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Posts Tagged ‘NGS’


     


SomaticSeq: An Ensemble Approach with Machine Learning to Detect Cancer Variants

June 16 at 1pm EDT Register for this Webinar |  View All Webinars

Accurate detection of somatic mutations has proven to be challenging in cancer NGS analysis, due to tumor heterogeneity and cross-contamination between tumor and matched normal samples. Oftentimes, a somatic caller that performs well for one tumor may not for another.

In this webinar we will introduce SomaticSeq, a tool within the Bina Genomic Management Solution (Bina GMS) designed to boost the accuracy of somatic mutation detection with a machine learning approach. You will learn:

  • Benchmarking of leading somatic callers, namely MuTect, SomaticSniper, VarScan2, JointSNVMix2, and VarDict
  • Integration of such tools and how accuracy is achieved using a machine learning classifier that incorporates over 70 features with SomaticSeq
  • Accuracy validation including results from the ICGC-TCGA DREAM Somatic Mutation Calling Challenge, in which Bina placed 1st in indel calling and 2nd in SNV calling in stage 5
  • Creation of a new SomaticSeq classifier utilizing your own dataset
  • Review of the somatic workflow within the Bina Genomic Management Solution

Speakers:

Li Tai Fang

Li Tai Fang
Sr. Bioinformatics Scientist
Bina Technologies, Part of
Roche Sequencing

Anoop Grewal

Anoop Grewal
Product Marketing Manager
Bina Technologies, Part of
Roche Sequencing

<Read full speaker bios here>

Cost: No cost!

Schedule conflict? Register now and you’ll receive a copy of the recording.

This webinar is compliments of: 

Bio-ITWorld.com/Bio-IT-Webinars

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Invivoscribe, Thermo Fisher Ink Cancer Dx Development Deal

Reporter: Stephen J. Williams, PhD

 

NEW YORK (GenomeWeb) – Invivoscribe Technologies announced today that it has formed a strategic partnership with Thermo Fisher Scientific to develop multiple next-generation sequencing-based in vitro cancer diagnostics.

Under the deal, Invivoscribe will develop and commercialize immune-oncology molecular diagnostics that run on Thermo’s Ion PGM Dx system, as well as associated bioinformatics software for applications in liquid biopsies. The tests will be specifically designed for both the diagnosis and minimal residual disease (MRD) monitoring of various hematologic cancers.

Additional terms of the arrangement were not disclosed.

“We are … very excited to provide our optimized NGS tests with comprehensive bioinformatics software so our customers can perform the entire testing and reporting process, including MRD testing, within their laboratories,” Invivoscribe CEO Jeffrey Miller said in a statement.

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Cambridge Healthtech Institute’s Third Annual

Clinical NGS Assays

Addressing Validation, Standards, and Clinical Relevance for Improved Outcomes

August 23-24, 2016 | Grand Hyatt Hotel | Washington, DC


View Preliminary Agenda

Molecular diagnostics, particularly next-generation sequencing (NGS), have become an integral component of disease diagnosis. Still, there is work to be done to establish these tools as the standard of care. The Third Annual Clinical NGS Assays event will address NGS assay validation, establishing NGS standards, and determining clinical relevance. The pros and cons of various techniques such as gene panels, whole exome, and whole genome sequencing will also be debated with regards to depth of coverage, clinical utility, and reimbursement. Overall, this event will address the needs of both researchers and clinicians while exploring strategies to increase collaboration for improved patient outcomes.

Special Early Registration Savings Available
Register Now to Save up to $450

Preliminary Agenda

ASSAY VALIDATION AND ANALYSIS

Best Practices for Using Genome in a Bottle Reference Materials to Benchmark Variant Calls
Justin Zook, National Institute of Standards and Technology

NGS in Clinical Diagnosis: Aspects of Quality Management
Pinar Bayrak-Toydemir, M.D., Ph.D., FACMG, Associate Professor, Pathology, University of Utah; Medical Director, Molecular Genetics and Genomics, ARUP Laboratories

Thorough Validation and Implementation of Preimplantation Genetic Screening for Aneuploidy by NGS
Rebekah Zimmerman, Ph.D., Laboratory Director, Clinical Genetics, Foundation for Embryonic Competence

EXOME INTERPRETATION CHALLENGES

Are We There Yet? The Odyssey of Exome Analysis and Interpretation
Avni B. Santani, Ph.D., Director, Genomic Diagnostics, Pathology and Lab Medicine, The Children’s Hospital of Philadelphia

Challenges in Exome Interpretation: Intronic Variants
Rong Mao, M.D., Associate Professor, Pathology, University of Utah; Medical Director, Molecular Genetics and Genomics, ARUP Laboratories

Exome Sequencing: Case Studies of Diagnostic and Ethical Challenges
Lora J. H. Bean, Ph.D., Assistant Professor, Human Genetics, Emory University

ESTABLISHING STANDARDS

Implementing Analytical and Process Standards
Karl V. Voelkerding, M.D., Professor, Pathology, University of Utah; Medical Director for Genomics and Bioinformatics, ARUP Laboratories

Assuring the Quality of Next-Generation Sequencing in Clinical Laboratory Practice
Shashikant Kulkarni, M.S., Ph.D., Professor, Pathology and Immunology; Head of Clinical Genomics, Genomics and Pathology Services; Director, Cytogenomics and Molecular Pathology, Washington University at St. Louis

