Medicine and Health Sciences Commons^™

Chapter 11: Genome-Wide Association Studies, William S. Bush, Jason H. Moore

Dartmouth Scholarship

Genome-wide association studies (GWAS) have evolved over the last ten years into a powerful tool for investigating the genetic architecture of human disease. In this work, we review the key concepts underlying GWAS, including the architecture of common diseases, the structure of common human genetic variation, technologies for capturing genetic information, study designs, and the statistical methods used for data analysis. We also look forward to the future beyond GWAS.

Joint Effect Of Genetic And Lifestyle Risk Factors On Type 2 Diabetes Risk Among Chinese Men And Women, Raquel Villegas, Ryan Delahanty, Yu-Tang Gao, Jirong Long, Scott M. Williams, Yong-Bing Xiang, Hui Cai, Hong-Lan Li, Frank Hu, Qiuyin Cai, Wei Zheng, Xiao-Ou Shu

Dartmouth Scholarship

More than 40 genetic susceptibility loci have been reported for type 2 diabetes (T2D). Recently, the combined effect of genetic variants has been investigated by calculating a genetic risk score. We evaluated 36 genome-wide association study (GWAS) identified SNPs in 2,679 T2D cases and 3322 controls in middle-age Han Chinese. Fourteen SNPs were significantly associated with T2D in analysis adjusted for age, sex and BMI. We calculated two genetic risk scores (GRS) (GRS1 with all the 36 SNPs and GRS2 with the 14 SNPs significantly associated with T2D). The odds ratio for T2D with each GRS point (per risk allele) …

Building A Statistical Model For Predicting Cancer Genes, Ivan P. Gorlov, Christopher J. Logothetis, Shenying Fang, Olga Y. Gorlova, Christopher Amos

Dartmouth Scholarship

More than 400 cancer genes have been identified in the human genome. The list is not yet complete. Statistical models predicting cancer genes may help with identification of novel cancer gene candidates. We used known prostate cancer (PCa) genes (identified through KnowledgeNet) as a training set to build a binary logistic regression model identifying PCa genes. Internal and external validation of the model was conducted using a validation set (also from KnowledgeNet), permutations, and external data on genes with recurrent prostate tumor mutations. We evaluated a set of 33 gene characteristics as predictors. Sixteen of the original 33 predictors were …

Quantitative, Spectrally-Resolved Intraoperative Fluorescence Imaging, Pablo A. Valdés, Frederic Leblond, Valerie L. Jacobs, Brian C. Wilson, Keith D. Paulsen, David W. Roberts

Dartmouth Scholarship

Intraoperative visual fluorescence imaging (vFI) has emerged as a promising aid to surgical guidance, but does not fully exploit the potential of the fluorescent agents that are currently available. Here, we introduce a quantitative fluorescence imaging (qFI) approach that converts spectrally-resolved data into images of absolute fluorophore concentration pixel-by-pixel across the surgical field of view (FOV). The resulting estimates are linear, accurate, and precise relative to true values, and spectral decomposition of multiple fluorophores is also achieved. Experiments with protoporphyrin IX in a glioma rodent model demonstrate in vivo quantitative and spectrally-resolved fluorescence imaging of infiltrating tumor margins for the …

Effect Of Genetic Variants, Especially Cyp2c9 And Vkorc1, On The Pharmacology Of Warfarin, Erik Fung, Nikolaos Patsopoulos, Steven Belknap, Daniel O'Rourke, John Robb, Jeffrey L. Anderson, Nicholas W. Shworak, Jason H. Moore

Dartmouth Scholarship

The genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and vitamin K-epoxide reductase complex unit 1 (VKORC1) are major determinants of anticoagulant response to warfarin. Together with patient demographics and clinical information, they account for approximately one-half of the warfarin dose variance in individuals of European descent. Recent prospective and randomized controlled trial data support pharmacogenetic guidance with their use in warfarin dose initiation and titration. Benefits from pharmacogenetics-guided warfarin dosing have been reported to extend beyond the period of initial dosing, with supportive data indicating benefits to at least 3 months. The genetic effects of VKORC1 and CYP2C9 in …

Privacy In Mobile Technology For Personal Healthcare, Sasikanth Avancha, Amit Baxi, David Kotz

