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Archive for the ‘Personalized and Precision Medicine & Genomic Research’ Category


Gene-editing Second International Summit in Hong Kong: George Church, “Let’s be quantitative before we start being accusatory”

 

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 11/30/2018

Gene editing takes a foreboding leap forward

He Jiankui. Photo: Zhang Wei/Chinese News Service/VCG via Getty Images

 

China is temporarily suspending the work of scientists who claimed twins were born after being genetically edited as embryos.

Why it matters: The scientific consensus is that gene editing embryos at this stage of science is “irresponsible.” But, while this particular experiment has not been verified, the fact is the technology is available to researchers, so there’s a growing call for international limitations on its use.

ICYMI: Chinese scientist He Jiankui announced earlier this week that twins were born after he used the gene-editing tool CRISPR-Cas9 to cut the CCR5 gene that’s known to play a role in HIV infection.

  • He stirred even more dismay when he mentioned the possibility of a second pregnancy.
  • China currently bans human implantation of gene-edited embryos. Its Ministry of Science and Technology is investigating the claims, per Xinhua.

There are concerns about the safety, efficacy and possible mosaicism, where a person can contain genes in both its edited and unedited forms, from cutting genes.

  • Editing embryos raises an even bigger concern: The genetic changes and all the unknowns around them can be passed down to future generations.

Between the lines: Not everyone viewed it as a complete disaster. For instance, Harvard Medical School’s George Daley suggested that it may be time to reconsider the massive amounts of research done over the past several years and look for plausible methods of moving forward.

What to watch: Scientists are cautious about predicting what the impact will be, in part because the details of this claim are thin. However, the debate is heating up and one concern is it will dampen important research.

  • Medical ethicist Jonathan Moreno from the University of Pennsylvania says the situation reminds him of other times in history where there were tremors in the science world, like the death of 18-year-old Jesse Gelsinger in 1999 from a gene therapy trial that led to years of diminished research.

The bottom line: The alarm over what could be next is real. But scientists hope the current debate will promote consensus on firm limits and promote transparency.

Go deeper:

SOURCE

From: Andrew Freedman <andrew.freedman@axios.com>

Date: Thursday, November 29, 2018 at 5:33 PM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Axios Science: About that climate report — Gene editing takes a foreboding step — Building in harms’ way

 

 

He Jiankui spoke at the second international summit on human genome editing in Hong Kong. (Alex Hofford/EPA-EFE/Shutterstock)

CRISPR-baby scientist faces the music

The scientist who claims to have helped produce the first people born with edited genomes faced a tough crowd yesterday at a gene-editing summit in Hong Kong. He Jiankui gave a 20-minute talk about his unpublished work in animals and humans before opening a 40-minute Q&A session (watch it here). He faced difficult questions about the ethics of his work and his choice to keep it mostly under wraps until after the babies were born, and left many unanswered.

Meanwhile, prominent geneticist George Church is one of the few scientists who seem to be looking on the bright side of He’s controversial claim. “Let’s be quantitative before we start being accusatory,” Church told Science. “As long as these are normal, healthy kids it’s going to be fine for the field and the family.”

Nature | 9 min read & Science | 6 min read

Read more: Genome-edited baby claim provokes international outcry

 

SOURCE

From: Nature Briefing <briefing@nature.com>

Reply-To: Nature Briefing <briefing@nature.com>

Date: Thursday, November 29, 2018 at 12:18 PM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: CRISPR-baby scientist faces the music at gene-editing summit

 

See

SAVE

The ethical red flags of genetically edited babies

Driving the news: Chinese scientist He Jiankui announced Sunday night that a pair of twin girls had been born from embryos he modified using the gene-editing tool known as CRISPR.

  • He hasn’t provided solid proof, but if it‘s true, it would be the first time the technology has been used to engineer a human.

What they’re saying: The inventors of CRISPR technology did not seem pleased with the development — one called for a moratorium on implantation edited embryos into potential mothers.

  • “I hope we will be more cautious in the next thing we try to do, and think more carefully about when you should use technology versus when you could use technology,” said Jessica Berg, a bioethicist at Case Western Reserve University.

Between the lines: Several specific factors in He’s work sent up ethical red flags.

  • Many scientists had assumed that, when this technology was first used in humans, it would edit out mutations tied to a single gene that were certain to cause a child pain and suffering once it was born — essentially, as a last resort.
  • But He used CRISPR to, as he put it, “close a door” that HIV could have one day traveled through. That has prompted some speculation that this project was more about testing the technology than serving an acute medical need.
  • “That should make us very uneasy about the whole situation,” Berg said. “Of all the things to have started with, it does make you a little suspicious about this particular choice.”

The intrigue: There’s a lot we still don’t know about He’s work, and that’s also contributing to an attitude of skepticism.

  • How many embryos did he edit and implant before these live births?
  • How will he know it worked? As the children age, they’ll likely have their blood drawn and those samples will be exposed to HIV in a lab, but researchers aren’t going to tell them to go out and have unprotected sex or use intravenous drugs — another reason HIV seems like an odd starting place for human gene editing.
  • How did this even happen? The university where He worked said he was on leave, and Chinese officials have said he’s under investigation. But gene editing is a pretty hard thing to freelance.

The other side: He defended his work in a video message, saying, “I understand my work will be controversial but I believe families need this technology and I’m willing to take the criticism for them.”

  • “Their parents don’t want a designer baby, just a child who won’t suffer from a disease which medicine can now prevent,” He said.

Yes, but: Now that this threshold may have been crossed, attempts to create “designer babies” — within the limitations of what CRISPR can do — probably aren’t far off, some experts fear.

  • There are “likely to be places that are less regulated than others, where people are going to attempt to see what they can do,” Berg said. “I wouldn’t say everything in the world has changed now, but it’s certainly the next step.”
SOURCE

https://www.axios.com/genetic-editing-baby-china-ethics-controversy-b33f8414-8b83-445c-bad5-d8407f8841f4.html

https://pharmaceuticalintelligence.com/2018/11/26/jennifer-doudna-and-npr-science-correspondent-joe-palca-several-interviews/

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The Future of Precision Cancer Medicine, Inaugural Symposium, MIT Center for Precision Cancer Medicine, December 13, 2018, 8AM-6PM, 50 Memorial Drive, Cambridge, MA

Reporter: Aviva Lev-Ari, PhD, RN

 

Aviva Lev-Ari, PhD, RN, Editor-in-Chief, will attend and cover this event in REAL TIME for

 http://pharmaceuticalintelligence.com 


Over the past decade, there have been major advancements in the field of precision medicine, leading to exciting new treatments for some cancer patients. Much attention has been focused on genomic profiling of tumors to identify genomic alterations that might guide selection of specific therapies for individual patients. Beyond genomics, however, there is a variety of other precision approaches that can identify and exploit cancer-specific biological mechanisms including proteomics, metabolomics, and computational modeling, resulting in the more effective use of existing cancer medicines. On Thursday, December 13, 2018, the MIT Center for Precision Cancer Medicine will hold its inaugural annual symposium in the Samberg Conference Center at MIT. This full-day event will feature leading researchers and clinicians, who will highlight recent advances in precision cancer medicine and share perspectives on the future. An industry panel will also discuss the barriers to instituting precision medicine into current and future clinical trials.

