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Archive for the ‘Computational Biology/Systems and Bioinformatics’ Category

Genetics of Aortic and Carotid Calcification: The Role of Serum Lipids

Reporter: Aviva Lev-Ari, PhD, RN

Genetic Loci for Coronary Calcification and Serum Lipids Relate to Aortic and Carotid Calcification

Daniel Bos, MD, M. Arfan Ikram, MD, PhD, Aaron Isaacs, PhD, Benjamin F.J. Verhaaren, MD, Albert Hofman, MD, PhD, Cornelia M. van Duijn, PhD, Jacqueline C.M. Witteman, PhD, Aad van der Lugt, MD, PhD and Meike W. Vernooij, MD, PhD

Author Affiliations

From the Departments of Radiology (D.B., M.A.I., B.F.J.V., A.v.d.L., M.W.V), Epidemiology (D.B., M.A.I., A.I., B.F.J.V., A.H., C.M.v.D., J.C.M.W., M.W.V.), and Genetic Epidemiology Unit (A.I., C.M.v.D.), Erasmus MC, Rotterdam, the Netherlands.

Correspondence to Meike W. Vernooij, MD, PhD, Department of Radiology, Erasmus MC, Gravendijkwal 230, PO Box 2040, 3000CA Rotterdam, the Netherlands. E-mailm.vernooij@erasmusmc.nl

Abstract

Background—Atherosclerosis in different vessel beds shares lifestyle and environmental risk factors. It is unclear whether this holds for genetic risk factors. Hence, for the current study genetic loci for coronary artery calcification and serum lipid levels, one of the strongest risk factors for atherosclerosis, were used to assess their relation with atherosclerosis in different vessel beds.

Methods and Results—From 1987 persons of the population-based Rotterdam Study, 3 single-nucleotide polymorphisms (SNPs) for coronary artery calcification and 132 SNPs for total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides were used. To quantify atherosclerotic calcification as a marker of atherosclerosis, all participants underwent nonenhanced computed tomography of the aortic arch and carotid arteries. Associations between genetic risk scores of the joint effect of the SNPs and of all calcification were investigated. The joint effect of coronary artery calcification–SNPs was associated with larger calcification volumes in all vessel beds (difference in calcification volume per SD increase in genetic risk score: 0.15 [95% confidence interval, 0.11–0.20] in aorta, 0.14 [95% confidence interval, 0.10–0.18] in extracranial carotids, and 0.11 [95% confidence interval, 0.07–0.16] in intracranial carotids). The joint effect of total cholesterol SNPs, low-density lipoprotein SNPs, and of all lipid SNPs together was associated with larger calcification volumes in both the aortic arch and the carotid arteries but attenuated after adjusting for the lipid fraction and lipid-lowering medication.

Conclusions—The genetic basis for aortic arch and carotid artery calcification overlaps with the most important loci of coronary artery calcification. Furthermore, serum lipids share a genetic predisposition with both calcification in the aortic arch and the carotid arteries, providing novel insights into the cause of atherosclerosis.

 SOURCE:

Circulation: Cardiovascular Genetics.2013; 6: 47-53

Published online before print December 16, 2012,

doi: 10.1161/ CIRCGENETICS.112.963934

 

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Gene Study of Blood Pressure Response to Dietary Potassium Intervention: Genetic Epidemiology of Salt Sensitivity

Reporter: Aviva Lev-Ari, PhD, RN

Genome-Wide Linkage and Positional Candidate Gene Study of Blood Pressure Response to Dietary Potassium Intervention

The Genetic Epidemiology Network of Salt Sensitivity Study

Tanika N. Kelly, PhD, James E. Hixson, PhD, Dabeeru C. Rao, PhD, Hao Mei, MD, PhD,Treva K. Rice, PhD, Cashell E. Jaquish, PhD, Lawrence C. Shimmin, PhD, Karen Schwander, MS, Chung-Shuian Chen, MS, Depei Liu, PhD, Jichun Chen, MD,Concetta Bormans, PhD, Pramila Shukla, MS, Naveed Farhana, MS, Colin Stuart, BS,Paul K. Whelton, MD, MSc, Jiang He, MD, PhD and Dongfeng Gu, MD, PhD

Author Affiliations

From the Department of Epidemiology (T.N.K., H.M., C.-S.C., J.H.), Tulane University School of Public Health and Tropical Medicine, and Department of Medicine (J.H.), Tulane University School of Medicine, New Orleans, La; Department of Epidemiology (J.E.H., L.C.S., C.B., P.S., N.F., C.S.), University of Texas School of Public Health, Houston, Tex; Division of Biostatistics (D.C.R., T.K.R., K.S.), Washington University School of Medicine, St Louis, Mo; Division of Prevention and Population Sciences (C.E.J.), National Heart, Lung, Blood Institute, Bethesda, Md; National Laboratory of Medical Molecular Biology (D.L.), Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Cardiovascular Institute and Fuwai Hospital (J.C., D.G.), Chinese Academy of Medical Sciences and Peking Union Medical College and Chinese National Center for Cardiovascular Disease Control and Research, Beijing, China; and Office of the President (P.K.W.), Loyola University Health System and Medical Center, Maywood, Ill.

Correspondence to Dongfeng Gu, MD, PhD, Division of Population Genetics and Prevention, Cardiovascular Institute and Fuwai Hospital, 167 Beilishi Rd, Beijing 100037, China. E-mail gudongfeng@vip.sina.com

Abstract

Background— Genetic determinants of blood pressure (BP) response to potassium, or potassium sensitivity, are largely unknown. We conducted a genome-wide linkage scan and positional candidate gene analysis to identify genetic determinants of potassium sensitivity.

Conclusions— Genetic regions on chromosomes 3 and 11 may harbor important susceptibility loci for potassium sensitivity. Furthermore, the AGTR1 gene was a significant predictor of BP responses to potassium intake.

SOURCE:

Circulation: Cardiovascular Genetics. 2010; 3: 539-547

Published online before print September 22, 2010,

doi: 10.1161/ CIRCGENETICS.110.940635

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Cardiometabolic Syndrome and the Genetics of Hypertension: The Neuroendocrine Transcriptome Control Points

Reporter: Aviva Lev-Ari, PhD, RN

 

Integrated Computational and Experimental Analysis of the Neuroendocrine Transcriptome in Genetic Hypertension Identifies Novel Control Points for the Cardiometabolic Syndrome

Ryan S. Friese, PhD, Chun Ye, PhD, Caroline M. Nievergelt, PhD, Andrew J. Schork, BS, Nitish R. Mahapatra, PhD, Fangwen Rao, MD, Philip S. Napolitan, BS, Jill Waalen, MD, MPH, Georg B. Ehret, MD, Patricia B. Munroe, PhD, Geert W. Schmid-Schönbein, PhD, Eleazar Eskin, PhD and Daniel T. O’Connor, MD

Author Affiliations

From the Departments of Bioengineering (R.S.F., G.W.S.-S.), Medicine (R.S.F., A.J.S., F.R., P.S.N., D.T.O.), Pharmacology (D.T.O.), and Psychiatry (C.M.N.), the Bioinformatics Program (C.Y.), and the Institute for Genomic Medicine (D.T.O.), University of California at San Diego; the VA San Diego Healthcare System, San Diego, CA (D.T.O.); the Departments of Computer Science & Human Genetics, University of California at Los Angeles (E.E.); the Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India (N.R.M.); Clinical Pharmacology and The Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom (P.B.M.); Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (G.B.E.); and Scripps Research Institute, La Jolla, CA (J.W.).

Correspondence to Daniel T. O’Connor, MD, Department of Medicine, University of California at San Diego School of Medicine, VASDHS (0838), Skaggs (SSPPS) Room 4256, 9500 Gilman Drive, La Jolla, CA 92093-0838. E-mail doconnor@ucsd.edu

Abstract

Background—Essential hypertension, a common complex disease, displays substantial genetic influence. Contemporary methods to dissect the genetic basis of complex diseases such as the genomewide association study are powerful, yet a large gap exists betweens the fraction of population trait variance explained by such associations and total disease heritability.