Sponsored Presentation to be Announced by Genection

PANEL DISCUSSION: GENE PANEL VS. WHOLE EXOME VS. WHOLE GENOME

Panelists:
John Chiang, Ph.D., Director, Casey Eye Institute, Oregon Health & Science University
Avni B. Santani, Ph.D., Director, Genomic Diagnostics, Pathology and Lab Medicine, The Children’s Hospital of Philadelphia
Additional Panelist to be Announced

DETERMINING CLINICAL SIGNIFICANCE AND RETURNING RESULTS

Utility of Implementing Clinical NGS Assays as Standard-of-Care in Oncology
Helen Fernandes, Ph.D., Pathology & Laboratory Medicine, Weill Cornell Medical College

An NGS Inter-Laboratory Study to Assess Performance and QC – Sponsored by Seracare
Andrea Ferreira-Gonzalez, Ph.D., Chair, Molecular Diagnostics Division, Pathology, Virginia Commonwealth University Medical School

This conference is part of the Eighth Annual Next-Generation Dx Summit.


Track Sponsor: SeraCare


For exhibit & sponsorship opportunities, please contact:

Joseph Vacca, M.Sc.
Associate Director, Business Development
Cambridge Healthtech Institute
T: (+1) 781-972-5431
E: jvacca@healthtech.com

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Roche is developing a high-throughput low cost sequencer for NGS

Reporter: Stephen J. Williams, PhD

 

Reported from Diagnostic World News

Long-Read Sequencing in the Age of Genomic Medicine

 

 

By Aaron Krol

December 16, 2015 | This September, Pacific Biosciences announced the creation of the Sequel, a DNA sequencer half the cost and seven times as powerful as its previous RS II instrument. PacBio, with its unique long-read sequencing technology, had already secured a place in high-end research labs, producing finished, highly accurate genomes and helping to explore the genetic “dark matter” that other next-generation sequencing (NGS) instruments miss. Now, in partnership with Roche Diagnostics, PacBio is repositioning itself as a company that can serve hospitals as well.

“Pseudogenes, large structural variants, validation, repeat disorders, polymorphic regions of the genome―all those are categories where you practically need PacBio,” says Bobby Sebra, Director of Technology Development at the Icahn School of Medicine at Mount Sinai. “Those are gaps in the system right now for short-read NGS.”

Mount Sinai’s genetic testing lab owns three RS II sequencers, running almost around the clock, and was the first lab to announce it had bought a Sequel just weeks after the new instruments were launched. (It arrived earlier this month and has been successfully tested.) Sebra’s group uses these sequencers to read parts of the genome that, thanks to their structural complexity, can only be assembled from long, continuous DNA reads.

There are a surprising number of these blind spots in the human genome. “HLA is a huge one,” Sebra says, referring to a highly variable region of the genome involved in the immune system. “It impacts everything from immune response, to pharmacogenomics, to transplant medicine. It’s a pretty important and really hard-to-genotype locus.”

Nonetheless, few clinical organizations are studying PacBio or other long-read technologies. PacBio’s instruments, even the Sequel, come with a relatively high price tag, and research on their value in treating patients is still tentative. Mount Sinai’s confidence in the technology is surely at least partly due to the influence of Sebra―an employee of PacBio for five years before coming to New York―and Genetics Department Chair Eric Schadt, at one time PacBio’s Chief Scientific Officer.

Even here, the sequencers typically can’t be used to help treat patients, as the instruments are sold for research use only. Mount Sinai is still working on a limited number of tests to submit as diagnostics to New York State regulators.

Physician Use

Roche Diagnostics, which invested $75 million in the development of the Sequel, wants to change that. The company is planning to release its own, modified version of the instrument in the second half of 2016, specifically for diagnostic use. Roche will initially promote the device for clinical studies, and eventually seek FDA clearance to sell it for routine diagnosis of patients.

In an email to Diagnostics World, Paul Schaffer, Lifecycle Leader for Roche’s sequencing platforms division, wrote that the new device will feature an integrated software pipeline to interpret test results, in support of assays that Roche will design and validate for clinical indications. The instrument will also have at least minor hardware modifications, like near field communication designed to track Roche-branded reagents used during sequencing.

This new version of the Sequel will probably not be the first instrument clinical labs turn to when they decide to start running NGS. Short-read sequencers are sure to outcompete the Roche machine on price, and can offer a pretty useful range of assays, from co-diagnostics in cancer to carrier testing for rare genetic diseases. But Roche can clear away some of the biggest barriers to entry for hospitals that want to pursue long-read sequencing.

Today, institutions like Mount Sinai that use PacBio typically have to write a lot of their own software to interpret the data that comes off the machines. Off-the-shelf analysis, with readable diagnostic reports for doctors, will make it easier for hospitals with less research focus to get on board. To this end, Roche acquired Bina, an NGS analysis company that handles structural variants and other PacBio specialties, in late 2014.

The next question will be whether Roche can design a suite of tests that clinical labs will want to run. Long-read sequencing is beloved by researchers because it can capture nearly complete genomes, finding the correct order and orientation of DNA reads. “The long-read technologies like PacBio’s are going to be, in the future, the showcase that ties it all together,” Sebra says. “You need those long reads as scaffolds to bring it together.”

