Showing papers by "Eric J. Topol published in 2017"

Influence of donor age on induced pluripotent stem cells

Abstract: Induced pluripotent stem cells (iPSCs) are being pursued as a source of cells for autologous therapies, many of which will be aimed at aged patients. To explore the impact of age on iPSC quality, we produced iPSCs from blood cells of 16 donors aged 21-100. We find that iPSCs from older donors retain an epigenetic signature of age, which can be reduced through passaging. Clonal expansion via reprogramming also enables the discovery of somatic mutations present in individual donor cells, which are missed by bulk sequencing methods. We show that exomic mutations in iPSCs increase linearly with age, and all iPSC lines analyzed carry at least one gene-disrupting mutation, several of which have been associated with cancer or dysfunction. Unexpectedly, elderly donors (>90 yrs) harbor fewer mutations than predicted, likely due to a contracted blood progenitor pool. These studies establish that donor age is associated with an increased risk of abnormalities in iPSCs and will inform clinical development of reprogramming technology.

Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals

Abstract: Diagnosis of monogenic as well as atypical forms of diabetes mellitus has important clinical implications for their specific diagnosis, prognosis, and targeted treatment. Single gene mutations that affect beta-cell function represent 1–2% of all cases of diabetes. However, phenotypic heterogeneity and lack of family history of diabetes can limit the diagnosis of monogenic forms of diabetes. Next-generation sequencing technologies provide an excellent opportunity to screen large numbers of individuals with a diagnosis of diabetes for mutations in disease-associated genes. We utilized a targeted sequencing approach using the Illumina HiSeq to perform a case-control sequencing study of 22 monogenic diabetes genes in 4016 individuals with type 2 diabetes (including 1346 individuals diagnosed before the age of 40 years) and 2872 controls. We analyzed protein-coding variants identified from the sequence data and compared the frequencies of pathogenic variants (protein-truncating variants and missense variants) between the cases and controls. A total of 40 individuals with diabetes (1.8% of early onset sub-group and 0.6% of adult onset sub-group) were carriers of known pathogenic missense variants in the GCK, HNF1A, HNF4A, ABCC8, and INS genes. In addition, heterozygous protein truncating mutations were detected in the GCK, HNF1A, and HNF1B genes in seven individuals with diabetes. Rare missense mutations in the GCK gene were significantly over-represented in individuals with diabetes (0.5% carrier frequency) compared to controls (0.035%). One individual with early onset diabetes was homozygous for a rare pathogenic missense variant in the WFS1 gene but did not have the additional phenotypes associated with Wolfram syndrome. Targeted sequencing of genes linked with monogenic diabetes can identify disease-relevant mutations in individuals diagnosed with type 2 diabetes not suspected of having monogenic forms of the disease. Our data suggests that GCK-MODY frequently masquerades as classical type 2 diabetes. The results confirm that MODY is under-diagnosed, particularly in individuals presenting with early onset diabetes and clinically labeled as type 2 diabetes; thus, sequencing of all monogenic diabetes genes should be routinely considered in such individuals. Genetic information can provide a specific diagnosis, inform disease prognosis and may help to better stratify treatment plans.

Critical Issues in Peripheral Arterial Disease Detection and Management

Abstract: HIS CALL-TO-ACTION document is an initiative of the Prevention of Atherothrombotic Disease Network, an international, multidisciplinary network, adjoined by the mutual goal of increasing awareness, detection, and treatment rates of peripheral arterial disease (PAD) and increasing awareness of the interrelationship between PAD and the risk of ischemic events. Although the prevalence of PAD in Europe and North America is estimated at approximately 27 million people, PAD remains a largely underdiagnosed and

A Whole Blood Molecular Signature for Acute Myocardial Infarction.

Abstract: Chest pain is a leading reason patients seek medical evaluation. While assays to detect myocyte death are used to diagnose a heart attack (acute myocardial infarction, AMI), there is no biomarker to indicate an impending cardiac event. Transcriptional patterns present in circulating endothelial cells (CEC) may provide a window into the plaque rupture process and identify a proximal biomarker for AMI. Thus, we aimed to identify a transcriptomic signature of AMI present in whole blood, but derived from CECs. Candidate genes indicative of AMI were nominated from microarray of enriched CEC samples, and then verified for detectability and predictive potential via qPCR in whole blood. This signature was validated in an independent cohort. Our findings suggest that a whole blood CEC-derived molecular signature identifies patients with AMI and sets the framework to potentially identify the earlier stages of an impending cardiac event when used in concert with clinical history and other diagnostics where conventional biomarkers indicative of myonecrosis remain undetected.