Methods and Results—We developed a novel, integrative method (combining animal models, transcriptomics, bioinformatics, molecular biology, and trait-extreme phenotypes) to identify candidate genes for essential hypertension and the metabolic syndrome. We first undertook transcriptome profiling on adrenal glands from blood pressure extreme mouse strains: the hypertensive BPH (blood pressure high) and hypotensive BPL (blood pressure low). Microarray data clustering revealed a striking pattern of global underexpression of intermediary metabolism transcripts in BPH. The MITRA algorithm identified a conserved motif in the transcriptional regulatory regions of the underexpressed metabolic genes, and we then hypothesized that regulation through this motif contributed to the global underexpression. Luciferase reporter assays demonstrated transcriptional activity of the motif through transcription factors HOXA3, SRY, and YY1. We finally hypothesized that genetic variation at HOXA3SRY, and YY1 might predict blood pressure and other metabolic syndrome traits in humans. Tagging variants for each locus were associated with blood pressure in a human population blood pressure extreme sample with the most extensive associations for YY1 tagging single nucleotide polymorphism rs11625658 on systolic blood pressure, diastolic blood pressure, body mass index, and fasting glucose. Meta-analysis extended the YY1results into 2 additional large population samples with significant effects preserved on diastolic blood pressure, body mass index, and fasting glucose.

Conclusions—The results outline an innovative, systematic approach to the genetic pathogenesis of complex cardiovascular disease traits and point to transcription factor YY1 as a potential candidate gene involved in essential hypertension and the cardiometabolic syndrome.

 SOURCE:

Circulation: Cardiovascular Genetics.2012; 5: 430-440

Published online before print June 5, 2012,

doi: 10.1161/ CIRCGENETICS.111.962415

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MicroRNA in Serum as Biomarker for Cardiovascular Pathologies: acute myocardial infarction, viral myocarditis,  diastolic dysfunction, and acute heart failure

Reporter: Aviva Lev-Ari, PhD, RN

Increased MicroRNA-1 and MicroRNA-133a Levels in Serum of Patients With Cardiovascular Disease Indicate Myocardial Damage

Yasuhide Kuwabara, MD, Koh Ono, MD, PhD, Takahiro Horie, MD, PhD, Hitoo Nishi, MD, PhD, Kazuya Nagao, MD, PhD, Minako Kinoshita, MD, PhD, Shin Watanabe, MD, PhD, Osamu Baba, MD, Yoji Kojima, MD, PhD, Satoshi Shizuta, MD, Masao Imai, MD,Toshihiro Tamura, MD, Toru Kita, MD, PhD and Takeshi Kimura, MD, PhD

Author Affiliations

From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan (Y. Kuwabara, K.O., T.H., H.N., K.N., M.K., S.W., O.B., Y. Kojima, S.S., M.I., T.T., T. Kimura); and Kobe City Medical Center General Hospital, Kobe, Japan (T. Kita).

Correspondence to Koh Ono, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawahara-cho, Sakyo-ku, Kyoto, Japan 606-8507. E-mail kohono@kuhp.kyoto-u.ac.jp

Abstract

Background—Recently, elevation of circulating muscle-specific microRNA (miRNA) levels has been reported in patients with acute myocardial infarction. However, it is still unclear from which part of the myocardium or under what conditions miRNAs are released into circulating blood. The purpose of this study was to identify the source of elevated levels of circulating miRNAs and their function in cardiovascular diseases.

Conclusions—These results suggest that elevated levels of circulating miRNA-133a in patients with cardiovascular diseases originate mainly from the injured myocardium. Circulating miR-133a can be used as a marker for cardiomyocyte death, and it may have functions in cardiovascular diseases.

SOURCE:

Circulation: Cardiovascular Genetics. 2011; 4: 446-454

Published online before print June 2, 2011,

doi: 10.1161/ CIRCGENETICS.110.958975

 

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Common Heart Failure: Clinical Considerations of Heritable Factors

Reporter: Aviva Lev-Ari, PhD, RN

 

Clinical Considerations of Heritable Factors in Common Heart Failure

Thomas P. Cappola, MD, ScM and Gerald W. Dorn II, MD

Author Affiliations

From the Department of Medicine, University of Pennsylvania, Philadelphia, PA (T.P.C.), and Center for Pharmacogenomics, Washington University School of Medicine, St Louis, MO (G.W.D.II.).

Correspondence to Gerald W. Dorn II, MD, Center for Pharmacogenomics, Washington University, 660 S Euclid Ave, Campus Box 8220, St Louis, MO 63110. E-mail gdorn@dom.wustl.edu

Introduction

Heart failure is a common condition responsible for at least 290 000 deaths each year in the United States alone.1 A small minority of heart failure cases are attributed to Mendelian or familial cardiomyopathies. The majority of systolic heart failure cases are not familial but represent the end result of 1 or many conditions that primarily injure the myocardium sufficiently to diminish cardiac output in the absence of compensatory mechanisms. Paradoxically, because they also injure the myocardium, it is the chronic actions of the compensatory mechanisms that in many instances contribute to the progression from simple cardiac injury to dilated cardiomyopathy and overt heart failure. Thus, the epidemiology of common heart failure appears to be just as sporadic as its major antecedent conditions (atherosclerosis, diabetes, hypertension, and viral myocarditis).

Familial trends in preclinical cardiac remodeling2 and risk of developing heart failure3reveal an important role for genetic modifiers in addition to clinical and environmental factors. Candidate gene studies performed over the past 10 years have identified a few polymorphic gene variants that modify risk or progression of common heart failure.4 Whole-genome sequencing will lead to the discovery of other genetic modifiers that were not candidates.5 The imminent availability of individual whole-genome sequences at a cost competitive with available genetic tests for familial cardiomyopathy will no doubt further expand the list of putative genetic heart failure modifiers. Heart failure risk alleles along with traditional clinical factors will need to be considered by clinical cardiologists in their design of optimal disease surveillance and prevention programs and in individually tailoring heart failure management.

The use of individual genetic make-up is likely to have the earliest and greatest impact on managing patients with heart failure by tailoring available pharmacotherapeutics to optimize patient response and minimize adverse effects (ie, the area of pharmacogenetics). Modern heart failure management has been derived and directed by the results of large, randomized, multicenter clinical trials. When standard therapies are applied according to the selection criteria used in these trials, they prolong average survival across affected populations or decrease the incidence of heart failure in populations at risk.6 For this reason, standardized treatment guidelines prescribe heart failure therapies according to trial designs, aiming for the same target doses and general treatment approaches,7 and largely ignore individual characteristics. In this article, we review established and emerging knowledge of genetic influence on common heart failure and try to anticipate how these genetic factors may be best used to eschew the cookie-cutter approach to heart failure management and move toward implementing a personalized medicine approach for the treatment and prevention of this important and prevalent disease.

The Concept of Genotype-Directed Personal Medical Management in Heart Failure

Variation in clinical heart failure progression and therapeutic response (either benefits or side effects) supports the need for a more individualized approach to disease management. On the basis of clinical stratification (eg, by etiology of heart failure as ischemic versus nonischemic, functional status, comorbid disease), physicians try to match each patient’s specific heart failure syndrome with a therapeutic regime devised to provide the most benefit. Standard heart failure pharmacotherapy currently comprises a minimum of 3 medications (angiotensin-converting enzyme [ACE] inhibitors, β-blockers, and aldosterone antagonists), with consideration of additional medications (hydralazine/isosorbide, angiotensin receptor blockers) and diuretics. The recommended target dosages for these agents, derived from their respective clinical trials, is rarely achieved,8 partly because of untoward clinical side effects such as low blood pressure or renal dysfunction. Accordingly, the published guidelines most often are applied in each individual patient using ad hoc approaches derived from personal experience and the “art of medicine.”

Technological advances in human genomics promise a different approach and are bringing cardiology into an era of clinically applied pharmacogenetics9 (whether we want to or not). As sequencing costs decline, it is not hard to envision that patients will present having had their entire genome already sequenced. The imperative to apply genome information in clinical settings will increase, as demonstrated by recent proof-of-concept studies.10 Our field seems poorly prepared for this type of evolution in care; Roden et al9 identified 3 major barriers: First is the absence of rapidly available genotype information in the clinical workflow. This barrier is being overcome with whole-genome sequencing, which (with proper analysis) promises a permanent and largely immutable genetic roadmap for individual disease risk and drug response at a cost comparable to many other clinical tests.11 Second, we must have the knowledge to properly apply information on genetic variants for the diseases we are managing and the drugs we are using. As we describe, this knowledge is accumulating for heart failure and for other cardiac conditions, and the rate at which we are gaining additional information and developing further expertise appears to be accelerating.