But that envisions a future in which doctors will want to sequence their patients’ entire genomes. When it comes to specific medical tests, targeting just a small part of the genome connected to disease, Roche will have to content itself with some niche applications where PacBio stands out.

Early Applications

“At this time we are not releasing details regarding the specific assays under development,” Schaffer told Diagnostics World in his email. “However, virology and genetics are a key focus, as they align with other high-priority Roche Diagnostics products.”

Genetic disease is the obvious place to go with any sequencing technology. Rare hereditary disorders are much easier to understand on a genetic level than conditions like diabetes or heart disease; typically, the pathology can be traced back to a single mutation, making it easy to interpret test results.

Some of these mutations are simply intractable for short-read sequencers. A whole class of diseases, the PolyQ disorders and other repeat disorders, develop when a patient has too many copies of a single, repetitive sequence in a gene region. The gene Huntingtin, for example, contains a long stretch of the DNA code CAG; people born with 40 or more CAG repeats in a row will develop Huntington’s disease as they reach early adulthood.

These disorders would be a prime target for Roche’s sequencer. The Sequel’s long reads, spanning thousands of DNA letters at a stretch, can capture the entire repeat region of Huntingtin at a stretch, unlike short-read sequencers that would tend to produce a garbled mess of CAG reads impossible to count or put in order.

Nonetheless, the length of reads is not the only obstacle to understanding these very obstinate diseases. “The entire category of PolyQ disorders, and Fragile X and Huntington’s, is really important,” says Sebra. “But to be frank, they’re the most challenging even with PacBio.” He suggests that, even without venturing into the darkest realms of the genome, a long-read sequencer might actually be useful for diagnosing many of the same genetic diseases routinely covered by other instruments.

That’s because, even when the gene region involved in a disease is well known, there’s rarely only one way for it to go awry. “An example of that is Gaucher’s disease, in a gene called GBA,” Sebra says. “In that gene, there are hundreds of known mutations, some of which you can absolutely genotype using short reads. But others, you would need to phase the entire block to really understand.” Long-read sequencing, which is better at distinguishing maternal from paternal DNA and highlighting complex rearrangements within a gene, can offer a more thorough look at diseases with many genetic permutations, especially when tracking inheritance through a family.

“You can think of long-read sequencing as a really nice way to supplement some of the inherited panels or carrier screening panels,” Sebra says. “You can also use PacBio to verify variants that are called with short-read sequencing.”

Virology is, perhaps, a more surprising focus for Roche. Diagnosing a viral (or bacterial, or fungal) infection with NGS only requires finding a DNA read unique to a particular species or strain, something short-read sequencers are perfectly capable of.

But Mount Sinai, which has used PacBio in pathogen surveillance projects, has seen advantages to getting the full, completely assembled genomes of the organisms it’s tracking. With bacteria, for instance, key genes that confer resistance to antibiotics might be found either in the native genome, or inside plasmids, small packets of DNA that different species of bacteria freely pass between each other. If your sequencer can assemble these plasmids in one piece, it’s easier to tell when there’s a risk of antibiotic resistance spreading through the hospital, jumping from one infectious species to another.

Viruses don’t share their genetic material so freely, but a similar logic can still apply to viral infections, even in a single person. “A virus is really a mixture of different quasi-species,” says Sebra, so a patient with HIV or influenza likely has a whole constellation of subtly different viruses circulating in their body. A test that assembles whole viral genomes—which, given their tiny size, PacBio can often do in a single read—could give physicians a more comprehensive view of what they’re dealing with, and highlight any quasi-species that affect the course of treatment or how the virus is likely to spread.

The Broader View

These applications are well suited to the diagnostic instrument Roche is building. A test panel for rare genetic diseases can offer clear-cut answers, pointing physicians to any specific variants linked to a disorder, and offering follow-up information on the evidence that backs up that call.

That kind of report fits well into the workflows of smaller hospital labs, and is relatively painless to submit to the FDA for approval. It doesn’t require geneticists to puzzle over ambiguous results. As Schaffer says of his company’s overall NGS efforts, “In the past two years, Roche has been actively engaged in more than 25 partnerships, collaborations and acquisitions with the goal of enabling us to achieve our vision of sample in to results out.”

But some of the biggest ways medicine could benefit from long-read sequencing will continue to require the personal touch of labs like Mount Sinai’s.

Take cancer, for example, a field in which complex gene fusions and genetic rearrangements have been studied for decades. Tumors contain multitudes of cells with unique patchworks of mutations, and while long-read sequencing can pick up structural variants that may play a role in prognosis and treatment, many of these variants are rarely seen, little documented, and hard to boil down into a physician-friendly answer.

An ideal way to unravel a unique cancer case would be to sequence the RNA molecules produced in the tumor, creating an atlas of the “transcriptome” that shows which genes are hyperactive, which are being silenced, and which have been fused together. “When you run something like IsoSeq on PacBio and you can see truly the whole transcriptome, you’re going to figure out all possible fusions, all possible splicing events, and the true atlas of reads,” says Sebra. “Cancer is so diverse that it’s important to do that on an individual level.”

