Search tips
Search criteria

Results 1-25 (63)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
more »
1.  Comparison of 24-hour Holter Monitoring with 14-day Novel Adhesive Patch Electrocardiographic Monitoring 
The American journal of medicine  2013;127(1):10.1016/j.amjmed.2013.10.003.
Cardiac arrhythmias are remarkably common and routinely go undiagnosed because they are often transient and asymptomatic. Effective diagnosis and treatment can substantially reduce the morbidity and mortality associated with cardiac arrhythmias. The Zio Patch (iRhythm Technologies, Inc, San Francisco, Calif) is a novel, single-lead electrocardiographic (ECG), lightweight, Food and Drug Administration–cleared, continuously recording ambulatory adhesive patch monitor suitable for detecting cardiac arrhythmias in patients referred for ambulatory ECG monitoring.
A total of 146 patients referred for evaluation of cardiac arrhythmia underwent simultaneous ambulatory ECG recording with a conventional 24-hour Holter monitor and a 14-day adhesive patch monitor. The primary outcome of the study was to compare the detection arrhythmia events over total wear time for both devices. Arrhythmia events were defined as detection of any 1 of 6 arrhythmias, including supraventricular tachycardia, atrial fibrillation/flutter, pause greater than 3 seconds, atrioventricular block, ventricular tachycardia, or polymorphic ventricular tachycardia/ventricular fibrillation. McNemar’s tests were used to compare the matched pairs of data from the Holter and the adhesive patch monitor.
Over the total wear time of both devices, the adhesive patch monitor detected 96 arrhythmia events compared with 61 arrhythmia events by the Holter monitor (P < .001).
Over the total wear time of both devices, the adhesive patch monitor detected more events than the Holter monitor. Prolonged duration monitoring for detection of arrhythmia events using single-lead, less-obtrusive, adhesive-patch monitoring platforms could replace conventional Holter monitoring in patients referred for ambulatory ECG monitoring.
PMCID: PMC3882198  PMID: 24384108
Atrial fibrillation; Cardiac arrhythmias; Electrocardiographic; Holter monitor; iRhythm; Zio Patch
2.  Pocket Mobile Echocardiography: The Next-Generation Stethoscope? A Comparison of Rapidly Acquired PME Images to Standard TTE 
Annals of internal medicine  2011;155(1):33-38.
A new miniature high-resolution pocket-mobile echocardiographic (PME) device has become available to clinicians, but there are no data available comparing this technology with standard transthoracic echo (TTE) examination.
To assess the potential validity of PME imaging as a quick assessment of cardiovascular disease by direct comparison to standard TTE.
Ultrasonographers attempted to acquire seven standard echocardiography views with the PME prior to performing comprehensive standard TTEs. In blinded fashion, images from the two modalities were compared by two experienced echocardiographers and two cardiology fellows.
This work was funded in part by Scripps Health and the NIH UL1 RR025774 (Scripps Translational Science Institute, Clinical and Translational Science Award).
Scripps Clinic/Green Hospital
97 consecutive unselected patients
Comparisons were made in regards to ejection fraction (EF), segmental wall motion abnormalities (WMA), left ventricular end-diastolic dimension (LVEDD), inferior vena cava (IVC) size, aortic and mitral valve pathology, and pericardial effusion.
PME images were adequate for interpretation of EF in 95% of the studies, LVEDD 95%, mitral valve 90%, WMA 83%, aortic valve 83%, and IVC 75%. Compared to standard TTE, PME interpretation by attendings and fellows had an accuracy of 97% and 93% for EF, respectively. Likewise, accuracy for WMA was 90% and 87% ; LVEDD 94% and 91%; aortic stenosis 97% and 95%; mitral abnormality 88% and 82%; and IVC size 81% and 74%.
As this was a validation study of imaging alone, further evaluation with clinician image acquisition is needed.
PME images obtained rapidly by skilled ultrasonographers provide excellent visualization in the vast majority of patients and correlate well with standard, comprehensive TTE. Such validation needs to be extended to untrained clinicians in larger and diverse patient populations before broad dissemination of this technology can be recommended.