The third and perhaps most formidable barrier is the lack of clinical evidence showing how real-time application of genetic information can best benefit patients. As has been broadly communicated to the medical community and lay public, common functional gene variants in CYP2C19 can impair the transformation of clopidogrel into its active metabolite, leading to increased risk of stent thrombosis after percutaneous coronary intervention.12 The relevant question thus becomes the following: If physicians have this information at the time of clinical care and reacted by adjusting clopidogrel dose or substituting prasugrel, which is unaffected by CYP2C19genotype,13 would there be any improvement in clinical outcome? It is also important to consider whether any observed benefits justify the additional costs of genetic testing and for the alternate drug. Studies are currently examining these questions, and similar clinical trials will prospectively examine whether a genotype-guided strategy of warfarin dosing will be superior to the standard genotype-blinded approach in reaching target anticoagulation goals. At this time, there are no similar prospective, randomized, blinded trials of genotype-guided care for common heart failure.

Emerging Variants

The variants described here are established, but new ones are emerging. Although findings in heart failure genome-wide association studies have been limited, we can expect additional common heart failure variants to emerge as sample sizes increase.65 The CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium published a genome-wide association study of incident heart failure that tested for associations between >2.4 million HapMap-imputed polymorphisms in >20 000 subjects.7 They identified 2 loci associated with heart failure, rs10519210 (15q22, containing USP3 encoding a ubiquitin-specific protease) in subjects of European ancestry and rs11172782 (12q14, containing LRIG3encoding a leucine-rich, immunoglobulin-like domain-containing protein of uncertain function) in subjects of African ancestry.66 In a companion study using the same population and genotyping results, mortality analysis of the subgroup of individuals who developed heart failure implicated an intronic SNP in CMTM7 (CKLF-like MARVEL transmembrane domain-containing 7).67 These genetic associations require independent replication and further study to identify the underlying biological mechanisms.

A recently published genome-wide association study by a European consortium on dilated cardiomyopathy identified common variants in BAG3 (BCL2-associated athanogene 3) associated with heart failure57 and identified rare BAG3 missense and truncation mutations that segregate with familial cardiomyopathy. These findings were consistent with an earlier exome-sequencing study that identifiedBAG3 as a familial dilated cardiomyopathy gene and showed recapitulation of cardiomyopathy with BAG3 morpholino knockdown in zebra fish.68 Together, these studies convincingly support variation in BAG3 as a genetic risk factor of cardiomyopathy and heart failure. It is noteworthy that both common and rare functional variations were identified at this locus. A unifying hypothesis for these findings, which needs to be formally tested, is that common variants in BAG3 serve as proxies for rare functional BAG3 mutations with large effects. In this situation, the underlying genetic lesion is a rare variant with a large functional effect. This has recently been described for common variants in MYH6 that correlated with rare functional MYH6 variants to cause sick sinus syndrome.69 It is premature to speculate on the clinical applications of these newer findings.

Moving Knowledge to Practice

A small number of genomic variants have been identified that modify heart failure by affecting well-understood physiological systems. The principal barrier preventing their adoption in practice may be lack of evidence showing how application of this information can best be used for clinical benefit. Trials testing genotype targeting of antiplatelet therapy and anticoagulation will be completed in the coming years. The findings from these studies will likely determine the level of enthusiasm for conducting genotype-guided trials of β-blockers and RAAS antagonists in heart failure. Given that the lifetime risk of heart failure in the United States is estimated at 1 in 5, even a small favorable effect on heart failure prevention or outcome through use of genome-guided therapy has the potential for a large public health impact. We therefore believe that a near-term goal should be to conduct pharmacogenomic trials in heart failure based on our current understanding of heart failure variants.

Looking ahead, unbiased approaches will continue to reveal a large number heart failure-modifying variants (both common and rare). Based on experience in other complex phenotypes, such has height70 and plasma lipid levels,71 the underlying genetic mechanisms for many new heart failure variants will be completely unknown, and their sheer number will preclude detailed experimentation using murine models to figure them out. Leveraging these variants for clinical application is a challenge that we will be forced to confront.

As our ability to identify rare, disease-causing variants improves through personal genome sequencing, we will be faced with the additional problem of how best to estimate the disease risk conferred by a sequence variant for which there has been no biological validation. In probabilistic terms, because there are 3 billion nucleotides in the human genome and over twice that many humans on the planet, it is likely that a nucleotide substitution for every position is represented in someone. Obviously, it will be impossible to recombinantly express and functionally characterize every DNA variant that is going to be implicated in heart failure. Bioinformatics filters have been used to try and separate functionally significant from insignificant variants based on the likelihood of changing transcript expression or protein function. These tools are limited but will improve if we tailor their results to the known characteristics of each gene product. For example, current approaches to categorize amino acid substitutions as conservative or nonconservative based only on charge or side chains can be improved by molecular modeling that incorporates protein-specific structure-function information. This approach has been used to estimate the pathogenicity of myosin heavy chain (MHC) mutations in an effort to determine which mutations are likely to cause familial cardiomyopathy when linkage analysis is not feasible.72 In concept, this approach can be applied to any protein for which structure-function activities have been finely mapped to distinct domains.

A promising extension of this approach may be to use evolutionary genetics to infer disease causality. Again, using the MHC genes as examples, human genome data show a greater prevalence of nonsynonymous gene variants in MYH6, which encodes the minor cardiac α-MHC isoform, compared with the adjacent MYH7, which encodes the major β-MHC isoform. This disparity suggests a greater tolerance for protein changes in the α-MHC isoform and negative selection against these in β-MHC. We can infer, therefore, that amino acid changes are more likely to have adverse impacts in MYH7-encoded β-MHC. If this paradigm survives prospective testing, then the forthcoming explosion of individual genetic data not only will present a massive problem in interpretation, but also will provide the genetic information by which analyses of rare sequence variants across large unaffected populations can help to differentiate the tolerable variants from those that are more likely to alter disease risk.

Each Reference above is found in:

http://circgenetics.ahajournals.org/content/4/6/701.full

SOURCE: 

Circulation: Cardiovascular Genetics.2011; 4: 701-709

doi: 10.1161/ CIRCGENETICS.110.959379

 

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Genomics in Medicine – Establishing a Patient-Centric View of Genomic Data

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 12/13, 2013

Second  Annual
Genomics in Medicine
Establishing a Patient-Centric View of  Genomic Data
February 13-14, 2014 | San Francisco,  CA

Dr. Michael Christman, President and CEO of the  Coriell Institute for Medical Research, to Present “Using a  Patient’s Genetic Information in the Real World” at the Second  Annual Genomics in Medicine  Symposium

When  a patient needs a new prescription, it will be necessary for the  physician to quickly and securely access his/her genetic data to  understand drug efficacy prior to dosing. Who will patients and  doctors trust to store and interpret the data? Coriell and the CPMC  research study have defined several of the key barriers to  accelerate the adoption and routine use of genomics in medicine and  have proposed solutions that are generally  applicable.

Dr.  Christman is an expert in genetics and genomics, with a focus on the  integration of genome information into the delivery of clinical  care. In 2007, he joined Coriell and initiated the Coriell  Personalized Medicine Collaborative® (CPMC®), a research study  evaluating the utility of using the knowledge of genetics in  medicine. Prior to joining Coriell, he served as professor and  founding chair of the Department of Genetics and Genomics for Boston  University School of Medicine. There he led an international team of  scientists in one of the first genome-wide association studies using  the Framingham Heart Study cohort, published in Science magazine.  Dr. Christman received his bachelor’s degree in chemistry with  honors from the University of North Carolina, Chapel Hill, his  doctorate in biochemistry from the University of California,  Berkeley, and was a Jane Coffin Childs postdoctoral fellow at the  Massachusetts Institute of Technology.