Occasionally, looking at the whole transcriptome, and seeing how a mutation in one gene affects an entire network of related genes, can reveal an unexpected treatment option―repurposing a drug usually reserved for other cancer types. But that takes a level of attention and expertise that is hard to condense into a mass-market assay.

And, Sebra suggests, there’s another reason for medical centers not to lean too heavily on off-the-shelf tests from vendors like Roche.

Devoted as he is to his onetime employer, Sebra is also a fan of other technologies now emerging to capture some of the same long-range, structural information on the genome. “You’ve now got 10X Genomics, BioNano, and Oxford Nanopore,” he says. “Often, any two or even three of those technologies, when you merge them together, can get you a much more comprehensive story, sometimes faster and sometimes cheaper.” At Mount Sinai, for example, combining BioNano and PacBio data has produced a whole human genome much more comprehensive than either platform can achieve on its own.

The same is almost certainly true of complex cases like cancer. Yet, while companies like Roche might succeed in bringing NGS diagnostics to a much larger number of patients, they have few incentives to make their assays work with competing technologies the way a research-heavy institute like Mount Sinai does.

“It actually drives the commercialization of software packages against the ability to integrate the data,” Sebra says.

Still, he’s hopeful that the Sequel can lead the industry to pay more attention to long-read sequencing in the clinic. “The RS II does a great job of long-read sequencing, but the throughput for the Sequel is so much higher that you can start to achieve large genomes faster,” he says. “It makes it more accessible for people who don’t own the RS II to get going.” And while the need for highly specialized genetics labs won’t be falling off anytime soon, most patients don’t have the luxury of being treated in a hospital with the resources of Mount Sinai. NGS companies increasingly see physicians as some of their most important customers, and as our doctors start checking into the health of our genomes, it would be a shame if ubiquitous short-read sequencing left them with blind spots.

Source: http://diagnosticsworldnews.com/2015/12/16/long-read-sequencing-age-genomic-medicine.aspx

 

 

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How Will FDA’s new precisionFDA Science 2.0 Collaboration Platform Protect Data?

Reporter: Stephen J. Williams, Ph.D.

As reported in MassDevice.com

FDA launches precisionFDA to harness the power of scientific collaboration

FDA VoiceBy: Taha A. Kass-Hout, M.D., M.S. and Elaine Johanson

Imagine a world where doctors have at their fingertips the information that allows them to individualize a diagnosis, treatment or even a cure for a person based on their genes. That’s what President Obama envisioned when he announced his Precision Medicine Initiative earlier this year. Today, with the launch of FDA’s precisionFDA web platform, we’re a step closer to achieving that vision.

PrecisionFDA is an online, cloud-based, portal that will allow scientists from industry, academia, government and other partners to come together to foster innovation and develop the science behind a method of “reading” DNA known as next-generation sequencing (or NGS). Next Generation Sequencing allows scientists to compile a vast amount of data on a person’s exact order or sequence of DNA. Recognizing that each person’s DNA is slightly different, scientists can look for meaningful differences in DNA that can be used to suggest a person’s risk of disease, possible response to treatment and assess their current state of health. Ultimately, what we learn about these differences could be used to design a treatment tailored to a specific individual.

The precisionFDA platform is a part of this larger effort and through its use we want to help scientists work toward the most accurate and meaningful discoveries. precisionFDA users will have access to a number of important tools to help them do this. These tools include reference genomes, such as “Genome in the Bottle,” a reference sample of DNA for validating human genome sequences developed by the National Institute of Standards and Technology. Users will also be able to compare their results to previously validated reference results as well as share their results with other users, track changes and obtain feedback.

Over the coming months we will engage users in improving the usability, openness and transparency of precisionFDA. One way we’ll achieve that is by placing the code for the precisionFDA portal on the world’s largest open source software repository, GitHub, so the community can further enhance precisionFDA’s features.Through such collaboration we hope to improve the quality and accuracy of genomic tests – work that will ultimately benefit patients.

precisionFDA leverages our experience establishing openFDA, an online community that provides easy access to our public datasets. Since its launch in 2014, openFDA has already resulted in many novel ways to use, integrate and analyze FDA safety information. We’re confident that employing such a collaborative approach to DNA data will yield important advances in our understanding of this fast-growing scientific field, information that will ultimately be used to develop new diagnostics, treatments and even cures for patients.

fda-voice-taha-kass-1x1Taha A. Kass-Hout, M.D., M.S., is FDA’s Chief Health Informatics Officer and Director of FDA’s Office of Health Informatics. Elaine Johanson is the precisionFDA Project Manager.

 

The opinions expressed in this blog post are the author’s only and do not necessarily reflect those of MassDevice.com or its employees.

So What Are the Other Successes With Such Open Science 2.0 Collaborative Networks?

In the following post there are highlighted examples of these Open Scientific Networks and, as long as

  • transparancy
  • equal contributions (lack of heirarchy)

exists these networks can flourish and add interesting discourse.  Scientists are already relying on these networks to collaborate and share however resistance by certain members of an “elite” can still exist.  Social media platforms are now democratizing this new science2.0 effort.  In addition the efforts of multiple biocurators (who mainly work for love of science) have organized the plethora of data (both genomic, proteomic, and literature) in order to provide ease of access and analysis.