The Pathway to Patient Data Ownership and Better Health

Abstract: Digital health data are rapidly expanding to include patient-reported outcomes, patient-generated health data, and social determinants of health. Measurements collected in clinical settings are being supplemented by data collected in daily life, such as data derived from wearable sensors and smartphone apps, and access to other data, such as genomic data, is rapidly increasing. One projection suggests that a billion individuals will have their whole genome sequenced in the next several years.1 These additional sources of data, whether patientgenerated, genomic, or other, are critical for a comprehensive picture of an individual’s health. Enabling access to personal health data, clinical or patient-generated, may benefit patients and health care professionals. Research is beginning to show that providing patients with their complete health data may help improve their health. For example, timely access to laboratory results can increase patient engagement.2 Access to physician notes after appointments appears to encourage individuals to improve their health and participate in decision-making, with electronically engaged patients demonstrating more successful medication adherence, quality outcomes, and symptom management.3 Economic benefits may include the avoidance of duplicative imaging or laboratory tests.4 Clinicians may also benefit from more informed patients. For example, they may score higher in quality performance programs because patients who are more informed may better adhere to treatment plans and hence may improve clinician

Molecular Autopsy for Sudden Death in the Young: Is Data Aggregation the Key?

Abstract: The Scripps Molecular Autopsy (MA) study seeks to incorporate genetic testing into the postmortem examination of cases of sudden death in the young (< 45 years old). Here we describe the results from the first two years of the study, which consisted of whole exome sequencing (WES) of a cohort of 50 cases predominantly from San Diego County. Apart from the individual description of cases, we analyzed the data at the cohort-level, which brought new perspectives on the genetic causes of sudden death. We investigated the advantages and disadvantages of using WES compared to a gene panel for cardiac disease (usually the first genetic test used by medical examiners). In an attempt to connect complex clinical phenotypes with genotypes, we classified samples by their genetic fingerprint. Finally, we studied the benefits of analyzing the mitochondrial DNA genome. In this regard, we found that half of the cases clinically diagnosed as sudden infant death syndrome had an increased ratio of heteroplasmic variants, and that the variants were also present in the mothers. We believe that community-based data aggregation and sharing will eventually lead to an improved classification of variants. Allele frequencies for the all cases can be accessed via our genomics browser at https://genomics.scripps.edu/browser.

Genome-Wide Linkage Analysis of Large Multiple Multigenerational Families Identifies Novel Genetic Loci for Coronary Artery Disease

Abstract: Coronary artery disease (CAD) is the leading cause of death, and genetic factors contribute significantly to risk of CAD. This study aims to identify new CAD genetic loci through a large-scale linkage analysis of 24 large and multigenerational families with 433 family members (GeneQuest II). All family members were genotyped with markers spaced by every 10 cM and a model-free nonparametric linkage (NPL-all) analysis was carried out. Two highly significant CAD loci were identified on chromosome 17q21.2 (NPL score of 6.20) and 7p22.2 (NPL score of 5.19). We also identified four loci with significant NPL scores between 4.09 and 4.99 on 2q33.3, 3q29, 5q13.2 and 9q22.33. Similar analyses in individual families confirmed the six significant CAD loci and identified seven new highly significant linkages on 9p24.2, 9q34.2, 12q13.13, 15q26.1, 17q22, 20p12.3, and 22q12.1, and two significant loci on 2q11.2 and 11q14.1. Two loci on 3q29 and 9q22.33 were also successfully replicated in our previous linkage analysis of 428 nuclear families. Moreover, two published risk variants, SNP rs46522 in UBE2Z and SNP rs6725887 in WDR12 by GWAS, were found within the 17q21.2 and 2q33.3 loci. These studies lay a foundation for future identification of causative variants and genes for CAD.

Moving Beyond Clinical Risk Scores with a Mobile App for the Genomic Risk of Coronary Artery Disease

Abstract: Primary prevention of coronary artery disease (CAD) is important for individuals at increased risk, and largely consists of healthy lifestyle modifications and initiation of medications when appropriate - including statins. Defining the inherent risk for any given individual typically relies on traditional risk factors established decades ago by the Framingham Heart Study. Unfortunately, recent studies have indicated that these traditional clinical risk factors systematically overestimate the risk of CAD across all major ancestries. This has increased the number of patients that would be eligible for statin therapy for the primary prevention of CAD but would likely receive little benefit and potentially incur negative consequences. On the other hand, researchers have demonstrated that genetic factors can effectively identify a subset of high risk individuals, and that the benefit from statin therapy is greatest among individuals with the highest genetic risk score (GRS). These individuals also receive the greatest absolute benefit from healthy lifestyle choices, being able to titrate their risk to normal levels despite high genetic predisposition. However, it is not yet possible for the average individual to discover their genetic risk because no tools are currently available to make such a determination. Here, we present a free mobile app - MyGeneRank - that can provide this information. Individuals may choose to use this knowledge to complement traditional risk assessments, and make critical decisions regarding lifelong statin therapy and lifestyle changes. As of 1/25/2017, MyGeneRank is currently in closed beta and will soon be available to the public.