PMCID: PMC3733444  PMID: 21727291
cardiovascular disease; echocardiography; imaging
3.  Personalized medicine: risk prediction, targeted therapies and mobile health technology 
BMC Medicine  2014;12:37.
Personalized medicine is increasingly being employed across many areas of clinical practice, as genes associated with specific diseases are discovered and targeted therapies are developed. Mobile apps are also beginning to be used in medicine with the aim of providing a personalized approach to disease management. In some areas of medicine, patient-tailored risk prediction and treatment are applied routinely in the clinic, whereas in other fields, more work is required to translate scientific advances into individualized treatment. In this forum article, we asked specialists in oncology, neurology, endocrinology and mobile health technology to discuss where we are in terms of personalized medicine, and address their visions for the future and the challenges that remain in their respective fields.
PMCID: PMC3938085  PMID: 24580858
Diabetes; Genetics; Mobile health; Oncology; Personalized medicine; Smartphone; Stroke; Targeted therapy
4.  Fluid phase biopsy for detection and characterization of circulating endothelial cells in myocardial infarction 
Physical biology  2014;11(1):016002.
Elevated levels of circulating endothelial cells (CECs) occur in response to various pathological conditions including myocardial infarction (MI). Here, we adapted a fluid phase biopsy technology platform that successfully detects circulating tumor cells in blood of cancer patients (HD-CTC assay), to create a High-Definition Circulating Endothelial Cell (HD-CEC) assay for the detection and characterization of CECs. Peripheral blood samples were collected from 79 MI patients, 25 healthy controls and 6 patients undergoing vascular surgery (VS). CECs were defined by positive staining for DAPI, CD146 and von Willebrand Factor and negative staining for CD45. In addition, CECs exhibited distinct morphological features that enable differentiation from surrounding white blood cells. CECs were found both as individual cells and as aggregates. CEC numbers were higher in MI patients compared with healthy controls. VS patients had lower CEC counts when compared with MI patients but were not different from healthy controls. Both HD-CEC and CellSearch® assays could discriminate MI patients from healthy controls with comparable accuracy but the HD-CEC assay exhibited higher specificity while maintaining high sensitivity. Our HD-CEC assay may be used as a robust diagnostic biomarker in MI patients.
PMCID: PMC4143170  PMID: 24406475
5.  Bridging Anti-Platelet Therapy With the Intravenous Agent Cangrelor In Patients Undergoing Cardiac Surgery 
Thienopyridines are among the most widely prescribed medications, but their use can be complicated by the unanticipated need for surgery. Despite increased risk of thrombosis, guidelines recommend discontinuing thienopyridines 5–7 days prior to surgery to minimize bleeding.
To evaluate the use of cangrelor, an intravenous, reversible P2Y12 platelet inhibitor for bridging thienopyridine-treated patients to coronary artery bypass grafting (CABG).
Design, Setting, and Patients
Prospective, randomized double-blind, placebo-controlled, multicenter trial, in patients (n=210) with an acute coronary syndrome (ACS) or treated with a coronary stent on a thienopyridine awaiting CABG to receive either cangrelor or placebo after an initial open-label, dose-finding phase (n=11) conducted between January 2009 and April 2011.
Thienopyridines were stopped and patients administered cangrelor or placebo for at least 48 hours, which was discontinued 1–6 hours prior to CABG.
Main outcome measures
The primary efficacy endpoint was platelet reactivity (measured in P2Y12 Reaction Units [PRU]), assessed daily with the VerifyNow™ P2Y12 assay. The main safety endpoint was excessive CABG-related bleeding.
The dose of cangrelor determined in the open-label stage was 0.75 µg/kg/min. In the randomized phase, a greater proportion of patients treated with cangrelor had low levels of platelet reactivity throughout the entire treatment period compared with placebo (primary endpoint, PRU<240: 98.8% (83/84) vs. 19.0% (16/84); relative risk [RR]: 5.2, 95% confidence interval [CI]:3.3–8.1, p<0.001). Excessive CABG-related bleeding occurred in 11.8% (12/102) vs. 10.4% (10/96) in the cangrelor and placebo groups, respectively (RR=1.1, 95% CI: 0.5–2.5, p=0.763). There were no significant differences in major bleeding prior to CABG, although minor bleeding was numerically higher with cangrelor.