 


Keynote Address

Charles Sawyers

Charles Sawyers, MD

Chair, Human Oncology and Pathogenesis Program
Memorial Sloan Kettering Cancer Center

Speakers

Andrea Califano

Andrea Califano, PhD

Clyde and Helen Wu Professor of Chemical Systems Biology, Columbia University
Chair, Department of Systems Biology, Columbia University
Director, JP Sulzberger Columbia Genome Center
Associate Director, Herbert Irving Comprehensive Cancer Center

Chris Love

J. Christopher Love, PhD

Professor of Chemical Engineering, MIT
Associate Member, Ragon Institute of MGH, MIT and Harvard
Member, Koch Institute, MIT

Richard Marais

Richard Marais, PhD

Professor of Molecular Oncology
Director, CRUK Manchester Institute
The University of Manchester

Kenna Mills Shaw

Kenna Mills Shaw, PhD

Executive Director
Sheikh Khalifa Bin Zayed al Nahyan Institute for Personalized Cancer Therapy
MD Anderson Cancer Center

Alice Shaw

Alice Shaw, MD, PhD

Professor, Harvard Medical School
Director, Thoracic Cancer Program, Massachusetts General Hospital

Matt Vander Heiden

Matthew Vander Heiden, MD, PhD

Associate Professor of Biology, MIT
Associate Director, Koch Institute
Member, MIT Center for Precision Cancer Medicine

Mike Yaffe

Michael B. Yaffe, MD, PhD

David H. Koch Professor of Science, MIT
Professor of Biology and Biological Engineering, MIT
Director, MIT Center for Precision Cancer Medicine
Director, Koch Institute Clinical Investigator Program

Jean Zhao

Jean Zhao, PhD

Professor of Biological Chemistry and Molecular Pharmacology
Harvard Medical School and Dana-Farber Cancer Institute


Panelists: Barriers to Instituting Precision Medicine in Clinical Trials

Hammerman

Peter Hammerman, MD, PhD

Global Head, Translational Research
Oncology Disease Area
Novartis Institutes for BioMedical Research

Ho

Steffan N. Ho, MD, PhD

Vice President, Head of Translational Oncology
Pfizer Global Product Development

Shiva Malek

Shiva Malek, PhD

Director and Principal Scientist
Department of Discovery Oncology
Genentech Inc

Marks

Kevin Marks, PhD

VP of Biology
Agios Pharmaceuticals

Michael Rothenberg

S. Michael Rothenberg, MD, PhD

Vice-President, Research and Development
Loxo Oncology, Inc.

Angela Koehler

Moderator:

Angela Koehler, PhD

Goldblith Career Development Professor in Applied Biology, MIT
Member, Koch Institute for Integrative Cancer Research
Member, MIT Center for Precision Cancer Medicine

SOURCE

https://ki.mit.edu/news/events/cpcmsymposium-2018

https://www.eventbrite.com/e/mit-center-for-precision-cancer-medicine-inaugural-symposium-tickets-50424019600

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Precision Medicine Market to surpass USD 96.6 Bn by 2024, study by Global Market Insights, Inc.

Reporter: Aviva Lev-Ari, PhD, RN

 

Precision Medicine Market to surpass USD 96.6 Bn by 2024

The Precision Medicine Market is set to grow from its current market value of more than $47.8 billion to over $96.6 billion by 2024; as reported in the latest study by Global Market Insights, Inc.

Advancements in cancer biology will ensure development in gene sequencing technique and other platforms available for cancer treatment. Furthermore, rising development in field of bioinformatics that support gene sequencing to initiate formulations of precision medicines will enhance the precision medicine market growth in foreseeable future.

Increase in adoption rate of gene therapy in developed economies with relatively high-income level will further enhance the precision medicine market growth. Rising incidences of genetic disorders has positively influenced the business growth. According to WHO, sickle cell anemia affects around millions of people globally every year. Along with sickle cell anemia, there are many other genetic diseases such as thalassemia, hemophilia and others that are prevalent globally. Moreover, increase in research and development activities that boosts the production and manufacturing of precision medicine in emerging countries such as Africa and Brazil will augment the industry growth in future. However, high cost of precision medicines may restrain the market growth.

Precision Medicine Market

 

 

Bioinformatics segment was valued at USD 7.4 billion in 2017 and is expected to have considerable growth during the forecast timeframe. Bioinformatics is composed of information that includes data for gene sequencing, amino acid sequences of proteins and structural classification of protein enabling efficient drug development process for treating diseases such as cancer at molecular level. Additionally, bioinformatics is also used to determine the treatment for hereditary metabolic disorders that will drive the segmental growth in forthcoming years.

Oncology segment will experience 11.1% CAGR during the forecast timeframe. High segmental growth can be attributed to the increasing prevalence of cancer globally. According to Globocan 2018, the number of new cancer cases are estimated to be 18.1 million cases. Development of target novel therapies and precision medicines has drastically reduced the mortality rates and hence, high demand for precision medicine in cancer treatment will drive the segmental growth in foreseeable future.

Pharmaceutical companies segment of precision medicine market accounted for 37.1% in 2017 owing to the increasing R&D efforts for drug development activities. Pharmaceutical companies are currently trying to develop precision medicines for rare genetic diseases. According to Global genes, there are around 7,000 rare genetic diseases discovered.

U.S. precision market will experience 9.7% CAGR during the forecast timeframe. Enormous market growth will be due to increasing cases of rare genetic diseases. Furthermore, certain initiatives undertaken by the regulatory bodies have also positively impacted availability of precision medicines.

U.S. Precision Medicine Market Size, By Technology, 2017 & 2024 (USD Million)

Germany precision medicine market was valued at USD 2.6 billion in 2017 and high segmental growth will be due to the growing pediatric as well as adult population susceptible to metabolic diseases such as diabetes. According to NCBI, prevalence of Type 2 diabetes is high in the German population. Researchers and scientists have geared up efforts to develop precision medicines that are altered according to patient’s genome ensuring efficient treatment of genetic disorders.

Prominent industry players operational in the precision medicines market include Biocrates Life Sciences AG, Eagle Genomics Ltd, Ferrer inCode, Intomics, Laboratory Corporation of America Holdings, NanoString Technologies, Novartis, Pfizer, Qiagen, Quest Diagnostics, F. Hoffmann-La Roche, Silicon Biosystems, Tepnel Pharma Services, Teva Pharmaceuticals.