Dartmouth Scholarship

Information technology can improve the quality, efficiency, and cost of healthcare. In this survey, we examine the privacy requirements of \emphmobile\/ computing technologies that have the potential to transform healthcare. Such \emphmHealth\/ technology enables physicians to remotely monitor patients' health, and enables individuals to manage their own health more easily. Despite these advantages, privacy is essential for any personal monitoring technology. Through an extensive survey of the literature, we develop a conceptual privacy framework for mHealth, itemize the privacy properties needed in mHealth systems, and discuss the technologies that could support privacy-sensitive mHealth systems. We end with a list of …

Comparative Study Of Influenza Virus Replication In Mdck Cells And In Primary Cells Derived From Adenoids And Airway Epithelium, Natalia A. Ilyushina, Mine R. Ikizler, Yoshihiro Kawaoka, Larisa G. Rudenko

Dartmouth Scholarship

Although clinical trials with human subjects are essential for determination of safety, infectivity, and immunogenicity, it is de- sirable to know in advance the infectiousness of potential candidate live attenuated influenza vaccine strains for human use. We compared the replication kinetics of wild-type and live attenuated influenza viruses, including H1N1, H3N2, H9N2, and B strains, in Madin-Darby canine kidney (MDCK) cells, primary epithelial cells derived from human adenoids, and human bron- chial epithelium (NHBE cells). Our data showed that despite the fact that all tissue culture models lack a functional adaptive im- mune system, differentiated cultures of human epithelium exhibited …

Regulatory T-Cells And Associated Pathways In Metastatic Renal Cell Carcinoma (Mrcc) Patients Undergoing Dc-Vaccination And Cytokine-Therapy, Adrian Schwarzer, Benita Wolf, Jan L. Fisher, Thomas Schwaab, Sven Olek, Udo Baron, Craig R. Tomlinson, John D. Seigne, Nancy A. Crosby, Jiang Gui, Thomas H. Hampton, Camilo E. Fadul, John A. Heaney, Marc S. Ernstoff

Dartmouth Scholarship

Purpose: To evaluate CD4+CD25+FOXP3+ T regulatory cells (TREG) and associated immune-regulatory pathways in peripheral blood lymphocytes (PBL) of metastatic renal cell carcinoma (mRCC) patients and healthy volunteers. We subsequently investigated the effects of immunotherapy on circulating TREG combining an extensive phenotype examination, DNA methylation analysis and global transcriptome analysis.

Design: Eighteen patients with mRCC and twelve volunteers (controls) were available for analysis. TREG phenotype was examined using flow cytometry (FCM). TREG were also quantified by analyzing the epigenetic status of the FOXP3 locus using methylation specific PCR. As a third approach, RNA of the PBL was hybridized to Affymetrix GeneChip …

Genetic Association Analysis Of Complex Diseases Incorporating Intermediate Phenotype Information, Yafang Li, Jian Huang, Christopher I. Amos

Dartmouth Scholarship

Genetic researchers often collect disease related quantitative traits in addition to disease status because they are interested in understanding the pathophysiology of disease processes. In genome-wide association (GWA) studies, these quantitative phenotypes may be relevant to disease development and serve as intermediate phenotypes or they could be behavioral or other risk factors that predict disease risk. Statistical tests combining both disease status and quantitative risk factors should be more powerful than case-control studies, as the former incorporates more information about the disease. In this paper, we proposed a modified inverse-variance weighted meta-analysis method to combine disease status and quantitative intermediate …

In Utero Exposures, Infant Growth, And Dna Methylation Of Repetitive Elements And Developmentally Related Genes In Human Placenta, Charlotte S. Wilhelm-Benartzi, E. Andres Houseman, Matthew A. Maccani, Graham M. Poage, Devin C. Koestler, Scott M. Langevin, Luc A. Gagne, Carolyn E. Banister, James F. Padbury, Carmen J. Marsit

Dartmouth Scholarship

BACKGROUND:

Fetal programming describes the theory linking environmental conditions during embryonic and fetal development with risk of diseases later in life. Environmental insults in utero may lead to changes in epigenetic mechanisms potentially affecting fetal development.

OBJECTIVES:

We examined associations between in utero exposures, infant growth, and methylation of repetitive elements and gene-associated DNA in human term placenta tissue samples.