Among patients who must wait for cardiac surgery after thienopyridine discontinuation, the use of cangrelor compared with placebo resulted in a higher rate of maintenance of platelet inhibition.
PMCID: PMC3774162  PMID: 22253393
6.  Characteristics of Genomic Test Consumers Who Spontaneously Share Results with Their Health Care Provider 
Health communication  2013;29(1):10.1080/10410236.2012.717216.
To evaluate the characteristics of direct-to-consumer (DTC) genomic test consumers who spontaneously shared their test results with their health care provider.
Utilizing data from the Scripps Genomic Health Initiative we compared demographic, behavioral, and attitudinal characteristics of DTC genomic test consumers who shared their results with their physician or health care provider versus those who did not share. We also compared genomic risk estimates between the two groups.
Of 2024 individuals assessed at approximately 6 months post-testing, a total of 540 individuals (26.5%) reported sharing their results with their physician or health care provider. Those who shared were older (p<.001), had a higher income (p=.01), were more likely to be married (p=.005), and more likely to identify with a religion (p=.004). As assessed prior to undergoing testing, sharers also showed higher exercise (p=.003) and lower fat intake (p=.02), and expressed fewer overall concerns about testing (p=.001) and fewer concerns related to the privacy of their genomic information (p=.03). The genomic disease risk estimates disclosed were not associated with sharing.
In a DTC genomic testing context, physicians and other health care providers may be more likely to encounter patients who are more health conscious and have fewer concerns about the privacy of their genomic information. Genomic risk itself does not appear to be a primary determinant of sharing behavior among consumers.
PMCID: PMC3679226  PMID: 23384116
direct-to-consumer; genomic testing; genetic risk assessment; disclosure of genetic results; consumer characteristics; personalized medicine
7.  Genome-Wide Linkage Scan Identifies Two Novel Genetic Loci for Coronary Artery Disease: In GeneQuest Families 
PLoS ONE  2014;9(12):e113935.
Coronary artery disease (CAD) is the leading cause of death worldwide. Recent genome-wide association studies (GWAS) identified >50 common variants associated with CAD or its complication myocardial infarction (MI), but collectively they account for <20% of heritability, generating a phenomena of “missing heritability”. Rare variants with large effects may account for a large portion of missing heritability. Genome-wide linkage studies of large families and follow-up fine mapping and deep sequencing are particularly effective in identifying rare variants with large effects. Here we show results from a genome-wide linkage scan for CAD in multiplex GeneQuest families with early onset CAD and MI. Whole genome genotyping was carried out with 408 markers that span the human genome by every 10 cM and linkage analyses were performed using the affected relative pair analysis implemented in GENEHUNTER. Affected only nonparametric linkage (NPL) analysis identified two novel CAD loci with highly significant evidence of linkage on chromosome 3p25.1 (peak NPL  = 5.49) and 3q29 (NPL  = 6.84). We also identified four loci with suggestive linkage on 9q22.33, 9q34.11, 17p12, and 21q22.3 (NPL  = 3.18–4.07). These results identify novel loci for CAD and provide a framework for fine mapping and deep sequencing to identify new susceptibility genes and novel variants associated with risk of CAD.
PMCID: PMC4259362  PMID: 25485937
8.  Characterization of Circulating Endothelial Cells in Acute Myocardial Infarction 
Science translational medicine  2012;4(126):126ra33.