FINAL AGENDA

RETURNING GENOMIC INFORMATION TO THE  PATIENT

KEYNOTE  PRESENTATION
Incidental Findings in Genomic  Medicine: The Debate and the Data
Robert C.  Green, M.D., MPH, Director, G2P Research Program; Associate  Director, Research, Partners Center for Personalized Genetic  Medicine, Division of Genetics, Department of Medicine, Brigham and  Women’s Hospital and Harvard Medical  School

Genomic Medicine Implementations for  Primary Care
Erwin Bottinger, M.D., The Irene and  Dr. Arthur Fishberg Professor of Medicine; Director, The Charles  Bronfman Institute for Personalized Medicine, Icahn School of  Medicine, Mount Sinai

Ethical Issues Related to the  Return of Incidental Findings in  Children/Families
Ingrid A. Holm, M.D., MPH,  Director, Phenotyping Core, Program in Genomics, Divisions of  Genetics and Endocrinology, Boston Children’s  Hospital

EMERGING TOOLS TO ENABLE  PHYSICIAN USE

Reducing the Complexity of  Clinical Omics Reporting for Clinicians and  Laboratories   [Listen  to Podcast <http://www.chicorporate.com/click-thru/131500/?email=avivalev-ari@alum.berkeley.edu> ]
Jonathan Hirsch, Founder &  President, Syapse

Beyond Sequence: Integration of Full-Genome  Technologies for Personalized Medicine in the  Clinic
Raphael Lehrer, Founder and Chief Scientist,  GeneKey

Targeted NGS of Clinical Samples:  Overcoming the Challenges of Obtaining High Quality Data from Low  Quality DNA
Diane Ilsley, Ph.D., Marketing Manager,  Genomic Services, Asuragen
Sponsored  by:
<http://www.asuragen.com/>

BRIDGING THE  GAP BETWEEN RESEARCH AND  TREATMENT

Genome Sequencing in the Clinic:  Found the Variants – Now What?
Jennifer Friedman,  M.D., Associate Clinical Professor, Neurosciences and Pediatrics,  UCSD/Rady Children’s Hospital San Diego

The  Answer is There, but I Don’t Understand It: Solutions from the Front  Line
Vanya Gant, Ph.D., FRCP, FRCPath, Divisional  Clinical Director for Infection, The Department of Microbiology,  UCLH NHS Foundation Trust

Using a Patient’s  Genetic Information in the Real World
Michael F.  Christman, Ph.D., President and CEO, Coriell Institute for Medical  Research

Developing Clinical Sequencing Assays  at Einstein-Montefiore
Cristina Montagna, Ph.D.,  Associate Professor, Genetics, Albert Einstein College of  Medicine

THE IMPACT OF DTC  TESTING

Direct-to-Consumer Genetic  Testing: Balancing the Good and the Bad
Nazneen  Aziz, Ph.D., Director, Molecular Medicine, Transformation Program  Office, College of American  Pathologists

Crowdsourcing Genetic  Discovery
Nicholas Eriksson, Ph.D., Principal  Scientist, Statistical Genetics,  23andMe

Personal Genomics through Smart Digital  Media
Patrick Merel, Ph.D., Founder & CEO,  Portable Genomics

> Sponsored Presentation  (Opportunities  Available
<http://www.triconference.com/click-thru/127354/?email=avivalev-ari@alum.berkeley.edu> )

The Ethical and Social  Implications of Direct-to-Consumer Genetic  Testing
Sandra Soo-Jin Lee, Ph.D., Senior Research  Fellow, Center for Biomedical Ethics, Stanford University Medical  School

THE IMPACT AND EVOLVING ROLE OF  GENETIC COUNSELING

Next-Generation Genetic  Counseling
Ramji Srinivasan, CEO & Co-Founder,  Counsyl

TDTC(CC) – Consumers, Clinicians and  Counseling
Erica Ramos, MS, CGC, Clinical Genomics  Specialist, Certified Genetic Counselor, Translational and Consumer  Genomics, Illumina, Inc.

For  exhibit and sponsorship information, including sponsored  podium presentations <http://www.triconference.com/click-thru/127354/?email=avivalev-ari@alum.berkeley.edu> , please  contact:

Jon Stroup  (Companies A-K)
Manager, Business  Development
Cambridge Healthtech Institute
T: (+1)  781-972-5483
E: jstroup@healthtech.com

Joseph Vacca (Companies  L-Z)
Manager, Business Development
Cambridge Healthtech  Institute
T: (+1) 781-972-5431
E: jvacca@healthtech.com 

Cambridge Healthtech Institute’s Second Annual

Part of the 21st Annual Molecular Medicine Tri-Conference
February 13-14, 2014 | Westin St. Francis | San Francisco, CA

Cambridge Healthtech Institute’s Second Annual Genomics in Medicine symposium will provide insight into common implementation issues as they relate to practicing clinicians, as well as address the evolving role of genomics in guiding diagnoses and treatments. Special focus will be given to processing and delivering complex data to the practicing physician. Integration of decision-making tools with existing patient records will also be discussed. This symposium will provide a forum for those hoping to learn more about genomic medicine as well as those currently practicing and looking for an update on the field’s latest advances.

Thursday, February 13

7:30 am Registration and Morning Coffee

RETURNING GENOMIC INFORMATION TO THE PATIENT

9:00 Chairperson’s Opening Remarks

9:05 KEYNOTE PRESENTATION:

Incidental Findings in Genomic Medicine: The Debate and the Data

Robert C. Green, M.D., MPH, Director, G2P Research Program; Associate Director, Research, Partners Center for Personalized Genetic Medicine, Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School

Genomics is being rapidly integrated into medicine with many unanswered questions about how and how much risk information should be communicated, and how such information will influence physician and patient behaviors, health outcomes and health care costs. This presentation will summarize data from over 10 years of experimental work in translational genomics and health outcomes, discuss recent ACMG recommendations for incidental findings and preview results from our newest NIH-funded studies, the ongoing MedSeq Project and the recently funded BabySeq Project.

9:35 Genomic Medicine Implementations for Primary Care

Erwin Bottinger, M.D., The Irene and Dr. Arthur Fishberg Professor of Medicine; Director, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine, Mount Sinai

Increasingly, genomic discoveries provide opportunities to personalize medication use and prediction and prevention of common chronic diseases. However, effective integration of genomic medicine in busy primary care practices is hampered by multiple barriers, including provider education gaps and negative impact on clinical workflow. Innovative programs for real-time, point-of-care integration of genomic medicine for primary care providers through genome-informed clinical decision support enabled in electronic health records will be presented.

10:05 Ethical Issues Related to the Return of Incidental Findings in Children/Families

Ingrid A. Holm, M.D., MPH, Director, Phenotyping Core, Program in Genomics, Divisions of Genetics and Endocrinology, Boston Children’s Hospital

10:35 Coffee Break with Exhibit and Poster Viewing

EMERGING TOOLS TO ENABLE PHYSICIAN USE

11:05 Reducing the Complexity of Clinical Omics Reporting for Clinicians and Laboratories

Jonathan Hirsch, Founder & President, Syapse

Syapse has built a cloud-based software platform that enables the use of omics at the point of care through an interactive web portal. We will describe how clinical omics labs use the Syapse platform to maintain an evolving omics knowledgebase which drives updated clinical reporting through interactive, intuitive interfaces designed for ease of use and comprehension. We will describe how hospitals use the Syapse platform to place omics results in the context of clinical guidelines, enabling physicians to easily adopt and integrate omics into their clinical workflow.

11:35 Beyond Sequence: Integration of Full-Genome Technologies for Personalized Medicine in the Clinic

Raphael Lehrer, Founder and Chief Scientist, GeneKey

Here we describe how we have used a combination of multiple full genome technologies to triangulate on key dysregulated mechanisms in a patient’s sample. By using a combination of systems biology and statistical analysis, we are able to draw conclusions far more precise than one could from sequence alone. We describe how we have applied in the clinic with patients and their oncologists and what we have seen/learned to date, including cases where the dysfunction is not mutation-based.

Sponsored by

Asuragen

12:05 pm Targeted NGS of Clinical Samples: Overcoming the Challenges of Obtaining High Quality Data from Low Quality DNA

Diane Ilsley, Ph.D., Marketing Manager, Genomic Services, Asuragen

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:05 Session Break

BRIDGING THE GAP BETWEEN RESEARCH AND TREATMENT

1:50 Chairperson’s Remarks

1:55 Genome Sequencing in the Clinic: Found the Variants – Now What?

Jennifer Friedman, M.D., Associate Clinical Professor, Neurosciences and Pediatrics, UCSD/Rady Children’s Hospital San Diego

Advances in genome sequencing hold tremendous promise for providing answers and tailored therapies for undiagnosed patients. How to interpret, transmit and act upon volumes of complex data remains a challenge for sequencing providers, physicians and their patients. This presentation will use case-based examples to demonstrate promises and pitfalls encounter along the way.

2:25 The Answer is There but I Don’t Understand It: Solutions from the Front Line

Vanya Gant, Ph.D., FRCP, FRCPath, Divisional Clinical Director for Infection, The Department of Microbiology, UCLH NHS Foundation Trust

This talk will introduce the concept and fundamental problem of how to present complex NGS datasets to clinicians – and how this will be critical for rapid uptake. A case study outlining the principles behind a very new and innovative pathology project and way of delivering healthcare diagnostics will also be presented.