METHODS:

Placental tissues and associated demographic and clinical data were obtained from subjects delivering at Women and Infants Hospital in Providence, Rhode Island (USA). Methylation levels of long interspersed nuclear element-1 (LINE-1) and the Alu element AluYb8 were determined in …

Understanding Sharing Preferences And Behavior For Mhealth Devices, Aarathi Prasad, Jacob Sorber, Timothy Stablein, Denis Anthony, David Kotz

Dartmouth Scholarship

mHealth devices offer many potential benefits to patients, health providers and others involved in the patients' healthcare. If patients are not in control of the collection and sharing of their personal health information, they will have privacy concerns even while enjoying the benefits of the devices. We investigated patients' willingness to share their personal health information, collected using mHealth devices, with their family, friends, third parties and the public. Our findings are based on a user study conducted with 41 participants. The best way to understand people's privacy concerns is to give them the opportunity to use the device and …

Thr 163 Phosphorylation Causes Mcl-1 Stabilization When Degradation Is Independent Of The Adjacent Gsk3-Targeted Phosphodegron, Promoting Drug Resistance In Cancer, Shanna K. Nifoussi, Julie A. Vrana, Aaron M. Domina, Alfredo De Biasio, Jingang Gui, Mark A. Gregory, Stephen R. Hann, Ruth W. Craig

Dartmouth Scholarship

The antiapoptotic Bcl-2 family member Mcl-1 is a PEST protein (containing sequences enriched in proline, glutamic acid, serine, and threonine) and is subject to rapid degradation via multiple pathways. Impaired degradation leading to the maintenance of Mcl-1 expression is an important determinant of drug resistance in cancer. Phosphorylation at Thr 163 in the PEST region, stimulated by 12-O-tetradecanoylphorbol acetic acid (TPA)-induced activation of extracellular signal-regulated kinase (ERK), is associated with Mcl-1 stabilization in BL41-3 Burkitt lymphoma cells. This contrasts with the observation that Thr 163 phosphorylation in normal fibroblasts primes glycogen synthase kinase (GSK3)-induced phosphorylation at Ser 159, producing a …

Influenza-Infected Neutrophils Within The Infected Lungs Act As Antigen Presenting Cells For Anti-Viral Cd8+ T Cells, Matthew M. Hufford, Graham Richardson, Haixia Zhou, Balaji Manicassamy, Adolfo Garcia-Sastre, Richard I. Enelow, Thomas J. Braciale

Dartmouth Scholarship

Influenza A virus (IAV) is a leading cause of respiratory tract disease worldwide. Anti-viral CD8⁺ T lymphocytes responding to IAV infection are believed to eliminate virally infected cells by direct cytolysis but may also contribute to pulmonary inflammation and tissue damage via the release of pro-inflammatory mediators following recognition of viral antigen displaying cells. We have previously demonstrated that IAV antigen expressing inflammatory cells of hematopoietic origin within the infected lung interstitium serve as antigen presenting cells (APC) for infiltrating effector CD8⁺ T lymphocytes; however, the spectrum of inflammatory cell types capable of serving as APC was not …

Rice Consumption And Urinary Arsenic Concentrations In U.S. Children, Matthew A. Davis, Todd A. Mackenzie, Kathryn L. Cottingham, Diane Gilbert-Diamond, Tracy Punshon, Margaret R. Karagas

Dartmouth Scholarship

Background: In adult populations, emerging evidence indicates that humans are exposed to arsenic by ingestion of contaminated foods such as rice, grains, and juice; yet little is known about arsenic exposure among children.

Objectives: Our goal was to determine whether rice consumption contributes to arsenic exposure in U.S. children.

Methods: We used data from the nationally representative National Health and Nutrition Examination Survey (NHANES) to examine the relationship between rice consumption (measured in 0.25 cups of cooked rice per day) over a 24-hr period and subsequent urinary arsenic concentration among the 2,323 children (6–17 years of age) who participated in …

Quantifying The Clinical Significance Of Cannabis Withdrawal, David J. Allsop, Jan Copeland, Melissa M. Norberg, Shanlin Fu, Anna Molnar, John Lewis, Alan J. Budney

Dartmouth Scholarship

Background and Aims:

Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt.