Acute myocardial infarction (MI), which involves the rupture of existing atheromatous plaque, remains highly unpredictable despite recent advances in the diagnosis and treatment of coronary artery disease. Accordingly, a biomarker that can predict an impending MI is desperately needed. Here, we characterize circulating endothelial cells (CECs) using the first automated and clinically feasible CEC 3-channel fluorescence microscopy assay in 50 consecutive patients with ST-elevation myocardial infarction (STEMI) and 44 consecutive healthy controls. CEC counts were significantly elevated in MI cases versus controls with median numbers of 19 and 4 cells/ml respectively (p = 1.1 × 10−10). A receiver-operating characteristic (ROC) curve analysis demonstrated an area under the ROC curve of 0.95, suggesting near dichotomization of MI cases versus controls. We observed no correlation between CECs and typical markers of myocardial necrosis (ρ=0.02, CK-MB; ρ=−0.03, troponin). Morphologic analysis of the microscopy images of CECs revealed a 2.5-fold increase (P<0.0001) in cellular area and 2-fold increase (P<0.0001) in nuclear area of MI CECs versus healthy control, age-matched CECs, as well as CECs obtained from patients with preexisting peripheral vascular disease. The distribution of CEC images containing from 2 up to 10 nuclei demonstrates that MI patients are the only group to contain more than 3 nuclei/image, indicating that multi-cellular and multi-nuclear clusters are specific for acute MI. These data indicate that CECs may serve as promising biomarkers for the prediction of atherosclerotic plaque rupture events.
PMCID: PMC3589570  PMID: 22440735
Genomics  2011;98(4):233-241.
Advances in DNA sequencing technologies have made it possible to rapidly, accurately and affordably sequence entire individual human genomes. As impressive as this ability seems, however, it will not likely to amount to much if one cannot extract meaningful information from individual sequence data. Annotating variations within individual genomes and providing information about their biological or phenotypic impact will thus be crucially important in moving individual sequencing projects forward, especially in the context of the clinical use of sequence information. In this paper we consider the various ways in which one might annotate individual sequence variations and point out limitations in the available methods for doing so. It is arguable that, in the foreseeable future, DNA sequencing of individual genomes will become routine for clinical, research, forensic, and personal purposes. We therefore also consider directions and areas for further research in annotating genomic variants.
PMCID: PMC4074010  PMID: 21839162
Sequencing; functional analysis; computer modeling; genomic variation
A number of recent genome-wide association (GWA) studies have identified unequivocal statistical associations between inherited genetic variations, mostly single nucleotide polymorphisms (SNPs), and common complex diseases such as diabetes, cardiovascular disease, and obesity. Genotyping individuals for these variations has the potential to help redefine how pharmacologic agents undergo clinical development. By identifying carriers of known genomic variants that contribute to susceptibility, a high risk population can be defined as well as individuals with potential for a better response to a drug. We evaluated the potential utility that selecting individuals for a trial on the basis of genotype identified in contemporary GWA studies would have had on recently described clinical trials. We pursued this by constraining both the risks of a disease outcome associated with particular genotypes and overall drug responses to those actually observed in genetic association and clinical trial studies, respectively. We pursued these evaluations in the context of clinical trials investigating drugs for macular degeneration, obesity, heart disease, type II diabetes, prostate cancer and Alzheimer’s disease. We show that the increase in incidence of outcomes in trials restricted to individuals with specific genotypic profiles can result in substantial reductions in requisite sample sizes for such trials. In addition, we also derive realistic bounds for samples sizes for clinical trials investigating pharmacogenetic effects that leverage genetic variations identified in recent association studies.
PMCID: PMC2892229  PMID: 20309761
Polymorphism; Translational medicine; Drug validation; DNA sequencing; Study Design
12.  Multi-allelic haplotype association identifies novel information different from single-SNP analysis: A new protective haplotype in the LRP8 gene is against familial and early-onset CAD and MI 
Gene  2013;521(1):78-81.