2:55 Refreshment Break with Exhibit and Poster Viewing

3:25 Using a Patient’s Genetic Information in the Real World

Michael F. Christman, Ph.D., President and CEO, Coriell Institute for Medical Research

When a patient needs a new prescription, it will be necessary for the physician to quickly and securely access his/her genetic data to understand drug efficacy prior to dosing. Who will patients and doctors trust to store and interpret the data? Coriell and the CPMC research study have defined several of the key barriers to accelerate the adoption and routine use of genomics in medicine and have proposed solutions that are generally applicable.

3:55 Developing Clinical Sequencing Assays at Einstein-Montefiore

Cristina Montagna, Ph.D., Associate Professor, Genetics, Albert Einstein College of Medicine

We developed a program to introduce Next-Generation Sequencing (NGS) to address the needs of individuals receiving clinical care at Montefiore Medical Center. After extensive dialogue with clinicians, we designed a custom gene panel, spanning 5Mb and consisting of 650 genes targeting known Mendelian loci, some pediatric diseases and several hotspot genes in various cancer types. By building a basic infrastructure for transitioning NSG in the clinic we have encountered roadblocks and established protocols to overcome these.

4:25 Breakout Discussions (see website for details)

5:25 Close of Day

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Cambridge Healthtech Institute’s Sixth Annual

Integrated R&D Informatics & Knowledge Management

Supporting Collaboration, Externalization, Globalization & Translational Research

February 10-12, 2014 | Moscone North Convention Center | San Francisco, CA

Reporter: Aviva Lev-Ari, PhD, RN

For the past five years, Integrated R&D Informatics & Knowledge Management has brought together senior executives and leaders in R&D informatics from pharma, large biotech and their partners to discuss the latest ways to manage the integration of data from disparate sources to create valuable knowledge for their organizations. This year’s conference will focus on addressing how informatics teams are enabling and supporting internal collaboration along with externalization of data, helping deal with pre-competitive activities, as well as continuing to support translational research, all directed at the overall goal of improving productivity and efficiency in a cost-effective manner.

 

Day 1 | Day 2 | Day 3 | Download Brochure

Monday, February 10

10:30 am Conference Program Registration

 

EXTERNAL COLLABORATION BEST PRACTICES: GETTING VALUE OUT OF DATA WITH YOUR COLLABORATORS

11:50 Chairperson’s Opening Remarks

Martin Leach, Vice President, Research & Development IT, Biogen Idec

12:00 pm Roche’s Translational and Clinical Research Center (TCRC): How Our Big Data and Externalization Strategy Impacts Drug Discovery

Juergen Hammer, Ph.D., MBA, Pharma Research and Early Development Informatics (pREDi), pREDi Center Head; Global Head, Disease & Translational Informatics, Roche Translational Clinical Research Center

Pharmaceutical companies increasingly embed their research and early development organizations into vibrant academic hubs to enhance innovation and asset finding. Roche has recently opened “TCRC, Inc.”, soon to be located in New York City. The presentation will focus on our Big Data and Externalization approaches to support the TCRC, and will exemplify how we impact drug development decisions using informatics.

12:30 The Lilly Open Innovation Drug Discovery Program (OIDD)

Daniel H. Robertson, Ph.D., Senior Director, LRL IT Research, Eli Lilly and Company

Through OIDD, Lilly has established a network of top global research talent at academic and biotech institutions to provide them access to proprietary, in vitro phenotypic, and target-based assays (PD2 and TargetD2). In addition to supplying data that may lead to potential collaborations, Lilly has recently been partnering to deploy additional design tools for OIDD investigators to assist in designing compounds submitted to the assays through this collaboration.

1:00 Session Break

Sponsored by
Elsevier

1:15 Luncheon Presentation I: Building and Linking Disease and Drug Target Profiles Using Semantic Search Technologiesnt

Maria Shkrob, Ph.D.,Senior Bioinformatics Scientist, Elsevier

Researchers face a growing challenge in managing vast quantities of unstructured data to find relevant information that can guide their research. A new semantic search engine that incorporates text-mining capability along with customizable dictionaries and taxonomies rapidly finds facts and provides summary tables from multiple sources, including scientific abstracts and full-texts, grant applications, and in-house documents. This ability to accurately retrieve and summarize information significantly increases researcher productivity compared to traditional keyword search.

1:45 Luncheon Presentation II (Sponsorship Opportunity Available) 

2:15 Session Break

2:30 Chairperson’s Remarks

Martin Leach, Vice President, Research & Development IT, Biogen Idec

2:35 Building an Informatics Ecosystem for Externalized R&D

Sándor Szalma, Ph.D., Head, External Innovation, R&D IT, Janssen Research & Development, LLC

Pharma companies have historically been involved in many partnerships fueling their discovery engines, supported with non-optimal IT systems. With recent wide-spread adaptation of hosted solutions and cloud computing, there is an opportunity now to implement informatics solutions such that collaborative exploration of the data generated in partnerships becomes possible. We also discuss the opportunities to build parts of the ecosystem in a pre-competitive manner and our experience in deploying open source tools.

3:05 Cloud Solutions Spanning Applications across R&D, Development, G&A, and Compliance Functions

John Reynders, CIO, Moderna Therapeutics; former Vice President, Research & Development Information, AstraZeneca

This presentation will overview Moderna’s aggressive push into cloud solutions spanning applications across R&D, development, G&A, and compliance functions. Moderna’s cloud-based informatics workflows for the design, development, screening, and delivery of messenger RNA therapeutics will be shared along with associated challenges of Big Data, cloud security, collaboration, and cross-cloud integration.

3:35 PANEL DISCUSSION: Approaches and Lessons Learned to Build a Comprehensive R&D Search Capability

Martin Leach, Vice President, Research & Development IT, Biogen Idec

The accessibility of information within any R&D organization is key to the successful collaboration and development of a research pipeline. The holy grail for most research organizations is the one-stop search (aka. Google-like search for R&D). In this panel we will discuss the approaches a number of research organizations have taken, successes, failures and lessons learned.

Panelists:

John Koch, Director, Scientific Information Architecture & Search, Merck

Hongmei Huang, Ph.D., Director, NIBR IT, Novartis

Sponsored by
Thomson Reuters

4:05 Efficient Data Mining for Precision Medicine
Sirimon O’Charoen, Ph.D., Manager, Translational Medicine, Life Sciences Professional Services, Thomson Reuters

4:35 Refreshment Break and Transition to Plenary Keynote

 

5:00 Plenary Keynote Session (Click Here For More Details)

 

6:15 Grand Opening Reception in the Exhibit Hall with Poster Viewing

7:45 Close of Day

Tuesday, February 11

7:00 am Registration and Morning Coffee

 

8:00 Plenary Keynote Session (Click Here For More Details) 

 

Sponsored by
Slone Partners

9:15 Refreshment Break in the Exhibit Hall with Poster Viewing

 

REGISTRATION SYSTEMS

10:25 Chairperson’s Remarks

Arturo J. Morales, Ph.D., Global Lead, Biology Platform Informatics, Novartis Institutes for Biomedical Research

10:30 Registration Systems: Applications or Data Stores?

Arturo J. Morales, Ph.D., Global Lead, Biology Platform Informatics, Novartis Institutes for Biomedical Research

Registration systems are not applications that usually stand on their own. Their value comes from the enablement of downstream data analysis and sample tracking through proper management of concept and sample metadata. As such, most registration systems offer little intrinsic value to those that use it directly and user compliance can be a challenge. Thus, it is important to adapt to workflows, as opposed to making users adapt to them.

11:00 Development of a LIMS Platform to Manage Biological Therapeutics

David M. Sedlock, Ph.D., Senior Director, Research & Development Systems, Takeda Cambridge US

The management of biological samples for testing as biotherapeutic agents requires a unique type of LIMS to handle both workflows and sample registration. We are currently engaged in a couple of projects at Takeda to create a working solution for both research and preclinical development samples to be managed across multiple R&D sites. The project status and business impact will be reviewed.

11:30 An Enhanced Electronic Laboratory Notebook to Support Biologics Research and Development

Beth Basham, Ph.D., Director, Account Management, Biologics Discovery & IT Site Lead, Merck

Merck is evolving our electronic lab notebook from a straightforward paper notebook replacement to a platform that structures data and results, provides basic LIMS-like capabilities and enables powerful search and analytics. We will share our experiences in providing a solution to support some of the stages of biologics research and development.

