study was to understand the shared and unique elements of the host transcriptional response to different viral pathogens. We identified 162 subjects in the US and Sri Lanka with infections due to influenza, enterovirus/rhinovirus, human metapneumovirus, dengue virus, cytomegalovirus, Epstein Barr Virus, or adenovirus. Our dataset allowed us to identify common pathways at the molecular level as well as virus-specific differences in the host immune response. Conserved elements of the host response to these viral infections highlighted the importance of interferon pathway activation. However, the magnitude of the responses varied between pathogens. We also identified virus-specific responses to influenza, enterovirus/rhinovirus, and dengue infections. Influenza-specific differentially expressed genes (DEG) revealed up-regulation of pathways related to viral defense and down-regulation of pathways related to T cell and neutrophil responses. Functional analysis of entero/rhinovirus-specific DEGs revealed up-regulation of pathways for neutrophil activation, negative regulation of immune response, and p38MAPK cascade and down-regulation of virus defenses and complement activation. Functional analysis of dengue-specific up-regulated DEGs showed enrichment of pathways for DNA replication and cell division whereas down-regulated DEGs were mainly associated with erythrocyte and myeloid cell homeostasis, reactive oxygen and peroxide metabolic processes. In conclusion, our study will contribute to a better understanding of molecular mechanisms to viral infections in humans and the identification of biomarkers to distinguish different types of viral infections., Competing Interests: ELT, GSG, CWW, and TWB consult for and hold equity in Biomeme, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tsalik, Fiorino, Aqeel, Liu, Henao, Ko, Burke, Reller, Bodinayake, Nagahawatte, Arachchi, Devasiri, Kurukulasooriya, McClain, Woods, Ginsburg, Tillekeratne and Schughart.)
- Published
- 2021
- Full Text
- View/download PDF
46. Experience and Perceptions of a Family Health History Risk Assessment Tool among Multi-Ethnic Asian Breast Cancer Patients.
- Author
-
Yoon S, Goh H, Fung SM, Tang S, Matchar D, Ginsburg GS, Orlando LA, Ngeow J, and Wu RR
- Abstract
A family health history-based risk assessment is particularly valuable for guiding cancer screening and treatment strategies, yet an optimal implementation depends upon end-users' values and needs. This is not only true prior to disease development, but also for those already affected. The aim of this study is to explore perceptions of the value of knowing one's family health history (FHH)-based risk, experience using a patient-facing FHH tool and the potential of the tool for wider implementation. Twenty multi-ethnic Asian patients undergoing breast cancer treatment in Singapore completed an FHH-based risk assessment. Semi-structured one-on-one interviews were conducted and data were thematically analyzed. All participants were female and slightly more than half were Chinese. The acceptance and usage of an FHH risk assessment tool for cancers and its broader implementation was affected by a perceived importance of personal control over early detection, patient concerns of anxiety for themselves and their families due to risk results, concerns for genetic discrimination, adequacy of follow-up care plans and Asian cultural beliefs toward disease and dying. This study uniquely sheds light on the factors affecting Asian breast cancer patients' perceptions about undergoing an FHH-based risk assessment, which should inform steps for a broader implementation in Asian healthcare systems.
- Published
- 2021
- Full Text
- View/download PDF
47. Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.
- Author
-
Levy KD, Blake K, Fletcher-Hoppe C, Franciosi J, Goto D, Hicks JK, Holmes AM, Kanuri SH, Madden EB, Musty MD, Orlando L, Pratt VM, Ramos M, Wu R, and Ginsburg GS
- Published
- 2021
- Full Text
- View/download PDF
48. Assessment of the Feasibility of Using Noninvasive Wearable Biometric Monitoring Sensors to Detect Influenza and the Common Cold Before Symptom Onset.