Our previous studies identified a functional SNP, R952Q in the LRP8 gene, that was associated with increased platelet activation and familial and early-onset coronary artery disease (CAD) and myocardial infarction (MI) in American and Italian Caucasian populations. In this study, we analyzed four additional SNPs near R952Q (rs7546246, rs2297660, rs3737983, rs5177) to identify a specific LRP8 SNP haplotype that is associated with familial and early-onset CAD and MI. We employed a case–control association design involving 381 premature CAD and MI probands and 560 controls in GeneQuest, 441 individuals from 22 large pedigrees in GeneQuest II, and 248 MI patients with family history and 308 controls in an Italian cohort. Like R952Q, LRP8 SNPs rs7546246, rs2297660, rs3737983, and rs5177 were significantly associated with early-onset CAD/MI in both population-based and family-based association studies in GeneQuest. The results were replicated in the GeneQuest II family-based population and the Italian population. We then carried out a haplotype analysis for all five SNPs including R952Q. One common haplotype (TCCGC) was significantly associated with CAD (P = 4.0 × 10−11) and MI (P = 6.5 × 10−12) in GeneQuest with odds ratios of 0.53 and 0.42, respectively. The results were replicated in the Italian cohort (P = 0.004, OR = 0.71). The sib-TDT analysis also showed significant association between the TCCGC haplotype and CAD in GeneQuest II (P = 0.001). These results suggest that a common LRP8 haplotype TCCGC confers a significant protective effect on the development of familial, early-onset CAD and/or MI.
PMCID: PMC3919654  PMID: 23524007
LRP8; Haplotype; SNPs; Association study
13.  Pharmacogenomics in clinical practice and drug development 
Nature biotechnology  2012;30(11):10.1038/nbt.2424.
Genome-wide association studies (GWAS) of responses to drugs, including clopidogrel, pegylated-interferon and carbamazepine, have led to the identification of specific patient subgroups that benefit from therapy. However, the identification and replication of common sequence variants that are associated with either efficacy or safety for most prescription medications at odds ratios (ORs) >3.0 (equivalent to >300% increased efficacy or safety) has yet to be translated to clinical practice. Although some of the studies have been completed, the results have not been incorporated into therapy, and a large number of commonly used medications have not been subject to proper pharmacogenomic analysis. Adoption of GWAS, exome or whole genome sequencing by drug development and treatment programs is the most striking near-term opportunity for improving the drug candidate pipeline and boosting the efficacy of medications already in use.
PMCID: PMC3819119  PMID: 23138311
14.  Effect of Direct-to-Consumer Genomewide Profiling to Assess Disease Risk 
The New England journal of medicine  2011;364(6):524-534.
The use of direct-to-consumer genomewide profiling to assess disease risk is controversial, and little is known about the effect of this technology on consumers. We examined the psychological, behavioral, and clinical effects of risk scanning with the Navigenics Health Compass, a commercially available test of uncertain clinical validity and utility.
We recruited subjects from health and technology companies who elected to purchase the Health Compass at a discounted rate. Subjects reported any changes in symptoms of anxiety, intake of dietary fat, and exercise behavior at a mean (±SD) of 5.6±2.4 months after testing, as compared with baseline, along with any test-related distress and the use of health-screening tests.
From a cohort of 3639 enrolled subjects, 2037 completed follow-up. Primary analyses showed no significant differences between baseline and follow-up in anxiety symptoms (P = 0.80), dietary fat intake (P = 0.89), or exercise behavior (P = 0.61). Secondary analyses revealed that test-related distress was positively correlated with the average estimated lifetime risk among all the assessed conditions (β = 0.117, P<0.001). However, 90.3% of subjects who completed follow-up had scores indicating no test-related distress. There was no significant increase in the rate of use of screening tests associated with genomewide profiling, most of which are not considered appropriate for screening asymptomatic persons in any case.
In a selected sample of subjects who completed follow-up after undergoing consumer genomewide testing, such testing did not result in any measurable short-term changes in psychological health, diet or exercise behavior, or use of screening tests. Potential effects of this type of genetic testing on the population at large are not known. (Funded by the National Institutes of Health and Scripps Health.)
PMCID: PMC3786730  PMID: 21226570
15.  Multi-Center Validation of the Diagnostic Accuracy of a Blood-based Gene Expression Test for Assessment of Obstructive Coronary Artery Disease in Non-Diabetic Patients 
Annals of internal medicine  2010;153(7):425-434.
Diagnosis of significant coronary artery disease (CAD) in at risk patients can be challenging, typically including non-invasive imaging modalities and ultimately the gold standard of coronary angiography. Previous studies suggested that peripheral blood gene expression can reflect the presence of CAD.