Methods and Results:

A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment …

Predicting The Difficulty Of Pure, Strict, Epistatic Models: Metrics For Simulated Model Selection, Ryan J. Urbanowicz, Jeff Kiralis, Jonathan M. Fisher, Jason H. Moore

Dartmouth Scholarship

Background:

Algorithms designed to detect complex genetic disease associations are initially evaluated using simulated datasets. Typical evaluations vary constraints that influence the correct detection of underlying models (i.e. number of loci, heritability, and minor allele frequency). Such studies neglect to account for model architecture (i.e. the unique specification and arrangement of penetrance values comprising the genetic model), which alone can influence the detectability of a model. In order to design a simulation study which efficiently takes architecture into account, a reliable metric is needed for model selection.

Results:

We evaluate three metrics as predictors of relative model detection difficulty derived …

Design Of A Prostate Cancer Patient Navigation Intervention For A Veterans Affairs Hospital, Narissa J. Nonzee, June M. Mckoy, Alfred W. Rademaker, Peter Byer, Thanh H. Luu, Dachao Liu, Elizabeth A. Richey

Dartmouth Scholarship

Patient navigation programs have been launched nationwide in an attempt to reduce racial/ethnic and socio-demographic disparities in cancer care, but few have evaluated outcomes in the prostate cancer setting. The National Cancer Institute-funded Chicago Patient Navigation Research Program (C-PNRP) aims to implement and evaluate the efficacy of a patient navigation intervention for predominantly low-income minority patients with an abnormal prostate cancer screening test at a Veterans Affairs (VA) hospital in Chicago.

The Human Brain Intracerebral Microvascular System: Development And Structure, Miguel Marín-Padilla

Dartmouth Scholarship

The capillary from the meningeal inner pial lamella play a crucial role in the development and structural organization of the cerebral cortex extrinsic and intrinsic microvascular compartments. Only pial capillaries are capable of perforating through the cortex external glial limiting membrane (EGLM) to enter into the nervous tissue, although incapable of perforating the membrane to exit the brain. Circulatory dynamics and functional demands determine which capillaries become arterial and which capillaries become venous. The perforation of the cortex EGLM by pial capillaries is a complex process characterized by three fundamental stages: (1) pial capillary contact with the EGLM with fusion …

Herpes Simplex Virus 34.5 Interferes With Autophagosome Maturation And Antigen Presentation In Dendritic Cells, Philipe A. M. Gobeil, David A. Leib

Dartmouth Scholarship

The cellular autophagy response induced by herpes simplex virus 1 (HSV-1) is countered by the viral γ34.5 protein. γ34.5 modulates autophagy by binding to the host autophagy protein Beclin-1 and through this binding inhibits the formation of autophagosomes in fibroblasts and neurons. In contrast, in this study dendritic cells (DCs) infected with HSV-1 showed an accumulation of autophagosomes and of the long-lived protein p62. No such accumulations were observed in DCs infected with a γ34.5-null virus or a virus lacking the Beclin-binding domain (BBD) of γ34.5. To explore this further, we established stably transduced DC lines to show that γ34.5 …

Automatic And Robust Calibration Of Optical Detector Arrays For Biomedical Diffuse Optical Spectroscopy, Michael A. Mastanduno, Shudong Jiang, Roberta Diflorio-Alexander, Brian W. Pogue, Keith Paulsen

Dartmouth Scholarship

The design and testing of a new, fully automated, calibration approach is described. The process was used to calibrate an image-guided diffuse optical spectroscopy system with 16 photomultiplier tubes (PMTs), but can be extended to any large array of optical detectors and associated imaging geometry. The design goals were accomplished by developing a routine for robust automated calibration of the multi-detector array within 45 minutes. Our process was able to characterize individual detectors to a median norm of the residuals of 0.03 V for amplitude and 4.4 degrees in phase and achieved less than 5% variation between all the detectors …

Measuring Infertility In Populations: Constructing A Standard Definition For Use With Demographic And Reproductive Health Surveys, Maya N. Mascarenhas, Hoiwan Cheung, Colin D. Mathers, Gretchen A. Stevens

Dartmouth Scholarship

Background: Infertility is a significant disability, yet there are no reliable estimates of its global prevalence. Studies on infertility prevalence define the condition inconsistently, rendering the comparison of studies or quantitative summaries of the literature difficult. This study analyzed key components of infertility to develop a definition that can be consistently applied to globally available household survey data.