Source: https://www.gminsights.com/industry-analysis/precision-medicine-market

 

SOURCE for Request to Publish in pharmaceuticalintelligence.com

rom: Shankar Khatkale <shankar.k@gminsights.com>

Date: Tuesday, November 27, 2018 at 6:48 AM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Article Submission Request

Dear Editor,

An industry news titled ‘Precision Medicine Market Size worth $96.6bn by 2024’ by Global Market Insights is relevant to your esteemed website https://pharmaceuticalintelligence.com. This email is a suggestion to publish this news (content attached in word format or can be picked from link mentioned below) on your website with an objective to share the information with your audiences.

News Link: https://www.gminsights.com/pressrelease/precision-medicine-market

Looking forward to hear from you.

On behalf of and as instructed by Global Market Insights, Inc.

Best Regards,

Shankar Khatkale |SEO Executive

 

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Tweeter and Real Time Conference Press Coverage: Aviva Lev-Ari, PhD, RN
  1. LIVE eProceeding Day Two – The 14th Annual Personalized Medicine Conference: The Business of Personalization, November 15, 2018, HMS, Boston via

  2. Cary Pfeffer, M.D., Partner, Third Rock Ventures IP can’t be reduced by other country unfair trade

  3. Pellini – CMS will take the lead partnerships early and often in clinical trials,

  4. Michael Pellini, M.D., Managing Partner, Section 32; Board Member, Personalized Medicine Coalition Patients and Consumers will force in five years figuring out – every diagnosis of cancer will be sequenced to interpret results and paid for

  5. Salveen Richter, Goldman Sachs Sequencing cost plunged, public investors placing funding in start ups even without return in the horizon, companies with multiple modalities spurring innovation – Europe vs US, China has no FDA ,talent from US China

  6. Michael Pellini, M.D., Managing Partner, Section 32; Board Member, Personalized Medicine Coalition Diagnostics component inside 4.8 Trillion in the therapeutics selection in the system as a whole Foundation Medicine saw Roche for International reach

  7. William A. Sahlman, Ph.D., Baker Foundation Professor, Harvard Business School Biotech IPO, VC, windows slam shut, drug failure – drivers and non Increasing return to scale: AI, NGS, screening, – foreign money, Tsinghua went back to China from CA

  8. William A. Sahlman, Ph.D., Baker Foundation Professor, Harvard Business School market – can it sustain the opportunity – winners and losers innovative financial models Biotech IPO, VC, windows slam shut, drug failure – drivers and non

  9. Salveen Richter, C.F.A., Vice President, Research Division, Goldman Sachs Europe successful in financing Health care in the US system must change – investment will flee, to fund pricing drug is key in changing the system CART Pricing is key

  10. Michael Pellini, M.D., Managing Partner, Section 32; Board Member, Personalized Medicine Coalition Impasse or Inflection Point? it s Inflection Point NOT an Impasse Diagnostics component inside 4.8 Trillion in the therapeutics selection in system

  11. Cary Pfeffer, M.D., Partner, Third Rock Ventures MS drug efficacy was in 50% non respondents 25% Genomic sequencing to identify patient populations – target therapy Mayocardia – drug in CVD for patients identified by Genomics Genomics develop drugs

  12. Michael Pellini, M.D., Managing Partner, Section 32; Board Member, Personalized Medicine Coalition Impasse or Inflection Point? it s Inflection Point NOT an Impasse

  13. Kristine Bordenave, M.D., F.A.C.P., Corporate Medical Director, Humana CMS Guideline: every test ordered must guide treatment otherwise not covered

  14. Kristine Bordenave, M.D., F.A.C.P., Corporate Medical Director, Humana Guidelines on ordering genomic testing, AI can assist providers, MDs need to catch up on a weekly basis companion diagnostics and pharmaceutical paid together SOCare is paid

  15. Kristine Bordenave, M.D., F.A.C.P., Corporate Medical Director, Humana show us any value as good value – avoiding patient going to MDs Office, Hospital, ER – cost increase due to Pharmacogenomics testing $5K per test

  16. Scott Ramsey, M.D., Ph.D., Full Member, Fred Hutchinson Cancer Research Center; Director, Hutchinson Institute for Cancer Outcomes Research Pricing of Testing NGS and Targeted therapy represent a threat to adoption of Genomics in Medicine

  17. Kristine Bordenave, M.D., F.A.C.P., Corporate Medical Director, Humana What test needed to be ordered? Patient stay healthy NGS $650 – $2000 in 2018, in 2016 it was $25,000 cost of testing, cost of drugs

  18. Kristine Bordenave, M.D., F.A.C.P., Corporate Medical Director, Humana cost of doing the test vs not doing this test – assess value CMS – provide data on what is covered and what is not Humana: any missed opportunities, MD order tests of no impact MR

  19. Dr. Ramsey – Survival in this cohort NGS vs EGFR – improved survival 6 month longer, Increased survivals, why? cost of sequencing – #14 most influential – cost does not drive value #1 drug cost, out of pocket expense was the factor #2 survival

  20. Scott Ramsey, M.D., Ph.D., Full Member, Fred Hutchinson Cancer Research Center; Director, Hutchinson Institute for Cancer Outcomes Research Value and utility are interconnected cost effectiveness of NGS in melanoma: single gene testing, EGFR vs NGS

  21. Kristine Bordenave, M.D., F.A.C.P., Corporate Medical Director, Humanalabs, payers, providers, pharma — the GAP to be bridged opportunities to prevent and treat disease Payers, MDs, cost and impact, markers, Humana has a research division Use Tests

  22. MODERATOR | Daryl Pritchard, Ph.D., Senior Vice President, Science Policy, Personalized Medicine Coalition genetic profiling, adopt policy for mass deployment of NGS demonstrate value, payers needs little more that evidence exist for payer to cover

  23. Luba Greenwood, J.D., Strategic Business Development and Corporate Ventures, Verily (an Alphabet company) Patient need to own the genome data not a Databank

  24. Birgit Funke, Ph.D., F.A.C.M.G., Vice President, Clinical Affairs, Veritas Genetics; Associate Professor of Pathology (Part-Time), Harvard Medical School Risk prevention, driving DOWN operating cost curation of the Genome

  25. Luba Greenwood, J.D., Strategic Business Development and Corporate Ventures, Verily (an Alphabet company) Diagnostics in use to keep patients OUT of hospitals – management of chronic diseases

  26. Luba Greenwood, J.D., Strategic Business Development and Corporate Ventures, Verily (an Alphabet company) treatment solution therapeutics except og Oncology threatment is a strugle in the genomics field and pharmacogenomics General Medicine: CVD DM

  27. Keith Stewart, M.B., CH.B., Carlson and Nelson Endowed Director, Center for Individualized Medicine, Mayo Clinic genomics for detection of predisposition, inherited Barriers to deploy genomics: Knowledge, readiness of providers, cost of uninsured,

  28. Ellen Sigal Recipient of 14th PMC Award

  29. Sigal: Patient deserve right answers right choices, calls doctors on behave of patients treatments done out of the community in Academic hospitals – patients are scared to death. Patients are asking for options: Right testing, access to testing

  30. The 14th Annual Leadership in Personalized Medicine Award to Ellen V. Sigal, Ph.D., Chairperson, Founder, Friends of Cancer Research Patient Challenges: 90% are treated Community and they need a second opinion, insurance, access, clinical trials

  31.  Retweeted

    Frederick Banting, awarded the Nobel Prize for the discovery of insulin, was born on this day in 1891. The discovery of insulin is one of the biggest breakthroughs in medicine and has saved millions of lives.