12:00 pm Biological Registration Systems at UCB and How They Integrate into the Discovery Workflow

David Lee, Ph.D., Principal Scientist, Informatics, UCB

The benefits of informatics-driven data management systems are well known in the small molecule therapeutics arena. Extending these systems to supporting biotherapeutics presents a number of challenges. We present a novel data management system, BioQuest, integrating bespoke and best in class software systems designed to capture and integrate NBE data at UCB. We will focus on registration systems, in particular on the antibody and non-antibody protein registration system based on the Genedata Biologics platform.

12:30 Session Break

Sponsored by
CambridgeSemantics

12:40 Luncheon Presentation I

Speaker to be Announced

1:10 Luncheon Presentation II (Sponsorship Opportunity Available)

1:40 Refreshment Break in the Exhibit Hall with Poster Viewing

 

PRE-COMPETITIVE COLLABORATION & SUPPORTING PUBLIC-PRIVATE PARTNERSHIPS

2:15 Chairperson’s Remarks

Barry Bunin, Ph.D., CEO, Collaborative Drug Discovery (CDD, Inc.)

Sponsored by
CollaborativeDrugDiscovery

2:20 Modern Drug Research Informatics Applications to CNS, Infectious, Neglected, Rare, and Commercial Diseases

Barry Bunin, Ph.D., CEO, Collaborative Drug Discovery (CDD, Inc.)

There are currently hundreds of commodity technologies for handling scientific information – each with its own scope and limitations. The application of collaborative technologies to interrogate potency, selectively, and therapeutic windows of small molecule structure activity relationship (SAR) data will be presented in 5 case studies. Given external (public and collaborative) data grows faster than internal data, novel collaborative technologies to gracefully manage combined external and private data provide an ever-increasing competitive advantage.

2:50 tranSMART: Use Cases from Deployments Highlighting Emerging Models for Pre-Competitive Collaboration and Open Source Sustainability

Dan Housman, CTO, Translational Research, Recombinant By Deloitte

The tranSMART open source translational research knowledge management software continues to make forward progress since the initial release in 2012. Specific use cases from a variety of projects incorporating tranSMART will be walked through to highlight emerging pre-competitive collaboration models including opportunities, new capabilities, and unresolved challenges. The current state of open project sustainability and approaches taken by Recombinant and other groups to ensure the software increases in value for adopters will be explored.

3:20 The Innovative Medicines Initiative: Collaborating around Knowledge Management

Anthony Rowe, Ph.D., Principal Scientist, External Innovation, Johnson & Johnson

The Innovative Medicines Initiative (IMI) is a public-private partnership between the European Federation of Pharmaceutical Industry and Associates (EFPIA) and the European Union. It is dedicated to overcoming key bottlenecks in pharmaceutical research by enabling pre-competitive collaboration between industry and academic scientists. In this talk we will review the Knowledge Management activities undertaken by the IMI and how they are delivering new services and capabilities that can enhance pharmaceutical R&D.

 

Sponsored by
Certara

3:50 Bringing Scientific Data to Life: Agile Data Access and Analysis from Discovery to Development

Jonathan Feldmann, Vice President, Scientific Informatics, Certara

4:20 Valentine’s Day Celebration in the Exhibit Hall with Poster Viewing

5:20 Breakout Discussions in the Exhibit Hall

These interactive discussion groups are open to all attendees, speakers, sponsors, & exhibitors. Participants choose a specific breakout discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion.

Collaboration, Externalization and Privacy

Micahel H. Elliott, CEO, Atrium Research & Consulting

  • At what extent is data exchange required in the era of R&D virtualization?
  • How do we balance ollaboration with security risk?
  • What tools are required to enable virtualization?  Will these be vendor supplied or custom?

Biological Registration Systems

Arturo J. Morales, Ph.D., Global Lead, Biology Platform Informatics, Novartis Institutes for Biomedical Research

  • How do we implement systems that users want to use?
  • What are some good practices?
  • Where are data standards making a difference?

Data Integration Today

Ajay Shah, Ph.D., Director, Research Informatics, City of Hope National Medical Center

  • Building extensible software platform for integrating basic, clinical and translational research data – technology, data and cultural challenges
  • Integrating deeper analysis and natural language processing tools to leverage the platform for translational research
  • Case studies from participants and discussion

Translational Informatics

Shoibal Datta, Director, Data Sciences, Biogen Idec

  • What does the perfect translational informatics platform look like and how do we get there?
  • Where does translation stop?
  • What does the Affordable Care Act mean to the future of Real World Evidence

6:30 Close of Day

 

Wednesday, February 12

7:00 am Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee

 

8:00 Plenary Keynote Session (Click Here For More Details) 

 

9:45 Refreshment Break and Poster Competition Winner Announced in the Exhibit Hall

 

DATA INTEGRATION & SHARING: TOOLS AND POLICIES FOR VISUALIZATION AND ANALYSIS

10:35 Chairperson’s Remarks

Larry Hunter, Ph.D., Director, Center for Computational Pharmacology & Computational Bioscience Program, Professor, Pharmacology, University of Colorado

10:40 Knowledge-Based Analysis at Genomic Scale

Larry Hunter, Ph.D., Director, Center for Computational Pharmacology & Computational Bioscience Program, Professor, Pharmacology, University of Colorado

High-throughput instruments and the explosion of new results in the scientific literature is both a blessing and a curse to the bench researcher. Effective design and implementation of computational tools that genuinely facilitate the generation of novel and significant scientific insights remains poorly understood. This talk presents efforts that combine natural language processing for information extraction, graphical network models for semantic data integration, and some novel user interface approaches into a system that has facilitated several significant discoveries.

11:00 Combining Visual Analytics and Parallel Computing for Data-Driven Analysis Pipeline Selection and Optimization to Support the Big Data to Knowledge Transformation

Richard Scheuermann, Director, Informatics, J. Craig Venter Institute

This presentation describes our efforts at the J. Craig Venter Institute (JCVI) in collaboration with the Texas Advanced Computing Center (TACC) in the development of a high performance cyber-infrastructure that combines visual analytics and parallel computing for data-driven selection and optimization of analytical pipelines based on objective performance metrics. We demonstrate the application of these principles and infrastructure for the analysis of genome-wide gene expression and high-throughput, high dimensional flow cytometry data in clinical and translational research settings.

11:20 Real World Evidence for Pharma: Improving Traditional Research by Enhancing Real World Data Environment

Arpit Davé, Director, IT, Bristol-Myers Squibb

Life sciences organizations have started to change the way they discover, develop, and commercialize medicines to address patient, regulators and payer needs at every stage of the product lifecycle. Real world data (longitudinal and integrated patient information) is the key to answering complex questions in R&D and product commercialization. In order to access patient data across boundaries, companies and regulators are experimenting with various data and analytics collaboration models. This talk presents key lessons learned.

11:40 Spotfire Templates for Analysis & Visualization of Project Data

Sandhya Sreepathy, PMP, Head of Operations, Global Discovery Chemistry, Novartis

There has been a significant increase in the usage of Spotfire by project teams in Emeryville for visualization and analysis of data. To help streamline development activity and support the needs of project teams with data analysis and visualization, NIBR-IT in collaboration with computational chemistry group in Emeryville developed project based Spotfire templates. Templates were built leveraging existing technologies for retrieval/import of data and incorporated common elements of analysis and visualization(scaffold assignment, ligand, lipophilic efficiency, activity ratios, r-group decomposition etc). Predefined visualizations and filters helped accelerate project team decision making.

12:10 pm Session Break

12:20 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:00 Refreshment Break in the Exhibit Hall and Last Chance for Poster Viewing

 

HOW BIG DATA WILL DRIVE RESEARCH FORWARD

1:40 Chairperson’s Remarks

Michael H. Elliott, CEO, Atrium Research & Consulting LLC

1:45 Harnessing Big Data to Accelerate Drug Development

Vinod Kumar, Ph.D., Senior Investigator, Computational Biology, GlaxoSmithKline Pharmaceuticals

With the rapid development of high-throughput technologies and ever-increasing accumulation of whole genome-level datasets, an increasing number of diseases and drugs can be comprehensively characterized by the changes they induce in gene expression, protein, metabolites and phenotypes. Integrating and querying such large volumes of data, often spanning domains and residing in diverse sources, constitutes a significant obstacle. This talk presents two distinct approaches that utilize these data types to systematically evaluate and suggest new disease indications for new and existing drugs.