Methods: We proposed a standard definition of infertility and used it to generate prevalence estimates using 53 Demographic and Health Surveys (DHS). The analysis was restricted to the subset of DHS that contained detailed fertility information collected through the reproductive health calendar. …

Breast Milk From Tanzanian Women Has Divergent Effects On Cell-Free And Cell-Associated Hiv-1 Infection In Vitro, Magdalena A. Lyimo, Matilda Ngarina Mosi, Molly L. Housman, Muhammad Zain-Ul-Abideen, Frederick V. Lee, Alexandra L. Howell, Ruth I. Connor

Dartmouth Scholarship

Transmission of HIV-1 during breastfeeding is a significant source of new pediatric infections in sub-Saharan Africa. Breast milk from HIV-positive mothers contains both cell-free and cell-associated virus; however, the impact of breast milk on HIV-1 infectivity remains poorly understood. In the present study, breast milk was collected from HIV-positive and HIV-negative Tanzanian women attending antenatal clinics in Dar es Salaam. Milk was analyzed for activity in vitro against both cell-free and cell-associated HIV-1. Potent inhibition of cell-free R5 and X4 HIV-1 occurred in the presence of milk from all donors regardless of HIV-1 serostatus. Inhibition of cell-free HIV-1 infection positively …

The Mre11 Nuclease Is Critical For The Sensitivity Of Cells To Chk1 Inhibition, Ruth Thompson, Ryan Montano, Alan Eastman

Dartmouth Scholarship

The Chk1 kinase is required for the arrest of cell cycle progression when DNA is damaged, and for stabilizing stalled replication forks. As a consequence, many Chk1 inhibitors have been developed and tested for their potential to enhance DNA damage-induced tumor cell killing. However, inhibition of Chk1 alone, without any additional exogenous agent, can be cytotoxic. Understanding the underlying mechanisms of this sensitivity is critical for defining which patients might respond best to therapy with Chk1 inhibitors. We have investigated the mechanism of sensitivity in U2OS osteosarcoma cells. Upon incubation with the Chk1 inhibitor MK-8776, single-stranded DNA regions (ssDNA) and …

Tryptophan Hydroxylase-1 Regulates Immune Tolerance And Inflammation, Elizabeth C. Nowak, Victor C. De Vries, Anna Wasiuk, Cory Ahonen, Kathryn A. Bennett, Isabelle Le Mercier, Dae-Gon Ha, Randolph J. Noelle

Dartmouth Scholarship

Nutrient deprivation based on the loss of essential amino acids by catabolic enzymes in the microenvironment is a critical means to control in ammatory responses and immune tolerance. Here we report the novel nding that Tph-1 (tryptophan hydroxylase-1), a synthase which catalyses the conversion of tryptophan to serotonin and exhausts tryptophan, is a potent regulator of immunity. In models of skin allograft tolerance, tumor growth, and experimental autoimmune encephalomyelitis, Tph-1 de ciency breaks allograft tolerance, induces tumor remission, and intensi es neuroin ammation, respectively. All of these effects of Tph-1 de ciency are independent of its downstream product serotonin. Because …

Serial Analysis Of The Gut And Respiratory Microbiome In Cystic Fibrosis In Infancy: Interaction Between Intestinal And Respiratory Tracts And Impact Of Nutritional Exposures, J. C. Madan, D. C. Koestler, B. A. Stanton, L. Davidson, L. A. Moulton, M. L. Housman, J. H. Moore, M. F. Guill, H. G. Morrison, M. L. Sogin, T. H. Hampton, M. R. Karagas, P. E. Palumbo, J. A. Foster, P. L. Hibberd, G. A. O’Toole

Dartmouth Scholarship

Pulmonary damage caused by chronic colonization of the cystic fibrosis (CF) lung by microbial communities is the proximal cause of respiratory failure. While there has been an effort to document the microbiome of the CF lung in pediatric and adult patients, little is known regarding the developing microflora in infants. We examined the respiratory and intestinal microbiota development in infants with CF from birth to 21 months. Distinct genera dominated in the gut compared to those in the respiratory tract, yet some bacteria overlapped, demonstrating a core microbiota dominated by Veillonella and Streptococcus. Bacterial diversity increased significantly over time, …