Science and Curation: The New Practice of Web 2.0

Curation: an Essential Practice to Manage “Open Science”

The web 2.0 gave birth to new practices motivated by the will to have broader and faster cooperation in a more free and transparent environment. We have entered the era of an “open” movement: “open data”, “open software”, etc. In science, expressions like “open access” (to scientific publications and research results) and “open science” are used more and more often.

Curation and Scientific and Technical Culture: Creating Hybrid Networks

Another area, where there are most likely fewer barriers, is scientific and technical culture. This broad term involves different actors such as associations, companies, universities’ communication departments, CCSTI (French centers for scientific, technical and industrial culture), journalists, etc. A number of these actors do not limit their work to popularizing the scientific data; they also consider they have an authentic mission of “culturing” science. The curation practice thus offers a better organization and visibility to the information. The sought-after benefits will be different from one actor to the next.

Scientific Curation Fostering Expert Networks and Open Innovation: Lessons from Clive Thompson and others

  • Using Curation and Science 2.0 to build Trusted, Expert Networks of Scientists and Clinicians

Given the aforementioned problems of:

        I.            the complex and rapid deluge of scientific information

      II.            the need for a collaborative, open environment to produce transformative innovation

    III.            need for alternative ways to disseminate scientific findings

CURATION MAY OFFER SOLUTIONS

        I.            Curation exists beyond the review: curation decreases time for assessment of current trends adding multiple insights, analyses WITH an underlying METHODOLOGY (discussed below) while NOT acting as mere reiteration, regurgitation

 

      II.            Curation providing insights from WHOLE scientific community on multiple WEB 2.0 platforms

 

    III.            Curation makes use of new computational and Web-based tools to provide interoperability of data, reporting of findings (shown in Examples below)

 

Therefore a discussion is given on methodologies, definitions of best practices, and tools developed to assist the content curation community in this endeavor

which has created a need for more context-driven scientific search and discourse.

However another issue would be Individual Bias if these networks are closed and protocols need to be devised to reduce bias from individual investigators, clinicians.  This is where CONSENSUS built from OPEN ACCESS DISCOURSE would be beneficial as discussed in the following post:

Risk of Bias in Translational Science

As per the article

Risk of bias in translational medicine may take one of three forms:

  1. a systematic error of methodology as it pertains to measurement or sampling (e.g., selection bias),
  2. a systematic defect of design that leads to estimates of experimental and control groups, and of effect sizes that substantially deviate from true values (e.g., information bias), and
  3. a systematic distortion of the analytical process, which results in a misrepresentation of the data with consequential errors of inference (e.g., inferential bias).

This post highlights many important points related to bias but in summarry there can be methodologies and protocols devised to eliminate such bias.  Risk of bias can seriously adulterate the internal and the external validity of a clinical study, and, unless it is identified and systematically evaluated, can seriously hamper the process of comparative effectiveness and efficacy research and analysis for practice. The Cochrane Group and the Agency for Healthcare Research and Quality have independently developed instruments for assessing the meta-construct of risk of bias. The present article begins to discuss this dialectic.

  • Information dissemination to all stakeholders is key to increase their health literacy in order to ensure their full participation
  • threats to internal and external validity  represent specific aspects of systematic errors (i.e., bias)in design, methodology and analysis

So what about the safety and privacy of Data?

A while back I did a post and some interviews on how doctors in developing countries are using social networks to communicate with patients, either over established networks like Facebook or more private in-house networks.  In addition, these doctor-patient relationships in developing countries are remote, using the smartphone to communicate with rural patients who don’t have ready access to their physicians.

Located in the post Can Mobile Health Apps Improve Oral-Chemotherapy Adherence? The Benefit of Gamification.

I discuss some of these problems in the following paragraph and associated posts below:

Mobile Health Applications on Rise in Developing World: Worldwide Opportunity

According to International Telecommunication Union (ITU) statistics, world-wide mobile phone use has expanded tremendously in the past 5 years, reaching almost 6 billion subscriptions. By the end of this year it is estimated that over 95% of the world’s population will have access to mobile phones/devices, including smartphones.

This presents a tremendous and cost-effective opportunity in developing countries, and especially rural areas, for physicians to reach patients using mHealth platforms.

How Social Media, Mobile Are Playing a Bigger Part in Healthcare

E-Medical Records Get A Mobile, Open-Sourced Overhaul By White House Health Design Challenge Winners

In Summary, although there are restrictions here in the US governing what information can be disseminated over social media networks, developing countries appear to have either defined the regulations as they are more dependent on these types of social networks given the difficulties in patient-physician access.

Therefore the question will be Who Will Protect The Data?

For some interesting discourse please see the following post

Atul Butte Talks on Big Data, Open Data and Clinical Trials

 

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Reproductive Genetic Dx | Nov. 18-19 | Boston, MA
Reporter: Stephen J. Williams, Ph.D.
Reproductive Genetic Diagnostics
Advances in Carrier Screening, Preimplantation Diagnostics, and POC Testing
November 18-19, 2015  |  Boston, MA
healthtech.com/reproductive-genetic-diagnosticsMount Sinai Hospital’s Dr. Tanmoy Mukherjee to Present at Reproductive Genetic Diagnostics ConferenceTanmoy MukherjeePodcastNumerical Chromosomal Abnormalities after PGS and D&C
Tanmoy Mukherjee, M.D., Assistant Clinical Professor, Obstetrics, Gynecology and Reproductive Science, Mount Sinai Hospital
This review provides an analysis of the most commonly identified numerical chromosome abnormalities following PGS and first trimester D&C samples in an infertile population utilizing ART. Although monosomies comprised >50% of all cytogenetic anomalies identified following PGS, there were very few identified in the post D&C samples. This suggests that while monosomies occur frequently in the IVF population, they commonly do not implant.