2:15 Drug Process Design Improvement based on Data Management and Analysis

Valérie Vermylen, Knowledge Management, Director, GPS, UCB

Most of the scientific process data generated are not free to access, even if managed in databases. At UCB, data was recently made available including its context. It allows process developers to draw easily designed space and define critical parameters. To support investigation studies as impact analysis, manufacturing dashboards and trends are automatically published. An example of correlation between process data and patients’ clinical responses will be presented as an illustration of advanced data analysis.

2:45 The Library of Integrated Network-based Cellular Signatures (LINCS) Information FramEwork (LIFE)

Stephan C. Schürer, Ph.D., Associate Professor, Pharmacology, Center for Computational Science at Miller School of Medicine, University of Miami

The NIH-funded LINCS consortium is producing an extensive dataset of cellular response signatures to a variety of small molecule and genetic perturbations. We have been developing the LINCS Information FramEwork (LIFE) – a specialized knowledge-driven search system for LINCS data.

Sponsored by
Schrodinger

3:15 An Enhanced Molecular Design Platform That Fosters Ideation, Knowledge Transfer, and Collaboration

John Conway, Enterprise Informatics, Schrödinger, Inc.

Drug discovery is the ultimate team sport. Schrödinger is developing a collaborative and knowledge engineered platform—LiveDesign—to help scientists not only capture their ideas and best practices, but to exploit and share these with select team members. Above and beyond the aggregation of 2D data, this platform will allow users to bring together 3D data with its associated annotations. LiveDesign will ultimately lead to better patient outcomes, promoting better scientific communication by exposing data, ideas, and colleague feedback during the design and redesign phases of molecular discovery.

3:45 Refreshment Break

 

FROM BIG DATA TO TRANSLATIONAL INFORMATICS

4:00 Chairperson’s Remarks

Shoibal Datta, Ph.D., Director, Data Sciences, Biogen Idec

4:05 Designing and Building a Data Sciences Capability to Support R&D and Corporate Big Data Needs

Shoibal Datta, Ph.D., Director, Data Sciences, Biogen Idec

To achieve Biogen Idec’s strategic goals, we have built a cross-disciplinary team to focus on key areas of interest and the required capabilities. To provide a reusable set of IT services we have broken down our platform to focus on the Ingestion, Digestion, Extraction and Analysis of data. In this presentation, we will outline how we brought focus and prioritization to our data sciences needs, our data sciences architecture, lessons learned and our future direction.

4:35 Translational Informatics: Decomposing to Singularity

John Shon, M.D., Head, Translational Informatics IT, Johnson & Johnson

There has been an explosion of data across discovery, development, and beyond and all informatics groups are struggling with major challenges in computation, storage and analysis. In a large pharmaceutical environment, the value propositions of informatics lie primarily in three dimensions which I describe. In the larger hyperdynamic environments of research technologies, information technologies, and modern science, interdisciplinary and collaborative approaches become imperative to execute translational strategies effectively.

5:05 Integrating Translational Research Tools

Erik Bierwagen, Ph.D., Principal Programmer Analyst, Department of Bioinformatics, Genentech, Inc.

This talk will cover our efforts at creating an integrated informatics system for animal studies from birth to death and beyond. Our efforts span many different disciplines and groups, but share the common effort of integrating data seamlessly.

5:35 Close of Conference Program

SOURCE

 

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Species-specific Genetic Barcodes: Life Tech’s Capillary Electrophoresis Sequencers generated by

Reporter: Aviva Lev-Ari, PhD, RN

Life Tech said that it has also partnered with the Canadian Centre for DNA Barcoding for the iBOL project, a biodiversity study that aims to genetically catalog 500,000 species by late 2015 and 5 million in total.

Project researchers will use Life Tech’s capillary electrophoresis sequencers to generate species-specific genetic barcodes, which will be deposited in a reference library called Barcode of Life Data System. The partnership will focus on a project to study insects around the world and another one to study biodiversity patterns in Central and South America.

In addition, Life Tech and the center will work on developing metagenomic barcoding applications using the PGM sequencer.

Related Stories

SOURCE

http://www.genomeweb.com//node/1321146?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Management%20Shakeup%20at%20Hologic;%20Life%20Tech%20Partners%20on%20Saudi%20Genome%20Project;%20Cancer%20Driver%20Gene%20Study%20-%2012/09/2013%2010:50:00%20AM

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Silencing Cancers with Synthetic siRNAs

Larry H. Bernstein, MD, FCAP, Reviewer and Curator

Article ID #91: Silencing Cancers with Synthetic siRNAs. Published on 12/9/2013

WordCloud Image Produced by Adam Tubman

http://pharmaceuticalinnovation.com/2012-12-09/larryhbern/Silencing Cancers with Synthetic siRNAs

The challenge of cancer drug development has been marker by less than a century of development of major insights into the know of biochemical pathways and the changes in those pathways in a dramatic shift in enrgy utilization and organ development, and the changes in those pathways with the development of malignant neoplasia.  The first notable change is the Warburg Effect (attributed to the 1860 obsevation by Pasteur that yeast cells use glycolysis under anaerobic conditions).  Warburg also referred to earlier work by Meyerhoff, in a ratio of CO2 release to O2 consumption, a Meyerhoff ratio.  Much more was elucidated after the discovery of the pyridine nucleotides, which gave understanding of glycolysis and lactate production with a key two enzyme separation at the forward LDH reaction and the back reentry to the TCA cycle.  But the TCA cycle could be used for oxidative energy utilization in the mitochondria by oxidative phosphorylation elucidated by Peter Mitchell, or it can alternatively be used for syntheses, like proteins and lipid membrane structures.

A brilliant student in Leloir’s laboratory in Brazil undertook a study of isoenzyme structure in 1971, at a time that I was working under Nathan O. Kaplan on the mechanism of inhibition of mitochondrial malate dehydrogenase. In his descripton, taking into account the effect of substrates upon protein stability (FEBS) could be, in a prebiotic system, the form required in order to select protein and RNA in parallel or in tandem in a way that generates the genetic code (3 bases for one amino acid). Later, other proteins like reverse transcriptase, could transcribe it into the more stable DNA. Leloir had just finished ( a few years before 1971 but, not published by these days yet) a somehow similar reasoning about metabolic regions rich in A or in C or .. G or T.  He later spent time in London to study the early events in the transition of growing cells linked to ion fluxes, which he was attracted to by the idea that life is so strongly associated with the K (potassium) and Na (sodium) asymmetry.   Moreover, he notes that while DNA is the same no matter the cell is dead or alive,  and therefore,  it is a huge mistake to call DNA the molecule of life. In all life forms, you will find K reach inside and Na rich outside its membrane. On his return to Brazil, he accepted a request to collaborate with the Surgery department in energetic metabolism of tissues submitted to ischemia and reperfusion. This led me back to Pasteur and Warburg effects and like in Leloir´s time, he worked with a dimorphic yeast/mold that was considered a morphogenetic presentation of the Pasteur Effect.  His findings were as follows. In absence of glucose, a condition that prevents the yeast like cell morphology, which led to the study of an enzyme “half reaction”. The reaction that on the half, “seen in our experimental conditions did not followed classical thermodynamics” (According to Collowick & Kaplan (of your personal knowledge) vol. I See Utter and Kurahashi in it). This somehow contributed to a way of seeing biochemistry with modesty. The second and more strongly related to the Pasteur Effect was the use an entirely designed and produced in our Medical School Coulometer spirometer that measures oxygen consumption in a condition of constant oxygen supply. At variance with Warburg apparatus and Clark´s electrode, this oxymeters uses decrease in partial oxygen pressure and decrease electrical signal of oxygen polarography to measure it (Leite, J.V.P. Research in Physiol. Kao, Koissumi, Vassali eds Aulo Gaggi Bologna, 673-80-1971). “With this, I was able to measure the same mycelium in low and high “cell density” inside the same culture media. The result shows, high density one stops mitochondrial function while low density continues to consume oxygen (the internal increase or decrease in glycogen levels shows which one does or does not do it). Translation for today: The same genome in the same chemical environment behave differently mostly likely by its interaction differences. This previous experience fits well with what  I have to read by that time of my work with surgeons.  Submitted to total ischemia tissues mitochondrial function is stopped when they already have enough oxyhemoglobin (1) Epstein, Balaban and Ross Am J Physiol.243, F356-63 (1982) 2) Bashford , C. L, Biological membranes a practical approach Oxford Was. P 219-239 (1987).”