- Author
-
Grzesiak E, Bent B, McClain MT, Woods CW, Tsalik EL, Nicholson BP, Veldman T, Burke TW, Gardener Z, Bergstrom E, Turner RB, Chiu C, Doraiswamy PM, Hero A, Henao R, Ginsburg GS, and Dunn J
- Subjects
- Adult, Area Under Curve, Biological Assay, Biometry instrumentation, Cohort Studies, Common Cold virology, Early Diagnosis, Feasibility Studies, Female, Humans, Influenza, Human virology, Male, Mass Screening, Models, Biological, Sensitivity and Specificity, Virus Shedding, Young Adult, Biometry methods, Common Cold diagnosis, Influenza A Virus, H1N1 Subtype growth & development, Influenza, Human diagnosis, Rhinovirus growth & development, Severity of Illness Index, Wearable Electronic Devices
- Abstract
Importance: Currently, there are no presymptomatic screening methods to identify individuals infected with a respiratory virus to prevent disease spread and to predict their trajectory for resource allocation., Objective: To evaluate the feasibility of using noninvasive, wrist-worn wearable biometric monitoring sensors to detect presymptomatic viral infection after exposure and predict infection severity in patients exposed to H1N1 influenza or human rhinovirus., Design, Setting, and Participants: The cohort H1N1 viral challenge study was conducted during 2018; data were collected from September 11, 2017, to May 4, 2018. The cohort rhinovirus challenge study was conducted during 2015; data were collected from September 14 to 21, 2015. A total of 39 adult participants were recruited for the H1N1 challenge study, and 24 adult participants were recruited for the rhinovirus challenge study. Exclusion criteria for both challenges included chronic respiratory illness and high levels of serum antibodies. Participants in the H1N1 challenge study were isolated in a clinic for a minimum of 8 days after inoculation. The rhinovirus challenge took place on a college campus, and participants were not isolated., Exposures: Participants in the H1N1 challenge study were inoculated via intranasal drops of diluted influenza A/California/03/09 (H1N1) virus with a mean count of 106 using the median tissue culture infectious dose (TCID50) assay. Participants in the rhinovirus challenge study were inoculated via intranasal drops of diluted human rhinovirus strain type 16 with a count of 100 using the TCID50 assay., Main Outcomes and Measures: The primary outcome measures included cross-validated performance metrics of random forest models to screen for presymptomatic infection and predict infection severity, including accuracy, precision, sensitivity, specificity, F1 score, and area under the receiver operating characteristic curve (AUC)., Results: A total of 31 participants with H1N1 (24 men [77.4%]; mean [SD] age, 34.7 [12.3] years) and 18 participants with rhinovirus (11 men [61.1%]; mean [SD] age, 21.7 [3.1] years) were included in the analysis after data preprocessing. Separate H1N1 and rhinovirus detection models, using only data on wearble devices as input, were able to distinguish between infection and noninfection with accuracies of up to 92% for H1N1 (90% precision, 90% sensitivity, 93% specificity, and 90% F1 score, 0.85 [95% CI, 0.70-1.00] AUC) and 88% for rhinovirus (100% precision, 78% sensitivity, 100% specificity, 88% F1 score, and 0.96 [95% CI, 0.85-1.00] AUC). The infection severity prediction model was able to distinguish between mild and moderate infection 24 hours prior to symptom onset with an accuracy of 90% for H1N1 (88% precision, 88% sensitivity, 92% specificity, 88% F1 score, and 0.88 [95% CI, 0.72-1.00] AUC) and 89% for rhinovirus (100% precision, 75% sensitivity, 100% specificity, 86% F1 score, and 0.95 [95% CI, 0.79-1.00] AUC)., Conclusions and Relevance: This cohort study suggests that the use of a noninvasive, wrist-worn wearable device to predict an individual's response to viral exposure prior to symptoms is feasible. Harnessing this technology would support early interventions to limit presymptomatic spread of viral respiratory infections, which is timely in the era of COVID-19.