Attentive And Pre-Attentive Processes In Change Detection And Identification, Howard C. Hughes, Gideon Paul Caplovitz, Rebecca A. Loucks, Robert Fendrich

Dartmouth Scholarship

In studies of change blindness, observers often have the phenomenological impression that the blindness is overcome all at once, so that change detection, localization and identification apparently occur together. Three experiments are described that explore dissociations between these processes using a discrete trial procedure in which 2 visual frames are presented sequentially with no intervening inter-frame-interval. The results reveal that change detection and localization are essentially perfect under these conditions regardless of the number of elements in the display, which is consistent with the idea that change detection and localization are mediated by pre-attentive parallel processes. In contrast, identification accuracy …

Murine Gammaherpesvirus 68 Lana Acts On Terminal Repeat Dna To Mediate Episome Persistence, Aline C. Habison, Chantal Beauchemin, J. Pedro Simas, Edward J. Usherwood

Dartmouth Scholarship

Murine gammaherpesvirus 68 (MHV68) ORF73 (mLANA) has sequence homology to Kaposi’s sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA). LANA acts on the KSHV terminal repeat (TR) elements to mediate KSHV episome maintenance. Disruption of mLANA expression severely reduces the ability of MHV68 to establish latent infection in mice, consistent with the possibility that mLANA mediates episome persistence. Here we assess the roles of mLANA and MHV68 TR (mTR) elements in episome persistence. mTR-associated DNA persisted as an episome in latently MHV68-infected tumor cells, demonstrating that the mTR elements can serve as a cis-acting element for MHV68 episome maintenance. In some …

Microbiological Components In Mainstream And Sidestream Cigarette Smoke, Lennart Larsson, Christina Pehrson, Tenzin Dechen, Mardi Crane-Godreau

Dartmouth Scholarship

Research has shown that tobacco smoke contains substances of microbiological origin such as ergosterol (a fungal membrane lipid) and lipopolysaccharide (LPS) (in the outer membrane of Gram-negative bacteria). The aim of the present study was to compare the amounts of ergosterol and LPS in the tobacco and mainstream (MS) and sidestream (SS) smoke of some popular US cigarettes. We measured LPS 3-hydroxy fatty acids and fungal biomass biomarker ergosterol in the tobacco and smoke from cigarettes of 11 popular brands purchased in the US. University of Kentucky reference cigarettes were also included for comparison.

The Crispr/Cas Adaptive Immune System Of Pseudomonas Aeruginosa Mediates Resistance To Naturally Occurring And Engineered Phages, Kyle C. Cady, Joe Bondy-Denomy, Gary E. Heussler, Alan R. Davidson, George A. O'Toole

Dartmouth Scholarship

Here we report the isolation of 6 temperate bacteriophages (phages) that are prevented from replicating within the laboratory strain Pseudomonas aeruginosa PA14 by the endogenous CRISPR/Cas system of this microbe. These phages are only the second identified group of naturally occurring phages demonstrated to be blocked for replication by a nonengineered CRISPR/Cas system, and our results provide the first evidence that the P. aeruginosa type I-F CRISPR/Cas system can function in phage resistance. Previous studies have highlighted the importance of the protospacer adjacent motif (PAM) and a proximal 8-nucleotide seed sequence in mediating CRISPR/Cas-based immunity. Through engineering of a protospacer …

Coronary Heart Disease In Primary Care: Accuracy Of Medical History And Physical Findings In Patients With Chest Pain – A Study Protocol For A Systematic Review With Individual Patient Data, Jörg Haasenritter, Marc Aerts, Stefan Bösner, Frank Buntinx, Bernard Burnand, Lilli Herzig, J André Knottnerus, Girma Minalu, Staffan Nilsson, Walter Renier, Carol Sox, Carol Sox, Harold Sox, Norbert Donner-Banzhoff

Dartmouth Scholarship

Chest pain is a common complaint in primary care, with coronary heart disease (CHD) being the most concerning of many potential causes. Systematic reviews on the sensitivity and specificity of symptoms and signs summarize the evidence about which of them are most useful in making a diagnosis. Previous meta-analyses are dominated by studies of patients referred to specialists. Moreover, as the analysis is typically based on study-level data, the statistical analyses in these reviews are limited while meta-analyses based on individual patient data can provide additional information. Our patient-level meta-analysis has three unique aims. First, we strive to determine the …