Of course, the world of medical and pharmaceutical engagement with this problem, though changed in focus, has benefitted hugely from “The Human Genome Project”, and the events since the millenium, because of technology advances in instrumental analysis, and in bioinformatics and computational biology.  This has lead to recent advances in regenerative biology with stem cell “models”, to advances in resorbable matrices, and so on.  We proceed to an interesting work that applies synthetic work with nucleic acid signaling to pharmacotherapy of cancer.

Synthetic RNAs Designed to Fight Cancer

Fri, 12/06/2013 Biosci Technology
Xiaowei Wang and his colleagues have designed synthetic molecules that combine the advantages of two experimental RNA therapies against cancer. (Source: WUSTL/Robert J. Boston)In search of better cancer treatments, researchers at Washington University School of Medicine in St. Louis have designed synthetic molecules that combine the advantages of two experimental RNA therapies.  The study appears in the December issue of the journal RNA.
 RNAs play an important role in how genes are turned on and off in the body. Both siRNAs and microRNAs are snippets of RNA known to modulate a gene’s signal or shut it down entirely. Separately, siRNA and microRNA treatment strategies are in early clinical trials against cancer, but few groups have attempted to marry the two.   “These are preliminary findings, but we have shown that the concept is worth pursuing,” said Xiaowei Wang, assistant professor of radiation oncology at the School of Medicine and a member of the Siteman Cancer Center. “We are trying to merge two largely separate fields of RNA research and harness the advantages of both.”
 “We designed an artificial RNA that is a combination of siRNA and microRNA, The showed that the artificial RNA combines the functions of the two separate molecules, simultaneously inhibiting both cell migration and proliferation. They designed and assembled small interfering” RNAs, or siRNAs,  made to shut down– or interfere with– a single specific gene that drives cancer.  The siRNA molecules work extremely well at silencing a gene target because the siRNA sequence is made to perfectly complement the target sequence, thereby
  • silencing a gene’s expression.
Though siRNAs are great at turning off the gene target, they also have potentially dangerous side effects:
  • siRNAs inadvertently can shut down other genes that need to be expressed to carry out tasks that keep the body healthy.
 According to Wang and his colleagues, siRNAs interfere with off-target genes that closely complement their “seed region,” a short but important
  • section of the siRNA sequence that governs binding to a gene target.
 “We can never predict all of the toxic side effects that we might see with a particular siRNA,” said Wang. “In the past, we tried to block the seed region in an attempt to reduce the side effects. Until now,
  • we never tried to replace the seed region completely.”
 Wang and his colleagues asked whether
  • they could replace the siRNA’s seed region with the seed region from microRNA.
Unlike siRNA, microRNA is a natural part of the body’s gene expression. And it can also shut down genes. As such, the microRNA seed region (with its natural targets) might reduce
  • the toxic side effects caused by the artificial siRNA seed region. Plus,
  • the microRNA seed region would add a new tool to shut down other genes that also may be driving cancer.
 Wang’s group started with a bioinformatics approach, using a computer algorithm to design
  • siRNA sequences against a common driver of cancer,
  • a gene called AKT1 that encourages uncontrolled cell division.
They used the program to select siRNAs against AKT1 that also had a seed region highly similar to the seed region of a microRNA known to inhibit a cell’s ability to move, thus
  • potentially reducing the cancer’s ability to spread.
In theory, replacing the siRNA seed region with the microRNA seed region also would combine their functions
  • reducing cell division and
  • movement with a single RNA molecule.
 Of more than 1,000 siRNAs that can target AKT1,
  • they found only three that each had a seed region remarkably similar to the seed region of the microRNA that reduces cell movement.
 They then took the microRNA seed region and
  • used it to replace the seed region in the three siRNAs that target AKT1.
The close similarity between the two seed regions is required because
  • changing the original siRNA sequence too much would make it less effective at shutting down AKT1.
 They dubbed the resulting combination RNA molecule “artificial interfering” RNA, or aiRNA. Once they arrived at these three sequences using computer models,
  1. they assembled the aiRNAs and
  2. tested them in cancer cells.
 One of the three artificial RNAs that they built in the lab
  • combined the advantages of the original siRNA and the microRNA seed region that was transplanted into it.
This aiRNA greatly reduced both
  1. cell division (like the siRNA) and
  2. movement (like the microRNA).
And to further show proof-of-concept, they also did the reverse, designing an aiRNA that
  1. both resists chemotherapy and
  2. promotes movement of the cancer cells.
 “Obviously, we would not increase cell survival and movement for cancer therapy, but we wanted to show how flexible this technology can be, potentially expanding it to treat diseases other than cancer,” Wang said.
Source: WUSTL

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Computationally designed “self”-peptide could be used to better target drugs to tumors, to ensure pacemakers are not rejected, and to enhance medical imaging technologies

Reporter: Aviva Lev-Ari, PhD, RN

Synthetic Peptide Fools Immune System

Researchers have created a molecule that helps nanoparticles evade immune attack and could improve drug delivery.

By Dan Cossins | February 21, 2013

 

A macrophage at work in a mouse, stretching itself to gobble up two smaller particlesFLICKR, MAGNARAMA synthetic molecule attached to nanoparticles acts like a passport, convincing immune cells to let the particles pass unimpeded through the body, according to a study published today (February 21) in Science. The computationally designed “self”-peptide could be used to better target drugs to tumors, to ensure pacemakers are not rejected, and to enhance medical imaging technologies.

“It’s the first molecule that can be attached to anything to attenuate the innate immune system, which is currently limiting us from delivering therapeutic particles and implanting devices,” saidDennis Discher, a professor of biophysical engineering at the University of Pennsylvania and a coauthor of the study.

“This is really interesting work,” said Joseph DeSimone, a chemical engineer at the University of North Carolina, Chapel Hill, who was not involved in the research, in an e-mail to The Scientist. “[It] strongly validates the idea of using biological evasion strategies.”

Macrophages recognize, engulf, and clear out foreign invaders, whether they’re microbes entering through a wound or a drug-loaded nanoparticle injected to target disease. Previously, researchers have attempted to escape this response by coating nanoparticles with polymer “brushes” to physically block the adhesion of blood proteins that alert macrophages to the particles’ presence. But these brushes can only delay the macrophage-signaling proteins for so long, and they can hinder uptake by the diseased cells being targeted.

With that in mind, Discher and colleagues tried instead to find a way to convince macrophages that nanoparticles are part of the body. Their previous research had shown that a membrane protein called CD47, which binds to macrophages in humans, signals “self” to the immune system, so that particles with this protein are not attacked.

Examining the architecture of the bond between CD47 and its macrophage receptor, SIRPα, the researchers were able to design a synthetic self-peptide with a similarly snug fit. “This is the key, literally, to unlocking innate immune pacification,” said Discher.

When they chemically synthesized the 21-amino-acid self-peptide and attached it to nanobeads as small as viruses in mice genetically engineered to have human-like SIRPα receptors, the researchers showed that beads with the self-peptide stayed in the blood of for longer than beads with no peptide: 30 minutes after being injected with equal numbers of each type, there were 4 times as many beads with the peptide attached than without. The results demonstrate that the synthetic molecule can reduce the rate at which phagocytes clear the beads from the body, said Discher.

Then, in mice with human lung cancer, the researchers injected fluorescently dyed beads with and without the peptide, and saw that the “self”-beads got through the macrophage-filled spleen and liver and accumulated in greater numbers in the tumor, providing a brighter signal under when imaged. In fact, the self-beads provided a signal from the tumor as strong as beads coated with human CD47.

Finally, to see whether the biological evasion strategy can be successfully combined with targeting, the researchers loaded an anticancer drug into self-beads also coated with antibodies that target cancer cells. Sure enough, these antibody-coated self-beads consistently shrank tumors more than antibody-coated beads lacking the peptide. This confirmed that when antibodies draw the attention of the macrophage, the self-peptides inhibit the macrophage’s response, acting as a “don’t-eat-me” signal, said Discher.

The results demonstrate that the synthetic peptide can provide therapeutic nanoparticles with extra time in the body—time that improves drug delivery. Furthermore, the relative simplicity of the peptide means it can be easily synthesized, making it an attractive component for use in a variety of future applications.

“The findings are “compelling” and “the technology merits moving forward,” Omid Farokhzad, director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women’s Hospital, part of Harvard Medical School, said in an e-mail to The Scientist.

A crucial next step is to test the efficacy of synthetic self-peptides in humans, Farokhzad added. “The truly relevant test is looking at human pharmacokinetics to see circulating half-life advantages of nanoparticles and their effect on therapeutic outcome.”

P.L. Rodriguez et al., “Minimal ‘self’ peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles,” Science, 339: 971-74, 2013.

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