- Published
- 2021
- Full Text
- View/download PDF
49. Heparin-based blood purification attenuates organ injury in baboons with Streptococcus pneumoniae pneumonia.
- Author
-
Chen L, Kraft BD, Roggli VL, Healy ZR, Woods CW, Tsalik EL, Ginsburg GS, Murdoch DM, Suliman HB, Piantadosi CA, and Welty-Wolf KE
- Subjects
- Animals, Cytokines metabolism, Male, Papio, Pilot Projects, Pneumonia, Pneumococcal blood, Shock, Septic blood, Hemofiltration, Heparin chemistry, Pneumonia, Pneumococcal therapy, Shock, Septic therapy, Streptococcus pneumoniae metabolism
- Abstract
Bacterial pneumonia is a major cause of morbidity and mortality worldwide despite the use of antibiotics, and novel therapies are urgently needed. Building on previous work, we aimed to 1 ) develop a baboon model of severe pneumococcal pneumonia and sepsis with organ dysfunction and 2 ) test the safety and efficacy of a novel extracorporeal blood filter to remove proinflammatory molecules and improve organ function. After a dose-finding pilot study, 12 animals were inoculated with Streptococcus pneumoniae [5 × 10
9 colony-forming units (CFU)], given ceftriaxone at 24 h after inoculation, and randomized to extracorporeal blood purification using a filter coated with surface-immobilized heparin sulfate ( n = 6) or sham treatment ( n = 6) for 4 h at 30 h after inoculation. For safety analysis, four uninfected animals also underwent purification. At 48 h, necropsy was performed. Inoculated animals developed severe pneumonia and septic shock. Compared with sham-treated animals, septic animals treated with purification displayed significantly less kidney injury, metabolic acidosis, hypoglycemia, and shock ( P < 0.05). Purification blocked the rise in peripheral blood S. pneumoniae DNA, attenuated bronchoalveolar lavage (BAL) CCL4, CCL2, and IL-18 levels, and reduced renal oxidative injury and classical NLRP3 inflammasome activation. Purification was safe in both uninfected and infected animals and produced no adverse effects. We demonstrate that heparin-based blood purification significantly attenuates levels of circulating S. pneumoniae DNA and BAL cytokines and is renal protective in baboons with severe pneumococcal pneumonia and septic shock. Purification was associated with less severe acute kidney injury, metabolic derangements, and shock. These results support future clinical studies in critically ill septic patients.- Published
- 2021
- Full Text
- View/download PDF
50. Adaptive Multi-Channel Event Segmentation and Feature Extraction for Monitoring Health Outcomes.
- Author
-
She X, Zhai Y, Henao R, Woods CW, Chiu C, Ginsburg GS, Song PXK, and Hero AO
- Subjects
- Algorithms, Humans, Outcome Assessment, Health Care, Signal Processing, Computer-Assisted, Sleep, Influenza A Virus, H1N1 Subtype
- Abstract
Objective: To develop a multi-channel device event segmentation and feature extraction algorithm that is robust to changes in data distribution., Methods: We introduce an adaptive transfer learning algorithm to classify and segment events from non-stationary multi-channel temporal data. Using a multivariate hidden Markov model (HMM) and Fisher's linear discriminant analysis (FLDA) the algorithm adaptively adjusts to shifts in distribution over time. The proposed algorithm is unsupervised and learns to label events without requiring a priori information about true event states. The procedure is illustrated on experimental data collected from a cohort in a human viral challenge (HVC) study, where certain subjects have disrupted wake and sleep patterns after exposure to an H1N1 influenza pathogen., Results: Simulations establish that the proposed adaptive algorithm significantly outperforms other event classification methods. When applied to early time points in the HVC data, the algorithm extracts sleep/wake features that are predictive of both infection and infection onset time., Conclusion: The proposed transfer learning event segmentation method is robust to temporal shifts in data distribution and can be used to produce highly discriminative event-labeled features for health monitoring., Significance: Our integrated multisensor signal processing and transfer learning method is applicable to many ambulatory monitoring applications.
- Published
- 2021
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.