Effects of a 5-Lipoxygenase-Activating Protein Inhibitor on Biomarkers Associated With Risk of Myocardial Infarction

Abstract: CONTEXT Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase-activating protein (FLAP) gene are associated with risk of MI. OBJECTIVE To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk. DESIGN, SETTING, AND PATIENTS A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004. INTERVENTIONS Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks. MAIN OUTCOME MEASURES Changes in levels of biomarkers associated with risk of MI. RESULTS In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% CI, -2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events. CONCLUSION In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.

Abstract 13757: A Nationwide Trial of Screening for Undiagnosed Atrial Fibrillation in an At-Risk Population Using a Self-Applied ECG Recording Patch Sensor: Results of the Randomized Component of the mHealth Screening to Prevent Strokes (mSToPS) Trial

Abstract: Introduction: Undiagnosed atrial fibrillation (AF) can lead to strokes, the majority of which could be prevented through use of oral anticoagulants. Therefore, guidelines recommend opportunistic sc...

Pure Genius, the TV Series: Is There an ICD-10 Code for Hyperbole?

Abstract: When I heard that CBS was launching a television series about a young tech billionaire building a futuristic hospital to provide free cutting-edge care for complex patients, I was thrilled. I have made the case for the transformation of patient-centered health care through technology and was eager to see that vision imagined by others on TV. The vision quickly blurred when the miracle talk started. The show launched October 27, 2016, with a promotional tweet: “Welcome to Bunker Hill, where miracles happen every day.” The series focuses on two characters: James Bell (@AugustusPrew), a brazen 30-ish rich kid whose Silicon Valley success has taught him nothing is impossible and who’s used his endless fortune to build Bunker Hill Hospital, a high-tech medical center to cure patients who have been failed by health systems with conventional resources and imaginations; and Dr Walter Wallace (Dermot Mulroney), fired from Cincinnati General Hospital for giving chemotherapy to an 8-year-old who died. Wallace, having shown his willingness to break the rules for his patients’ well-being, is exactly what Bell needs in a senior surgeon, de facto chief medical officer, and conscience for Bunker Hill (“This is the Revolution,” Bell says—to be overt about it). Wallace resists Bell’s recruitment tactics for much of the first episode, defending Old World patient care values and denouncing gadgetry—“Medicine is ultimately a human endeavor,” he counsels. But he slowly, unsurprisingly succumbs to Bell’s charms, the power of watching patients rescued by ingenuity and technology from beyond-impossible odds, and some high-tech swag: as an enticement, Wallace undergoes whole-body 3-dimensional magnetic resonance imaging to be immortalized in a 3-D model. Each of the first 3 episodes presents 2 complex patients: 1. A pregnant woman diagnosed with some form of aggressive heart cancer whose urgent surgery must be perilously delayed so her child can reach viability and be delivered after 20 weeks’ gestation 2. A teenaged girl with Gerstmann-Sträussler-Scheinker syndrome (GSS) in a prolonged vegetative state who is fit with a brain-to-brain communication mechanism “to see if there is someone in there left to save” (there are “at least 24 separate [GSS] kindreds identified throughout the world,” UpToDate says, and Bell’s apparently makes 25; the knowledge that he will develop the autosomal-dominant, completely penetrant disease is his motivation for the entire Bunker Hill hospital project) 3. A boy with multiple comminuted lower extremity fractures from a motor vehicle crash rescued from amputation by “spider silk screw” technology 4. An anicteric woman with end-stage liver disease (vanishing bile duct syndrome, diagnosed by exhaled volatile organic compounds) who undergoes a lobar hepatic transplant from her estranged cirrhotic father whose liver is restored via real-time liver regeneration 5. A police officer with profound memory loss and child-like regression whose identity is restored via brain optogenetics 6. A morbidly obese woman found to have an unspecified obesogenic adrenal tumor that has prevented her from losing weight. Our ordinary health systems can only aspire to the results Pure Genius delivers twice an hour. Patients are cured, their lives are saved, or they have dramatic responses to unproven, otherwise unavailable treatments. And in each case Bell, without any medical training or background, makes the critical clinical decisions: “Best idea wins,” he says at the series’ beginning, and they’re usually his. He meets directly with patients and their families, makes extraordinary promises, dresses in scrubs, and uses technology that has never been applied to human beings. When the amnestic police officer does not respond to what the show calls neurostimulation, Bell blurts out, “I’ve always wanted to reprogram someone’s brain” and administers some form of optogenetic intervention that partially restores his memory. The notion that a medically untrained tech billionaire walking around in casual clothes and flip-flops can make life-and-death decisions for people using far-fetched, unchartered therapies is preposterous. There are certainly tech billionaires committed to improving medicine and public health, such as Mark Zuckerberg and Priscilla Chan’s Chan-Zuckerberg initiative and Sean Parker’s Dr Wallace works on a 3-D–printed heart as Angie Cheng (Brenda Song) looks on. “Pilot” (episode 1, season 1 of Pure Genius).