In a CHI podcast, Dr. Mukherjee discusses the current challenges facing reproductive specialists in regards to genetic diagnosis of recurrent pregnancy loss, as well as how NGS is affecting this type of testing > Listen to Podcast

Register  SAVE up to $200, Register by October 9

Learn More  |  Present a Poster  |  Sponsorship & Exhibit Information  |  View Brochure

CONFERENCE-AT-A-GLANCE

ADVANCES IN NGS AND OTHER TECHNOLOGIES

Keynote Presentation: Current and Expanding Invitations for Preimplantation Genetic Diagnosis (PGD)
Joe Leigh Simpson, MD, President for Research and Global Programs, March of Dimes Foundation

Next-Generation Sequencing: Its Role in Reproductive Medicine
Brynn Levy, Professor of Pathology & Cell Biology, CUMC; Director, Clinical Cytogenetics Laboratory, Co-Director, Division of Personalized Genomic Medicine, College of Physicians and Surgeons, Columbia University Medical Center, and the New York Presbyterian Hospital

CCS without WGA
Nathan Treff, Director, Molecular Biology Research, Reproductive Medicine Associates of New Jersey, Associate Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, Rutgers-Robert Wood Johnson Medical School, Adjunct Faculty Member, Department of Genetics, Rutgers-The State University of New Jersey

Concurrent PGD for Single Gene Disorders and Aneuploidy on a Single Trophectoderm Biopsy
Rebekah S. Zimmerman, Ph.D., FACMG, Director, Clinical Genetics, Foundation for Embryonic Competence

Live Birth of Two Healthy Babies with Monogenic Diseases and Chromosome Abnormality Simultaneously Avoided by MALBAC-based Combined PGD and PGS
Xiaoliang Sunney Xie, Ph.D., Mallinckrodt Professor of Chemistry and Chemical Biology, Department of Chemistry and Chemical Biology, Harvard University

Good Start GeneticsAnalytical Validation of a Novel NGS-Based Pre-implantation Genetic Screening Technology
Mark Umbarger, Ph.D., Director, Research and Development, Good Start Genetics


CLINICAL APPLICATIONS FOR ADVANCED TESTING TECHNOLOGIES

Expanded Carrier Screening for Monogenic Disorders
Peter Benn, Professor, Department of Genetics and Genome Sciences, University of Connecticut Health Center

Oocyte Mitochondrial Function and Testing: Implications for Assisted Reproduction
Emre Seli, MD, Yale School of Medicine

Preventing the Transmission of Mitochondrial Diseases through Germline Genome Editing
Alejandro Ocampo, Ph.D., Research Associate, Gene Expression Laboratory – Belmonte, Salk Institute for Biological Studies

Silicon BiosystemsRecovery and Analysis of Single (Fetal) Cells: DEPArray Based Strategy to Examine CPM and POC
Farideh Bischoff, Ph.D., Executive Director, Scientific Affairs, Silicon Biosystems, Inc.

> Sponsored Presentation (Opportunities Available)

Numerical Chromosomal Abnormalities after PGS and D&C
Tanmoy Mukherjee, M.D., Assistant Clinical Professor, Obstetrics, Gynecology and Reproductive Science, Mount Sinai Hospital

EMBRYO PREPARATION, ASSESSMENT, AND TREATMENT

Guidelines and Standards for Embryo Preparation: Embryo Culture, Growth and Biopsy Guidelines for Successful Genetic Diagnosis
Michael A. Lee, MS, TS, ELD (ABB), Director, Laboratories, Fertility Solutions

Current Status of Time-Lapse Imaging for Embryo Assessment and Selection in Clinical IVF
Catherine Racowsky, Professor, Department of Obstetrics, Gynecology & Reproductive Biology, Harvard Medical School; Director, IVF Laboratory, Brigham & Women’s Hospital

The Curious Case of Fresh versus Frozen Transfer
Denny Sakkas, Ph.D., Scientific Director, Boston IVF

Why Does IVF Fail? Finding a Single Euploid Embryo is Harder than You Think
Jamie Grifo, M.D., Ph.D., Program Director, New York University Fertility Center; Professor, New York University Langone Medical Center

BEST PRACTICES AND ETHICS

Genetic Counseling Bridges the Gap between Complex Genetic Information and Patient Care
MaryAnn W. Campion, Ed.D., MS, CGC; Director, Master’s Program in Genetic Counseling; Assistant Dean, Graduate Medical Sciences; Assistant Professor, Obstetrics and Gynecology, Boston University School of Medicine

Ethical Issues of Next-Generation Sequencing and Beyond
Eugene Pergament, M.D., Ph.D., FACMG, Professor, Obstetrics and Gynecology, Northwestern; Attending, Northwestern University Medical School Memorial Hospital

Closing Panel: The Future of Reproductive Genetic Diagnostics: Is Reproductive Technology Straining the Seams of Ethics?
Moderator:
Mache Seibel, M.D., Professor, OB/GYN, University of Massachusetts Medical School; Editor, My Menopause Magazine; Author, The Estrogen Window
Panelists:
Rebekah S. Zimmerman, Ph.D., FACMG, Director, Clinical Genetics, Foundation for Embryonic Competence
Denny Sakkas, Ph.D., Scientific Director, Boston IVF
Michael A. Lee, MS, TS, ELD (ABB), Director of Laboratories, Fertility Solutions
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Icelandic Population Genomic Study Results by deCODE Genetics come to Fruition: Curation of Current genomic studies

Reporter/Curator: Stephen J. Williams, Ph.D.