To validate a previously developed 23-gene expression-based classifier for diagnosis of obstructive CAD in non-diabetic patients.
Multi-center prospective trial with blood samples drawn prior to coronary angiography.
Thirty-nine US centers.
An independent validation cohort of 526 non-diabetic patients clinically-indicated for coronary angiography
Receiver-operator characteristics (ROC) analysis of classifier score measured by real-time polymerase chain reaction (RT-PCR), additivity to clinical factors, and reclassification of patient disease likelihood vs disease status defined by quantitative coronary angiography (QCA). Obstructive CAD defined as ≥50% stenosis in ≥1 major coronary artery by QCA.
The overall ROC curve area (AUC) was 0.70 ±0.02, (p<0.001); the classifier added to clinical variables (Diamond-Forrester method) (AUC 0.72 with classifier vs 0.66 without, p = 0.003). Net reclassification was improved by the classifier over Diamond-Forrester and an expanded clinical model (both p<0.001). At a score threshold corresponding to 20% obstructive CAD likelihood (14.75), the sensitivity and specificity were 85% and 43%, yielding NPV of 83% and PPV 46%, with 33% of patient scores below this threshold.
The study excluded patients with chronic inflammatory disorders, elevated white blood counts or cardiac protein markers, and diabetes.
This non-invasive whole blood test, based on gene expression and demographics, may be useful for assessment of obstructive CAD in non-diabetic patients without known CAD.
Primary Funding Source
CardioDx, Inc.
PMCID: PMC3786733  PMID: 20921541
16.  Transforming Medicine via Digital Innovation 
Science translational medicine  2010;2(16):16cm4.
The lack of plasticity of the medical profession and health care system in the face of new technology and information is about to be challenged on two major fronts in digital medicine: wireless technologies and genomics. These two areas have been characterized by unprecedented innovation and discovery at a breakneck pace. Whereas the 2000s saw the introduction of digital life-style devices, the 2010s will probably be known as the era of digital medical devices. These devices have exceptional promise for changing the future of medicine because of their ability to produce exquisitely detailed individual biological and physiological data.
PMCID: PMC3756088  PMID: 20371472
17.  The importance of phase information for human genomics 
Nature reviews. Genetics  2011;12(3):215-223.
Contemporary sequencing studies often ignore the diploid nature of the human genome because they do not routinely separate or ‘phase’ maternally and paternally derived sequence information. However, many findings — both from recent studies and in the more established medical genetics literature — indicate that relationships between human DNA sequence and phenotype, including disease, can be more fully understood with phase information. Thus, the existing technological impediments to obtaining phase information must be overcome if human genomics is to reach its full potential.
PMCID: PMC3753045  PMID: 21301473
18.  Miscues on the “lack of MEF2A mutations” in coronary artery disease 
Journal of Clinical Investigation  2005;115(6):1399-1400.
PMCID: PMC1137019  PMID: 15931371
19.  Impact of Proton Pump Inhibitor Therapy on the Efficacy of Clopidogrel in the CAPRIE and CREDO Trials 
Proton pump inhibitors (PPIs) may interfere with the metabolic activation of clopidogrel via inhibition of cytochrome P450 2C19, but the clinical implications remain unclear.
Methods and Results
The impact of PPI use on the 1‐year primary end point (ischemic stroke, myocardial infarction [MI], or vascular death) in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial and the 28‐day (all‐cause death, MI, or urgent target vessel revascularization) and 1‐year (all‐cause death, MI, or stroke) primary end points in the Clopidogrel for Reduction of Events During Observation (CREDO) trial were examined. Clopidogrel appeared to elevate risk for the primary end point in CAPRIE among PPI users (estimated hazard ratio [EHR] 2.66, 95% CI 0.94 to 7.50) while lowering it for non‐PPI users (EHR 0.90, 95% CI 0.83 to 0.99, interaction P=0.047). Moreover, PPI use was associated with worse outcomes in patients receiving clopidogrel (EHR 2.39, 95% CI 1.74 to 3.28) but not aspirin (EHR 1.04, 95% CI 0.70 to 1.57, interaction P=0.001). Clopidogrel did not significantly alter risk for the 1‐year primary end point in CREDO among PPI users (EHR 0.82, 95% CI 0.48 to 1.40) while lowering it for non‐PPI users (EHR 0.71, 95% CI 0.52 to 0.98, interaction P=0.682). Also, PPI use was associated with worse outcomes in both patients receiving clopidogrel (EHR 1.67, 95% CI 1.06 to 2.64) and those receiving placebo (EHR 1.56, 95% CI 1.06 to 2.30, interaction P=0.811).