  32. Amy Abernethy, M.D., Ph.D., Chief Medical Officer, Chief Scientific Officer, Senior Vice President, Oncology, Flatiron Health Technologies: AI, Countries with platforms Regulatory framework, reproducibility of results Taking care of people,

  33.   Retweeted

    I am covering this Conference at Harvard Medical School in Real Time, 11/14-11/15/2018 ⁦

  34. Edward Tepporn, Executive Vice President, Asian & Pacific Islander American Health Forum 1985 minorities education all surveys conducted in English, Asian American access to affordable health care services to accommodate services for communities

  35. Adolph P. Falcón, Executive Vice President, National Alliance for Hispanic Health community based organization 50 million improving healthcare access improve inclusion in science, no advancement in 45 years Hard to reach through – academic language

  36. Alex J. Carlisle, Ph.D., Chairman, CEO, National Alliance Against Disparities in Patient Health PM with focus on disparities, racialbiologic, socioecological Patient centered – raise health education Translation for interpretation Physicians&Patients

  37. Vence L. Bonham, Jr., J.D., Senior Advisor, Director on Genomics and Health Disparities, U.S. NHGRI Genomics data is of European dissents no diversity minority populations not represente sland populations not represented hispanics not

  38. Kimberly Popovits, proprietary test vs. test offered by all labs — different markets Utility agreed upon like “” demonstrate a pathway of product development that was already followed

  39. Kimberly Popovits, Chairman of the Board, CEO, President, Genomic Health – Oncology, Breast cancer molecular diagnostics Genomic testing saved the Health care System billions of dollars Genomic testing will not be placebo, 12 years study controlled

  40. Julie Khani, President, American Clinical Laboratory Association FDA will establish a center for Diagnostics, proposal for pre-certification like in Medical devices congress is involved in the decision making

  41. Michael Doherty, Senior Vice President, Head of Product Development, Head of Research & Development, Foundation Medicine – ex Genetech/Roche Operate in regulated environment, how to establish a company for long term companion diagnostics

  42. Joseph V. Ferrara, CEO, Boston Healthcare Associates Regulatory action for reimbursement of test new categories of tests: new payment if Innovation, PLA codes, 45 months approval, CPT codes

  43. Best Talk like last year by David King , keynote at

  44. David King, J.D., Chairman, CEO, LabCorp Non respondent – further researched MDs understanding, confidence of results PM Promise: close education GAP, convene on VALUE for individual cases not populations assess value among initiatives PM

  45. Tom Miller, Managing Partner, GreyBird Ventures LLC algorithms are behind the firewall of the Hospital, for privacy. the patient’s identity is not of central point, privacy is the key

  46. Radiology: SW used in detection of disease Personalized Medicine and AI Data mining of Text using AI Vital signs monitoring – providers can spot Arrhythmias earlier tagging images is a matual process

  47. Darrell M. West, Ph.D., Vice President of Governance Studies and Director of Center for Technology Innovation, Douglas Dillon Chair in Governance Studies, Interest in AI and in particular: Health care large part of the economy

  48. Gregg Talbert, Ph.D., Global Head of Digital and Personalized Health Care Partnering, Roche – Data on mutations Data falls short on Patient follow up (longitudinal data on Patients) curation of EMR IS NOT AN EASY OR AUTOMATED PROCESS i.e., IMAGES

  49. Tom Miller, Managing Partner, GreyBird Ventures LLC AI applied to capture unusual movement allowing to detect a forthcoming neurological event. Technologies used now

  50. Colin Hill, Chairman, CEO, Co-Founder, GNS Healthcare is moderator for and Medicine, panelists from , and The ⁦⁩ ⁦⁩ ⁦

  51. Bryce Olson, Global Marketing Director, Health and Life Sciences Group, Intel Corporation; stage IV prostate cancer patient Patient engage in their care, involvement in interpretation og ONES OWN Genome sequence is ate most engaging

  52. Emily Kramer-Golinkoff, Co-Founder, Emily’s Entourage, cystic fibrosis patient “Better for a is the Patient him/herself”

  53. Great Panel moderation by Toni Andreu scientific director of

  54.   Retweeted

    can help cancer patients live longer, healthier lives. Learn more about how we’re working to advance the field ‘s 11/15 when Ellen Sigal receives the 14th Annual Leadership in Personalized Medicine Award:

  55. Enjoyed most learning about the leading evolution in Genomics in Israel, UK, Canada and Finland

  56.   Retweeted

    In 14th Annual Elizabeth Nabel- made an excellent overview exploring the Promise of Personalized Medicine: Healthcare state-of-the-art; Digital health; Professionals-Payers-Providers relationships and next future challenges

  57. Amazing International Panel: UE, Israel, UK, Canada, Finland

  58. Great talk of a visionary in Management of Academic

  59. Great Confernec, 14th in one row

  60. Antonio L. Andreu, M.D., Ph.D., Scientific Director, EATRIS European Infrastructure for Translational Medicine General Medicine: Metabolomics, biological systems vs GENOMICS Medical care w/genomic testing, MDs will call to tell patients future news

    Translate Tweet

  61. Ora Dar, Ph.D., Senior Expert, Medical Sciences, consultant to the Israel Innovation Authority $300Miliion R&D sponsored clinical data on genomics, MDs are trained to place genomics data on EMR, epidemiology, sequencing of genetic diseases

  62. Liisa-Maria Voipio-Pulkki, M.D., Ph.D., Director General, Chief Medical Officer, Ministry of Social Affairs and Health, Finland Public sector is the majority of Health care systems, Expertise is as high as can be, entrepreneurship is on the rise

  63. Marc LePage, President, CEO, Genome Canada Social impact, adoption systems for focusing on rare diseases, following UK and US trends, 10 sites in Canada, aggregate the datethe National level, extract clinical data securely implementation expertise

  64. Tom Fowler, Ph.D., Deputy Chief Scientist, Building infrastructure, education, future, National approach to genomic testing, built in a National lab, scaling research

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LIVE eProceedings Day Two – The 14th Annual Personalized Medicine Conference: The Business of Personalization, November 15, 2018, HMS, Boston

Real Time Coverage: Aviva Lev-Ari, PhD, RN

 

PART II

 

The Business of Personalization

The successful implementation of [personalized medicine] will depend on the embrace of [its] principles in the business community.