 

UPDATED on 9/6/2017

On 9/6/2017, Aviva Lev-Ari, PhD, RN had attend a talk by Paul Nioi, PhD, Amgen, at HMS, Harvard BioTechnology Club (GSAS).

Nioi discussed his 2016 paper in NEJM, 2016, 374:2131-2141

Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

Paul Nioi, Ph.D., Asgeir Sigurdsson, B.Sc., Gudmar Thorleifsson, Ph.D., Hannes Helgason, Ph.D., Arna B. Agustsdottir, B.Sc., Gudmundur L. Norddahl, Ph.D., Anna Helgadottir, M.D., Audur Magnusdottir, Ph.D., Aslaug Jonasdottir, M.Sc., Solveig Gretarsdottir, Ph.D., Ingileif Jonsdottir, Ph.D., Valgerdur Steinthorsdottir, Ph.D., Thorunn Rafnar, Ph.D., Dorine W. Swinkels, M.D., Ph.D., Tessel E. Galesloot, Ph.D., Niels Grarup, Ph.D., Torben Jørgensen, D.M.Sc., Henrik Vestergaard, D.M.Sc., Torben Hansen, Ph.D., Torsten Lauritzen, D.M.Sc., Allan Linneberg, Ph.D., Nele Friedrich, Ph.D., Nikolaj T. Krarup, Ph.D., Mogens Fenger, Ph.D., Ulrik Abildgaard, D.M.Sc., Peter R. Hansen, D.M.Sc., Anders M. Galløe, Ph.D., Peter S. Braund, Ph.D., Christopher P. Nelson, Ph.D., Alistair S. Hall, F.R.C.P., Michael J.A. Williams, M.D., Andre M. van Rij, M.D., Gregory T. Jones, Ph.D., Riyaz S. Patel, M.D., Allan I. Levey, M.D., Ph.D., Salim Hayek, M.D., Svati H. Shah, M.D., Muredach Reilly, M.B., B.Ch., Gudmundur I. Eyjolfsson, M.D., Olof Sigurdardottir, M.D., Ph.D., Isleifur Olafsson, M.D., Ph.D., Lambertus A. Kiemeney, Ph.D., Arshed A. Quyyumi, F.R.C.P., Daniel J. Rader, M.D., William E. Kraus, M.D., Nilesh J. Samani, F.R.C.P., Oluf Pedersen, D.M.Sc., Gudmundur Thorgeirsson, M.D., Ph.D., Gisli Masson, Ph.D., Hilma Holm, M.D., Daniel Gudbjartsson, Ph.D., Patrick Sulem, M.D., Unnur Thorsteinsdottir, Ph.D., and Kari Stefansson, M.D., Ph.D.

N Engl J Med 2016; 374:2131-2141June 2, 2016DOI: 10.1056/NEJMoa1508419

Abstract
Article
References
Citing Articles (22)
Metrics

BACKGROUND

Several sequence variants are known to have effects on serum levels of non–high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease.

METHODS

We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability.

RESULTS

We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10−16), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10−6). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10−3).

CONCLUSIONS

ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.)

 

Amgen’s deCODE Genetics Publishes Largest Human Genome Population Study to Date

Mark Terry, BioSpace.com Breaking News Staff reported on results of one of the largest genome sequencing efforts to date, sequencing of the genomes of 2,636 people from Iceland by deCODE genetics, Inc., a division of Thousand Oaks, Calif.-based Amgen (AMGN).

Amgen had bought deCODE genetics Inc. in 2012, saving the company from bankruptcy.

There were a total of four studies, published on March 25, 2015 on the online version of Nature Genetics; titled “Large-scale whole-genome sequencing of the Icelandic population[1],” “Identification of a large set of rare complete human knockouts[2],” “The Y-chromosome point mutation rate in humans[3]” and “Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease[4].”

The project identified some new genetic variants which increase risk of Alzheimer’s disease and confirmed some variants known to increase risk of diabetes and atrial fibrillation. A more in-depth post will curate these findings but there was an interesting discrete geographic distribution of certain rare variants located around Iceland. The dataset offers a treasure trove of meaningful genetic information not only about the Icelandic population but offers numerous new targets for breast, ovarian cancer as well as Alzheimer’s disease.

View Mark Terry’s article here on Biospace.com.

“This work is a demonstration of the unique power sequencing gives us for learning more about the history of our species,” said Kari Stefansson, founder and chief executive officer of deCode and one of the lead authors in a statement, “and for contributing to new means of diagnosing, treating and preventing disease.”