In CREDO, the efficacy of clopidogrel was not significantly affected by PPI use. However, in CAPRIE, clopidogrel was beneficial to non‐PPI users while apparently harmful to PPI users. Whether this negative interaction is clinically important for patients receiving clopidogrel without aspirin needs further study.
PMCID: PMC3603228  PMID: 23525436
CAPRIE; clopidogrel; CREDO; drug–drug interaction; proton pump inhibitors
20.  Association of Direct-to-Consumer Genome-Wide Disease Risk Estimates and Self-Reported Disease 
Genetic epidemiology  2011;36(1):66-70.
The ongoing controversy surrounding direct-to-consumer (DTC) personal genomic tests intensified last year when the U.S. Government Accountability Office (GAO) released results of an undercover investigation of four companies that offer such testing. Among their findings, they reported that some of their donors received DNA-based predictions that conflicted with their actual medical histories. We aimed to more rigorously evaluate the relationship between DTC genomic risk estimates and self-reported disease by leveraging data from the Scripps Genomic Health Initiative (SGHI). We prospectively collected self-reported personal and family health history data for 3,416 individuals who went on to purchase a commercially available DTC genomic test. For 5 out of 15 total conditions studied, we found that risk estimates from the test were significantly associated with self-reported family and/or personal health history. The 5 conditions, included Graves’ disease, Type 2 Diabetes, Lupus, Alzheimer’s disease, and Restless Leg Syndrome. To further investigate these findings, we ranked each of the 15 conditions based on published heritability estimates and conducted post-hoc power analyses based on the number of individuals in our sample who reported significant histories of each condition. We found that high heritability, coupled with high prevalence in our sample and thus adequate statistical power, explained the pattern of associations observed. Our study represents one of the first evaluations of the relationship between risk estimates from a commercially available DTC personal genomic test and self-reported health histories in the consumers of that test.
PMCID: PMC3338895  PMID: 22127769
direct-to-consumer; genetic testing; genetic risk estimates; clinical validity; consumer genomics
21.  Clinical Implications of Human Population Differences in Genome-Wide Rates of Functional Genotypes 
Frontiers in Genetics  2012;3:211.
There have been a number of recent successes in the use of whole genome sequencing and sophisticated bioinformatics techniques to identify pathogenic DNA sequence variants responsible for individual idiopathic congenital conditions. However, the success of this identification process is heavily influenced by the ancestry or genetic background of a patient with an idiopathic condition. This is so because potential pathogenic variants in a patient’s genome must be contrasted with variants in a reference set of genomes made up of other individuals’ genomes of the same ancestry as the patient. We explored the effect of ignoring the ancestries of both an individual patient and the individuals used to construct reference genomes. We pursued this exploration in two major steps. We first considered variation in the per-genome number and rates of likely functional derived (i.e., non-ancestral, based on the chimp genome) single nucleotide variants and small indels in 52 individual whole human genomes sampled from 10 different global populations. We took advantage of a suite of computational and bioinformatics techniques to predict the functional effect of over 24 million genomic variants, both coding and non-coding, across these genomes. We found that the typical human genome harbors ∼5.5–6.1 million total derived variants, of which ∼12,000 are likely to have a functional effect (∼5000 coding and ∼7000 non-coding). We also found that the rates of functional genotypes per the total number of genotypes in individual whole genomes differ dramatically between human populations. We then created tables showing how the use of comparator or reference genome panels comprised of genomes from individuals that do not have the same ancestral background as a patient can negatively impact pathogenic variant identification. Our results have important implications for clinical sequencing initiatives.