 RAJU KUCHERLAPATI, PH.D.
Paul C. Cabot Professor of Genetics, Harvard Medical School

*** Speakers will be added to the schedule on a rolling basis as they are confirmed. ***

7:00 a.m.
Registration and Continental Breakfast

Joseph B. Martin Conference Center at Harvard Medical School
77 Avenue Louis Pasteur, Boston, MA 02115

8:00 a.m.
Opening Remarks

SPEAKER | Stephen L. Eck, M.D., Ph.D., Chief Medical Officer, Immatics U.S. Inc; Board Chair, Personalized Medicine Coalition

8:10 a.m.
Pioneering Precision: Inside the Pharmaceutical Industry’s Push Toward Personalized Medicine — A Fireside Chat

MODERATOR | Meg Tirrell, Reporter, CNBC

Daniel O’Day, CEO, Roche Pharmaceuticals

8:55 a.m.
Considering Costs: Evaluating Emerging Pharmaceutical and Insurance Industry Business Models in Personalized Medicine

The pharmaceutical industry is deeply invested in commercializing personalized therapies that must recoup fixed development costs from smaller patient populations covered by health insurance companies that are increasingly concerned about rising health care costs. In that context, this diverse panel will explore the viability of the business model for developing and paying for personalized medicines, tackling issues related to costs, prices, and access.

MODERATOR | Meg Tirrell, Reporter, CNBC

Peter Juhn, M.D., M.P.H., Global Head of Value-Based Partnerships, Amgen

Nick Leschly, CEO, Bluebird Bio

Michael Sherman, M.D., Chief Medical Officer, Senior Vice President, Harvard Pilgrim Health Care

Sean Tunis, M.D., Founder, CEO, Center for Medical Technology Policy

9:55 a.m.
Networking Break

Light refreshments provided.

Sponsored By

10:25 a.m.
Reinventing Research: Are Adaptive Platform Trials the Model of the Future? (A Harvard Business School Case Study)

Recognizing that traditional randomized controlled clinical trials can only study the safety and efficacy of a single therapy in one large population of patients, researchers in personalized medicine increasingly hope that “adaptive platform trials,” which employ advanced statistical techniques to simultaneously test the effectiveness of several personalized treatments in multiple sub-populations of patients, may be the key to new drug approvals in the future. Adaptive platform trials may make drug development more efficient by revealing which of several drug candidates are most promising for which patients, but maximizing the potential of these trials requires unprecedented collaboration among the institutions conducting and sponsoring research on various personalized treatments — and no obvious business models have emerged.

During this interactive case study discussion, professors from Harvard Business School will help us examine how researchers at the Dana-Farber Cancer Institute considered and addressed myriad challenges in their effort to design and operationalize an adaptive platform trial for glioblastoma patients, a deadly disease state for which there are few existing treatment options.

PRESENTED BY

Richard Hamermesh, D.B.A., Co-Faculty Chair, Harvard Business School Kraft Precision Medicine Accelerator; and

Ariel D. Stern, Ph.D., Assistant Professor, Technology and Operations Management Unit, Harvard Business School

11:40 a.m.
The 14th Annual Leadership in Personalized Medicine Award

INTRODUCTION | Steven D. Averbuch, M.D., Vice President, Head of Precision Medicine, Bristol-Myers Squibb

  • Ellen V. Sigal head of Friends of Cancer Research
  • Advanced science by Diagnostics Tests
  • Cancer Moonshot Program
  • Revolution therapies brought to market by Sigel’s sponsorship

AWARDEE | Ellen V. Sigal, Ph.D., Chairperson, Founder, Friends of Cancer Research

Friendly conversation:

  • Thanks to PMC
  • sister die on breast cancer at 40 with child of 4 1/2.
  • appointed to celebrate 20th year of American Cancer Association – Funding for Research, money spend in Washington is for Patients.
  • After ten years, interested in measurement of achieving evaluation, FDA structure was of interest.
  • Precision Medicine: biomarkers and targets for patients to define success for each patient, WHat is the right population for any drug, responders to drug therapy, if no response, change the drug.
  • Patient perspective: Challenges: 90% are treated in the Community and they need a second opinion, insurance, access, clinical trials done out of the community in Academic hospitals – patients are scared to death. Patients are asking for options: Right testing, access to testing involve insurance
  • combination therapy  – 6-8 months in advance,
12:10 p.m.
Bag Lunch
1:10 p.m.
Predicting and Preventing: Evaluating Progress Toward Personalized Medicine

The original architects of the personalized medicine paradigm envisioned an era in which clinicians could predict, prevent and treat disease based on an improved understanding of how human biology interacts with external environments. During this session, a panel of experts will examine our progress on each of these fronts during a wide-ranging conversation about personalized medicine’s past, present and future.

MODERATOR | Cynthia Casson Morton, Ph.D., William Lambert Richardson Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School

  • 1 Million volunteer participants for genome sequencing and microbiome data
  • PM Past, Present and Future
  • Issues that are rapidly evolving: Physician, Patients

Birgit Funke, Ph.D., F.A.C.M.G., Vice President, Clinical Affairs, Veritas Genetics; Associate Professor of Pathology (Part-Time), Harvard Medical School

  • Risk prevention,
  • driving DOWN operating cost curation of the Genome

Luba Greenwood, J.D., Strategic Business Development and Corporate Ventures, Verily (an Alphabet company)

  • view on diagnostics from Roche, CHemist and lawyer, Venture capital, beyond Genomics, from diagnosis to prognosis,at Verily projects tapping into the entire life span aspect of health
  • treatment solution therapeutics except og Oncology threatment is a strugle in the genomics field and pharmaco-genomics
  • Power the patients vs Genomics in Diabetes
  • Diagnostics in use to keep patients OUT of hospitals – management of chronic diseases
  • Patient need to own the genome data not a Databank

Keith Stewart, M.B., CH.B., Carlson and Nelson Endowed Director, Center for Individualized Medicine, Mayo Clinic

  • Hematologist, genomics apply genomics for detection of predisposition, inherited , Health genome sequencing,
  • Barriers to deploy genomics: Knowledge, readiness of providers, cost of uninsured,
  • Diagnostics high value low cost
  • drug adherence, pharmacists to be involved in drug adherence before refill
2:10 p.m.
Assessing the Assays: Determining the Clinical and Economic Utility of Genomic Sequencing

Advocates for personalized medicine have contended that genomic sequencing can deliver clinical and economic value to patients and the health system by allowing providers to more efficiently diagnose disease and develop treatment plans. Following increased use of genomic sequencing in clinical settings, many stakeholders, including payers, have begun to examine that value proposition more closely. During this session, a pharmaceutical industry representative, a payer, and a health economist will discuss the status and future of the emerging evidence regarding the clinical and economic utility of genomic sequencing, including studies recently commissioned by the Personalized Medicine Coalition.