The scale and ambition of the study is impressive, but perhaps more important, the research identified a new genetic variant that increases the risk of Alzheimer’s disease and already had identified an APP variant that is associated with decreased risk of Alzheimer’s Disease. It also confirmed variants that increase the risk of diabetes and a variant that results in atrial fibrillation.
The database of human genetic variation (dbSNP) contained over 50 million unique sequence variants yet this database only represents a small proportion of single nucleotide variants which is thought to exist. These “private” or rare variants undoubtedly contribute to important phenotypes, such as disease susceptibility. Non-SNV variants, like indels and structural variants, are also under-represented in public databases. The only way to fully elucidate the genetic basis of a trait is to consider all of these types of variants, and the only way to find them is by large-scale sequencing.

Curation of Population Genomic Sequencing Programs/Corporate Partnerships

Click on “Curation of genomic studies” below for full Table

Curation of genomic studies
Study Partners Population Enrolled Disease areas Analysis
Icelandic Genome

Project

deCODE/Amgen Icelandic 2,636 Variants related to: Alzheimer’s, cardiovascular, diabetes WES + EMR; blood samples
Genome Sequencing Study Geisinger Health System/Regeneron Northeast PA, USA 100,000 Variants related to hypercholestemia, autism, obesity, other diseases WES +EMR +MyCode;

– Blood samples

The 100,000 Genomes Project National Health Service/NHS Genome Centers/ 10 companies forming Gene Consortium including Abbvie, Alexion, AstraZeneca, Biogen, Dimension, GSK, Helomics, Roche,   Takeda, UCB Rare disorders population UK Starting to recruit 100,000 Initially rare diseases, cancer, infectious diseases WES of blood, saliva and tissue samples

Ref paper

Saudi Human Genome Program 7 centers across Saudi Arabia in conjunction with King Abdulaziz City Science & Tech., King Faisal Hospital & Research Centre/Life Technologies General population Saudi Arabia 20,000 genomes over three years First focus on rare severe early onset diseases: diabetes, deafness, cardiovascular, skeletal deformation Whole genome sequence blood samples + EMR
Genome of the Netherlands (GoNL) Consortium consortium of the UMCG,LUMCErasmus MCVU university and UMCU. Samples where contributed by LifeLinesThe Leiden Longevity StudyThe Netherlands Twin Registry (NTR), The Rotterdam studies, and The Genetic Research in Isolated Populations program. All the sequencing work is done by BGI Hong Kong. Families in Netherlands 769 Variants, SNV, indels, deletions from apparently healthy individuals, family trios Whole genome NGS of whole blood no EMR

Ref paper in Nat. Genetics

Ref paper describing project

Faroese FarGen project Privately funded Faroe Islands Faroese population 50,000 Small population allows for family analysis Combine NGS with EMR and genealogy reports
Personal Genome Project Canada $4000.00 fee from participants; collaboration with University of Toronto and SickKids Organization; technical assistance with Harvard Canadian Health System Goal: 100,000 ? just started no defined analysis goals yet Whole exome and medical records
Singapore Sequencing Malay Project (SSMP) Singapore Genome Variation Project

Singapore Pharmacogenomics Project

Malaysian 100 healthy Malays from Singapore Pop. Health Study Variant analysis Deep whole genome sequencing
GenomeDenmark four Danish universities (KU, AU, DTU and AAU), two hospitals (Herlev and Vendsyssel) and two private firms (Bavarian Nordic and BGI-Europe). 150 complete genomes; first 30 published in Nature Comm. ? See link
Neuromics Consortium University of Tübingen and 18 academic and industrial partners (see link for description) European and Australian 1,100 patients with neuro-

degenerative and neuro-

muscular disease

Moved from SNP to whole exome analysis Whole Exome, RNASeq

References

  1. Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, Besenbacher S, Magnusson G, Halldorsson BV, Hjartarson E et al: Large-scale whole-genome sequencing of the Icelandic population. Nature genetics 2015, advance online publication.
  2. Sulem P, Helgason H, Oddson A, Stefansson H, Gudjonsson SA, Zink F, Hjartarson E, Sigurdsson GT, Jonasdottir A, Jonasdottir A et al: Identification of a large set of rare complete human knockouts. Nature genetics 2015, advance online publication.
  3. Helgason A, Einarsson AW, Gumundsdottir VB, Sigursson A, Gunnarsdottir ED, Jagadeesan A, Ebenesersdottir SS, Kong A, Stefansson K: The Y-chromosome point mutation rate in humans. Nature genetics 2015, advance online publication.
  4. Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, Sulem P, Magnusson OT, Gudjonsson SA, Unnsteinsdottir U et al: Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nature genetics 2015, advance online publication.

Other post related to DECODE, population genomics, and NGS on this site include:

Illumina Says 228,000 Human Genomes Will Be Sequenced in 2014

CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics and Computational Genomics – Part IIB

Human genome: UK to become world number 1 in DNA testing

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

Sequencing the exomes of 1,100 patients with neurodegenerative and neuromuscular diseases: A consortium of 18 European and Australian institutions

University of California Santa Cruz’s Genomics Institute will create a Map of Human Genetic Variations

Three Ancestral Populations Contributed to Modern-day Europeans: Ancient Genome Analysis

Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations

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