PMCID: PMC3485509  PMID: 23125845
clinical sequencing; congenital disease; whole genome sequencing; population genetics
23.  Direct-to-consumer personalized genomic testing 
Human Molecular Genetics  2011;20(R2):R132-R141.
Over the past 18 months, there have been notable developments in the direct-to-consumer (DTC) genomic testing arena, in particular with regard to issues surrounding governmental regulation in the USA. While commentaries continue to proliferate on this topic, actual empirical research remains relatively scant. In terms of DTC genomic testing for disease susceptibility, most of the research has centered on uptake, perceptions and attitudes toward testing among health care professionals and consumers. Only a few available studies have examined actual behavioral response among consumers, and we are not aware of any studies that have examined response to DTC genetic testing for ancestry or for drug response. We propose that further research in this area is desperately needed, despite challenges in designing appropriate studies given the rapid pace at which the field is evolving. Ultimately, DTC genomic testing for common markers and conditions is only a precursor to the eventual cost-effectiveness and wide availability of whole genome sequencing of individuals, although it remains unclear whether DTC genomic information will still be attainable. Either way, however, current knowledge needs to be extended and enhanced with respect to the delivery, impact and use of increasingly accurate and comprehensive individualized genomic data.
PMCID: PMC3179383  PMID: 21828075
24.  Genetic structure of community acquired methicillin-resistant Staphylococcus aureus USA300 
BMC Genomics  2012;13:508.
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a significant bacterial pathogen that poses considerable clinical and public health challenges. The majority of the CA-MRSA disease burden consists of skin and soft tissue infections (SSTI) not associated with significant morbidity; however, CA-MRSA also causes severe, invasive infections resulting in significant morbidity and mortality. The broad range of disease severity may be influenced by bacterial genetic variation.
We sequenced the complete genomes of 36 CA-MRSA clinical isolates from the predominant North American community acquired clonal type USA300 (18 SSTI and 18 severe infection-associated isolates). While all 36 isolates shared remarkable genetic similarity, we found greater overall time-dependent sequence diversity among SSTI isolates. In addition, pathway analysis of non-synonymous variations revealed increased sequence diversity in the putative virulence genes of SSTI isolates.
Here we report the first whole genome survey of diverse clinical isolates of the USA300 lineage and describe the evolution of the pathogen over time within a defined geographic area. The results demonstrate the close relatedness of clinically independent CA-MRSA isolates, which carry implications for understanding CA-MRSA epidemiology and combating its spread.
PMCID: PMC3598774  PMID: 23009684
25.  Genomic information as a behavioral health intervention: can it work? 
Personalized medicine  2011;8(6):659-667.
Individuals can now obtain their personal genomic information via direct-to-consumer genetic testing, but what, if any, impact will this have on their lifestyle and health? A recent longitudinal cohort study of individuals who underwent consumer genome scanning found minimal impacts of testing on risk-reducing lifestyle behaviors, such as diet and exercise. These results raise an important question: is personal genomic information likely to beneficially impact public health through motivation of lifestyle behavioral change? In this article, we review the literature on lifestyle behavioral change in response to genetic testing for common disease susceptibility variants. We find that only a few studies have been carried out, and that those that have been done have yielded little evidence to suggest that the mere provision of genetic information alone results in widespread changes in lifestyle health behaviors. We suggest that further study of this issue is needed, in particular studies that examine response to multiplex testing for multiple genetic markers and conditions. This will be critical as we anticipate the wide availability of whole-genome sequencing and more comprehensive phenotyping of individuals. We also note that while simple communication of genomic information and disease susceptibility may be sufficient to catalyze lifestyle changes in some highly motivated groups of individuals, for others, additional strategies may be required to prompt changes, including more sophisticated means of risk communication (e.g., in the context of social norm feedback) either alone or in combination with other promising interventions (e.g., real-time wireless health monitoring devices).
PMCID: PMC3244209  PMID: 22199991
behavioral intervention; consumer genomics; direct-to-consumer; genetic risk; genetic testing; nudging; personalized medicine; social norm feedback; wireless monitoring

Results 1-25 (63)