MODERATOR Daryl Pritchard, Ph.D., Senior Vice President, Science Policy, Personalized Medicine Coalition

  • genetic profiling, adopt policy and procedures for mass deployment of NGS
  • show that it works – demonstrate value, payers and providers
  • a little more that evidence exist for payer to cover
  • rare diagnosed disease

Kristine Bordenave, M.D., F.A.C.P., Corporate Medical Director, Humana

  • labs, payers, providers, pharma — the GAP to be bridged
  • opportunities to prevent and treat disease
  • Payer, MDs, cost and impact, markers,
  • Humana has a research division Use Testing to find value, pharmacogenomics  – on Medicare, Medicaid patients
  • cost of doing the test vs not doing this test – assess value
  • pharmacisit, economist, statisticians – CMS – provide data on what is covered and what is not Humana: any missed opportunities, MD order tests of no impact per medical record
  • What test needed to be ordered? Patient stay healthy
  • NGS $650 – $2000 in 2018, in 2016 it was $25,000 cost of testing, cost of drugs
  • show us any value as good value – avoiding patient going to MDs Office, Hospital, ER – cost increase due to Pharmacogenomics testing $5K per test
  • Guidelines on ordering genomic testing, AI can assist providers, MDs need to catch up on a weekly basis
  • CMS Guideline: every test ordered must guide treatment otherwise not covered

Scott Ramsey, M.D., Ph.D., Full Member, Fred Hutchinson Cancer Research Center; Director, Hutchinson Institute for Cancer Outcomes Research

  • Value and utility are interconnected
  • cost effectiveness of NGS in melanoma: single gene testing – EGFR vs NGS – help clinicians to evaluate Lung Cancer
  • Flariton Database, 300 centers  – 140,000 – Patients got NGS – 7% ADDITIONAL patients founded mutations beyond EGFR
  • Survival in this cohort NGS vs EGFR – improved survival 6 month longer, mean survival 3 weeks long, not significant.
  • Increased survivals, why? cost of sequencing  – #14 most influential – cost does not drive value
  • #1 drug cost was the factor
  • #2 survival
  • marginal cost in platform comparison
  • Pricing of Testing NGS and Targeted therapy represent a threat to adoption of Genomics in Medicine
  • disparities and access – cost and patients: Partners and Mayo clinic patients are lucky

 

3:10 p.m.
PhRMA Foundation Challenge Awards: Developing Value Assessment Strategies That Align With Personalized Medicine

INTRODUCTION | Daryl Pritchard, Ph.D., Senior Vice President, Science Policy, Personalized Medicine Coalition

PRESENTER | Shreeram Aradhye, M.D., Head of Global Medical Affairs, Chief Medical Officer, Pharmaceuticals, Novartis; Board Member, PhRMA Foundation

#1 Prize $50,000 – Dr. Garrison, UK

#2 Prize $25,000 – Dr. Robim Hayeems, Hospital for Sick Children Institute, Toronto, Canada

#3 Prize @ $10,000  – Dr. A Le, PharmD., PhD, Western University of Health Sciences

3:20 p.m.
Networking Break

Light refreshments provided.

3:50 p.m.
Impasse or Inflection Point? — An Investment Analysis

Sustaining the pace of innovation in personalized medicine will require continued investment in new initiatives, but the financial outlook for the field remains unclear. In that context, this panel of investors will examine whether personalized medicine is at an impasse, an inflection point or somewhere in between.

MODERATOR | William A. Sahlman, Ph.D., Baker Foundation Professor, Harvard Business School

  • market – can it sustain the opportunity – winners and losers
  • innovative financial models
  • Biotech IPO, VC, windows slam shut, drug failure – drivers and non
  • Increasing return to scale: AI, NGS, screening, – foreign money, China
  • Tsinghua University went back to China from Silicon Valley

Cary Pfeffer, M.D., Partner, Third Rock Ventures

  • was a decade at Biogen, MS indication drug, no biomarkers for patients – efficacy was in 50% non respondents 25%
  • Genomic sequencing to identify patient populations – no good effective medicine without target therapy
  • Mayocardia – drug in CVD for patients identified by Genomics
  • Genomics information needed to develop drugs

Michael Pellini, M.D., Managing Partner, Section 32; Board Member, Personalized Medicine Coalition

  • Impasse or Inflection Point? it s Inflection Point NOT an Impasse
  • Diagnostics component inside 4.8 Trillion in the therapeutics selection in the system as a whole
  • Foundation Medicine saw Roche as Big brother with International reach
  • Patients and Consumers will force in five years figuring out – every diagnosis of cancer will be sequenced and the infrastructure to interpret results and paid for

Salveen Richter, C.F.A., Vice President, Research Division, Goldman Sachs

  • innovative and disruptive, orphan drugs, Health IT, US Market 3 trillion – size of the opportunity 80% genetically driven
  • Cancer, CART therapy, easier to pay by performance, cost of the drug itself. profit in the 1st generation od Pharma manufacturers
  • One time pricing vs further indications, annuity type system, Hemophilia – $19Million market,
  • Europe successful in financing Health care — in the US — system must change – investment will flee, to fund pricing drug is key in changing the system CART Pricing is still difficult to pay for
  • Sequencing cost plunged, public investors placing funding in start ups even without return in the horizon, companies with multiple modalities spurring innovation – confusing in the investment side, technologies become obsolete very fast
  • Europe vs US, China is different no regulation like FDA,talent from US Pharma went back to China

 

4:50 p.m.
Closing Remarks

SPEAKER | Edward Abrahams, Ph.D., President, Personalized Medicine Coalition

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NHLBI decision to halt Heart Stem-Cell Study (CONCERT-HF trial) due to concerns about Anversa’s Animal Studies, not due to any Data generated by the Clinical trial itself, no compromised patient safety by trial

Reporter: Aviva Lev-Ari, PhD, RN

Doubts about Anversa’s work arose in the early 2000s after other researchers failed to replicate his findings and questioned whether cardiac stem cells existed2,3,4.

Paper of Former HMS Prof. Withdrawn, Clinical Trial Paused after Harvard Requests Retractions

https://www.thecrimson.com/article/2018/10/31/medical-school-paper-retracted/

NHLBI NEWS

Statement

Statement on NHLBI decision to pause the CONCERT-HF trial

The National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, is pausing the CONCERT-HF trialexternal link, which involves patients with chronic heart failure. Recent calls for the retraction of journal articles in related fields of cell therapy research have raised concerns about the scientific foundations of this trial.  While none of the articles in question derive from the CONCERT-HF trial itself, the NHLBI convened CONCERT-HF’s Data and Safety Monitoring Board (DSMB) out of an abundance of caution to ensure the study continues to meet the highest standards for participant safety and scientific integrity. Informed by the DSMB recommendations of October 25, 2018, the NHLBI is pausing the trial. While the DSMB did not have any participant safety concerns, this pause enables the DSMB to complete its review.

The safety of all clinical trial participants is paramount to NHLBI. NHLBI will honor its commitment to CONCERT-HF participants and continue the follow-up protocol during this pause for all participants who have already been treated in the study. Participants are being notified of the status of the trial and how to request additional information.

The CONCERT-HF trial seeks to determine whether c-kit+ cells, either alone or in combination with mesenchymal stem cells derived from the bone marrow, are safe and benefit patients with chronic heart failure, who have very limited treatment options. Despite significant medical and surgical advances, patients with heart failure continue to experience a low quality of life and about half of them will die within five years of receiving a diagnosis.

The scientific basis of CONCERT-HF is supported by a body of evidence in several preclinical models in a number of studies in a variety of laboratories and was reviewed by a Protocol Review Committee (PRC) independent of the trial. The cell therapies that CONCERT-HF is testing are under an investigational new drug (IND) designation which is overseen by the U.S. Food and Drug Administration (FDA). The cells are produced by an accredited laboratory independent of the clinical sites. In addition, as part of standard oversight of clinical trials, the DSMB routinely reviews and monitors CONCERT-HF to ensure participant safety and that the study continues to ask compelling scientific questions with implications for patient care.

The DSMB’s review will be conducted as expeditiously as possible and will inform NHLBI’s future actions that will ensure the highest standards of participant safety and scientific integrity.

SOURCE

https://www.nhlbi.nih.gov/news/2018/statement-nhlbi-decision-pause-concert-hf-trial

References

  1. Quaini, F. et al. N. Engl. J. Med. 346, 5–15 (2002).
  1. Murry, C. E. et al. Nature 428, 664–668 (2004).
  1. Balsam, L. B. Nature 428, 668–673 (2004).
  1. Nygren, J. M. et al. Nature Med. 10, 494–501 (2004).

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Bioinformatics Tool Review: Genome Variant Analysis Tools

Curator: Stephen J. Williams, Ph.D.

Updated 11/15/2018

The following post will be an ongoing curation of reviews of gene variant bioinformatic software.

 

The Ensembl Variant Effect Predictor.

McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F.

Genome Biol. 2016 Jun 6;17(1):122. doi: 10.1186/s13059-016-0974-4.

Author information

1

European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK. wm2@ebi.ac.uk.

2

European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.

3

European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK. fiona@ebi.ac.uk.

Abstract

The Ensembl Variant Effect Predictor is a powerful toolset for the analysis, annotation, and prioritization of genomic variants in coding and non-coding regions. It provides access to an extensive collection of genomic annotation, with a variety of interfaces to suit different requirements, and simple options for configuring and extending analysis. It is open source, free to use, and supports full reproducibility of results. The Ensembl Variant Effect Predictor can simplify and accelerate variant interpretation in a wide range of study designs.

 

Rare diseases can be difficult to diagnose due to low incidence and incomplete penetrance of implicated alleles however variant analysis of whole genome sequencing can identify underlying genetic events responsible for the disease (Nature, 2015).  However, a large cohort is required for many WGS association studies in order to produce enough statistical power for interpretation (see post and here).  To this effect major sequencing projects have been initiated worldwide including:

A more thorough curation of sequencing projects can be seen in the following post:

Icelandic Population Genomic Study Results by deCODE Genetics come to Fruition: Curation of Current genomic studies

 

And although sequencing costs have dramatically been reduced over the years, the costs to determine the functional consequences of such variants remains high, as thorough basic research studies must be conducted to validate the interpretation of variant data with respect to the underlying disease, as only a small fraction of variants from a genome sequencing project will encode for a functional protein.  Correct annotation of sequences and variants, identification of correct corresponding reference genes or transcripts in GENCODE or RefSeq respectively offer compelling challenges to the proper identification of sequenced variants as potential functional variants.

To this effect, the authors developed the Ensembl Variant Effect Predictor (VEP), which is a software suite that performs annotations and analysis of most types of genomic variation in coding and non-coding regions of the genome.

Summary of Features

  • Annotation: VEP can annotate two broad categories of genomic variants
    • Sequence variants with specific and defined changes: indels, base substitutions, SNVs, tandem repeats
    • Larger structural variants > 50 nucleotides
  • Species and assembly/genomic database support: VEP can analyze data from any species with assembled genome sequence and annotated gene set. VEP supports chromosome assemblies such as the latest GRCh38, FASTA, as well as transcripts from RefSeq as well as user-derived sequences
  • Transcript Annotation: VEP includes a wide variety of gene and transcript related information including NCBI Gene ID, Gene Symbol, Transcript ID, NCBI RefSeq ID, exon/intron information, and cross reference to other databases such as UniProt
  • Protein Annotation: Protein-related fields include Protein ID, RefSeq ID, SwissProt, UniParc ID, reference codons and amino acids, SIFT pathogenicity score, protein domains
  • Noncoding Annotation: VEP reports variants in noncoding regions including genomic regulatory regions, intronic regions, transcription binding motifs. Data from ENCODE, BLUEPRINT, and NIH Epigenetics RoadMap are used for primary annotation.  Plugins to the Perl coding are also available to link other databases which annotate noncoding sequence features.
  • Frequency, phenotype, and citation annotation: VEP searches Ensembl databases containing a large amount of germline variant information and checks variants against the dbSNP single nucleotide polymorphism database. VEP integrates with mutational databases such as COSMIC, the Human Gene Mutation Database, and structural and copy number variants from Database of Genomic Variants.  Allele Frequencies are reported from 1000 Genomes and NHLBI and integrates with PubMed for literature annotation.  Phenotype information is from OMIM, Orphanet, GWAS and clinical information of variants from ClinVar.
  • Flexible Input and Output Formats: VEP supports input data format called “variant call format” or VCP, a standard in next-gen sequencing. VEP has the ability to process variant identifiers from other database formats.  Output formats are tab deliminated and give the user choices in presentation of results (HTML or text based)
  • Choice of user interface
    • Online tool (VEP Web): simple point and click; incorporates Instant VEP Functionality and copy and paste features. Results can be stored online in cloud storage on Ensembl.
    • VEP script: VEP is available as a downloadable PERL script (see below for link) and can process large amounts of data rapidly. This interface is powerfully flexible with the ability to integrate multiple plugins available from Ensembl and GitHub.  The ability to alter the PERL code and add plugins and code functions allows the flexibility to modify any feature of VEP.
    • VEP REST API: provides robust computational access to any programming language and returns basic variant annotation. Can make use of external plugins.

 

 

Watch Video on VES Instructional Webinar: https://youtu.be/7Fs7MHfXjWk

Watch Video on VES Web Version training on How to Analyze Your Sequence in VEP

 

 

Availability of data and materials

The dataset supporting the conclusions of this article is available from Illumina’s Platinum Genomes [93] and using the Ensembl release 75 gene set. Pre-built data sets are available for all Ensembl and Ensembl Genomes species [94]. They can also be downloaded automatically during set up whilst installing the VEP.

 

References

Large-scale discovery of novel genetic causes of developmental disorders.

Deciphering Developmental Disorders Study.

Nature2015 Mar 12;519(7542):223-8. doi: 10.1038/nature14135. PMID:25533962

Updated 11/15/2018

 

Research Points to Caution in Use of Variant Effect Prediction Bioinformatic Tools

Although we have the ability to use high throughput sequencing to identify allelic variants occurring in rare disease, correlation of these variants with the underlying disease is often difficult due to a few concerns:

  • For rare sporadic diseases, classical gene/variant association studies have proven difficult to perform (Meyts et al. 2016)
  • As Whole Exome Sequencing (WES) returns a considerable number of variants, how to differentiate the normal allelic variation found in the human population from disease-causing pathogenic alleles
  • For rare diseases, pathogenic allele frequencies are generally low

Therefore, for these rare pathogenic alleles, the use of bioinformatics tools in order to predict the resulting changes in gene function may provide insight into disease etiology when validation of these allelic changes might be experimentally difficult.

In a 2017 Genes & Immunity paper, Line Lykke Andersen and Rune Hartmann tested the reliability of various bioinformatic software to predict the functional consequence of variants of six different genes involved in interferon induction and sixteen allelic variants of the IFNLR1 gene.  These variants were found in cohorts of patients presenting with herpes simplex encephalitis (HSE). Most of the adult population is seropositive for Herpes Simplex Virus (HSV) however a minor fraction (1 in 250,000 individuals per year) of HSV infected individuals will develop HSE (Hjalmarsson et al., 2007).  It has been suggested that HSE occurs in individuals with rare primary immunodeficiencies caused by gene defects affecting innate immunity through reduced production of interferons (IFN) (Zhang et al., Lim et al.).

 

References

Meyts I, Bosch B, Bolze A, Boisson B, Itan Y, Belkadi A, et al. Exome and genome sequencing for inborn errors of immunity. J Allergy Clin Immunol. 2016;138:957–69.

Hjalmarsson A, Blomqvist P, Skoldenberg B. Herpes simplex encephalitis in Sweden, 1990-2001: incidence, morbidity, and mortality. Clin Infect Dis. 2007;45:875–80.

Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317:1522–7.

Lim HK, Seppanen M, Hautala T, Ciancanelli MJ, Itan Y, Lafaille FG, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology. 2014;83:1888–97.

 

Genes Immun. 2017 Dec 4. doi: 10.1038/s41435-017-0002-z.

Frequently used bioinformatics tools overestimate the damaging effect of allelic variants.

Andersen LL1Terczyńska-Dyla E1Mørk N2Scavenius C1Enghild JJ1Höning K3Hornung V3,4Christiansen M5,6Mogensen TH2,6Hartmann R7.

 

Abstract

We selected two sets of naturally occurring human missense allelic variants within innate immune genes. The first set represented eleven non-synonymous variants in six different genes involved in interferon (IFN) induction, present in a cohort of patients suffering from herpes simplex encephalitis (HSE) and the second set represented sixteen allelic variants of the IFNLR1 gene. We recreated the variants in vitro and tested their effect on protein function in a HEK293T cell based assay. We then used an array of 14 available bioinformatics tools to predict the effect of these variants upon protein function. To our surprise two of the most commonly used tools, CADD and SIFT, produced a high rate of false positives, whereas SNPs&GO exhibited the lowest rate of false positives in our test. As the problem in our test in general was false positive variants, inclusion of mutation significance cutoff (MSC) did not improve accuracy.

Methodology

  1. Identification of rare variants
  2. Genomes of nineteen Dutch patients with a history of HSE sequenced by WES and identification of novel HSE causing variants determined by filtering the single nucleotide polymorphisms (SNPs) that had a frequency below 1% in the NHBLI Exome Sequencing Project Exome Variant Server and the 1000 Genomes Project and were present within 204 genes involved in the immune response to HSV.
  3. Identified variants (204) manually evaluated for involvement of IFN induction based on IDBase and KEGG pathway database analysis.
  4. In-silico predictions: Variants classified by the in silico variant pathogenicity prediction programs: SIFT, Mutation Assessor, FATHMM, PROVEAN, SNAP2, PolyPhen2, PhD-SNP, SNP&GO, FATHMM-MKL, MutationTaster2, PredictSNP, Condel, MetaSNP, and CADD. Each program returned prediction scores measuring likelihood of a variant either being ‘deleterious’ or ‘neutral’. Prediction accuracy measured as

ACC = (true positive+true negative)/(true positive+true negative+false positive+false negative)

 

  1. Validation of prediction software/tools

In order to validate the predictive value of the software, HEK293T cells, deficient in IRF3, MAVS, and IKKe/TBK1, were cotransfected with the nine variants of the aforementioned genes and a luciferase reporter under control of the IFN-b promoter and luciferase activity measured as an indicator of IFN signaling function.  Western blot was performed to confirm the expression of the constructs.

 

Results

Table 2 Summary of the
bioinformatic predictions
HSE variants IFNLR1 variants Overall ACC
TN TP FN FP Total ACC TN TP FN FP Total ACC
Uniform cutoff
SIFT 4 1 0 4 9 0.56 8 1 0 7 16 0.56 0.56
Mutation assessor 6 1 0 2 9 0.78 9 1 0 6 16 0.63 0.68
FATHMM 7 1 0 1 9 0.89 0.89
PROVEAN 8 1 0 0 9 1.00 11 1 0 4 16 0.75 0.84
SNAP2 5 1 0 3 9 0.67 8 0 1 7 16 0.50 0.56
PolyPhen2 6 1 0 2 9 0.78 12 1 0 3 16 0.81 0.80
PhD-SNP 7 1 0 1 9 0.89 11 1 0 4 16 0.75 0.80
SNPs&GO 8 1 0 0 9 1.00 14 1 0 1 16 0.94 0.96
FATHMM MKL 4 1 0 4 9 0.56 13 0 1 2 16 0.81 0.72
MutationTaster2 4 0 1 4 9 0.44 14 0 1 1 16 0.88 0.72
PredictSNP 6 1 0 2 9 0.78 11 1 0 4 16 0.75 0.76
Condel 6 1 0 2 9 0.78 0.78
Meta-SNP 8 1 0 0 9 1.00 11 1 0 4 16 0.75 0.84
CADD 2 1 0 6 9 0.33 8 0 1 7 16 0.50 0.44
MSC 95% cutoff
SIFT 5 1 0 3 9 0.67 8 1 0 8 16 0.50 0.56
PolyPhen2 6 1 0 2 9 0.78 13 1 0 3 16 0.81 0.80
CADD 4 1 0 4 9 0.56 7 0 1 9 16 0.44 0.48

 

Note: TN: true negative, TP: true positive, FN: false negative, FP: false positive, ACC: accuracy

Functional testing (data obtained from reporter construct experiments) were considered as the correct outcome.

Three prediction tools (PROVEAN, SNP&GO, and MetaSNP correctly predicted the effect of all nine variants tested.

 

Other articles related to Genomics and Bioinformatics on this online Open Access Journal Include:

Finding the Genetic Links in Common Disease: Caveats of Whole Genome Sequencing Studies

 

Large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes

 

US Personalized Cancer Genome Sequencing Market Outlook 2018 –

 

Icelandic Population Genomic Study Results by deCODE Genetics come to Fruition: Curation of Current genomic studies

 

 

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