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NGS Leaders Blog

The CLARITY Challenge for Genome Interpretation

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clarity challengeJanuary 10, 2012 

Kevin Davies :Researchers at Children’s Hospital in Boston have launched the CLARITY Challenge - a $25,000 competition intended to set and advance standards for clinical genomic analysis and interpretation.

CLARITY stands for Children’s Leadership Award for the Reliable Interpretation and appropriate Transmission of Your genomic information. While the much publicized Archon X PRIZE presented by Medco will offer $10 million in prize money for essentially reaching the $1,000 genome early next year, the CLARITY contest focuses squarely on best practices in clinical genome interpretation and data delivery. The winning team will receive a $25,000 prize underwritten by Children's Hospital

The competition is open to academic and commercial researchers worldwide, with applications due no later than March 1, 2012. For logistical reasons, a maximum of 20 teams will be selected to participate in the competition. The winner of the competition, chosen by a panel of seven judges, will be announced in October 2012.

Industry partners include Life Technologies, which raised the prospect of a $1,000 genome in 2013 with the unveiling of its Ion Proton sequencer last week, and Complete Genomics.

“With the swift decline in the cost of sequencing, the time is rapidly approaching when genomic information will leap from the research bench to the doctor’s office and become a part of everyday care,” said Isaac Kohane, director of Children’s Hospital Boston’s informatics program and one of three competition co-organizers.

Coming Together   

Kohane told Bio-IT World that the idea for launching the contest emerged from the success his group enjoyed in running challenges for i2b2 (informatics for integrating biology & the bedside), focused on making data widely available. “The competitive aspect was nice, adds some spice, but [more importantly] it catalyzes teams coming together. I think that there’s a certain social process around these competitions, creating teams for a purpose that otherwise didn’t exist.”

In addition to helping the patients and their families, Kohane hopes to identify and bring together the best elements of competing pipelines, as he expects that there will be stronger and weaker components for each pipeline. “There’ll be one overall winner, but separate and transparent grading of different components of the pipelines.”

“Clearly, we’re going to need teams” to tackle the challenges of clinical genome interpretation, he says. “One of my favorite publications in 2011 was a paper in Nature Biotechnology from Mike Snyder and colleagues, in which they compared Complete Genomics sequence data to Illumina. They found that there was [only a] 93% concordance for single nucleotide polymorphisms (SNPs), which is terrible! And on copy number variants (CNVs), only 24% concordance. That tells me that every point in the pipeline -- from measurement to assembly to annotation, interpretation and generation of reports – all those points are, to be kind, open for improvement.”

The best way to stimulate “a public and transparent improvement of that pipeline” is to compare them side by side, he says, not only for the Consumer Reports-style value but also “to promote best practices in different pipelines, so they can be adopted and shared.”

Three pediatric patients at the Manton Center have been selected, including two with neuromuscular disorders. In each case, doctors strongly suspect a genetic basis for the childrens’ conditions, but “despite the best efforts of clinical geneticists at several sites, the genetic lesion has yet to be identified,” says Kohane.

Manton Center director Alan Beggs recruited the three families taking part. “Their response ranged from enthusiastic and very excited to cautiously optimistic,” says Kohane. Getting IRB approval from Children’s Hospital was tough, he says, in part because of the data sharing requirements.

Each patient and their parents will be sequenced. Life Technologies will sequence the exomes of each volunteer, while Complete Genomics will do whole genome sequencing.

“The project underscores Complete Genomics’ commitment to, and the industry’s path towards, using high quality, accurate genomic information from whole-genome sequencing (WGS) to improve patient care,” said Complete Genomics CEO Clifford Reid. “Through this CLARITY Challenge, we anticipate the discovery of the genetic basis of the children’s unknown disorders and also the creation of best practices for interpreting and presenting actionable results to physicians, patients and their families.”

Judge and Jury 

The seven judges were chosen for their expertise in different parts of the pipeline. They are: Russ Altman (Stanford), Elaine Lyon (ARUP Labs), Joseph Majzoub (Children’s Hospital), David McCallie Jr (Cerner Medical Informatics Institute), Peter Neupert (Microsoft Health Solutions Group), Peter Szolovits (MIT) and Hunt Willard (Duke University).

Among the questions they will be asking: Is the assembly done well? Are the annotations credible? Does the report look readable? Does it make clinical sense? “Not inconsequentially, for a medical director, can they understand the link between the report and the original data? For example, the details of a CNV algorithm are not always transparent to the clinical end user,” says Kohane.

Kohane praises the progress made by a handful of genomics groups in annotating medical genomes, including the work of the team at the Medical College of Wisconsin. “They all did a terrific job, heroic efforts – from the publications, it seems evident they’ve used lots of computation and inspiration and knowledge of the disease(s). What’s not clear is that the effort could be generalized, across a large number of diseases. We’ve seen panels of experts working hard to help one patient using everything they had, where much of it is in their head.”

Children’s Hospital staff note a number of potential pitfalls to be overcome by the contesting teams, including:

- Inconsistent or non-specific sequencing results and non-interoperable processes
- Conflicting gene variant annotations and classification
- A hodge-podge of non-standardized databases
- Lack of standards concerning individual privacy and data access
- Resulting reports that are not clear or useful to doctors, genetic counselors and patients

Full information about the CLARITY Challenge is available at: http://www.childrenshospital.org/CLARITY 

What Were the Best NGS Papers of 2011?

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 de novo genome assemblyJanuary 10, 2012 

Kevin Davies : 

In its blog, The Spittoon, 23andMe recently posted a Top Ten list of the consumer genomics firm’s favorite research papers of 2011 

Not surprisingly, the selections focus on the plethora of genome-wide association studies (GWAS) that still dominate many of the leading genetics journals. 23andMe’s top choice just happened to be one of its own papers, but I wouldn’t quibble with that decision too much.

Last summer in PLoS Genetics, 23andMe researchers published a paper mapping two novel risk genes for Parkinson’s disease by mining data on thousands of Parkinson’s sufferers among its 125,000 customers. The 23andMe strategy flips traditional GWAS on its head: rather than select thousands of individuals with a particular disorder and then perform a GWAS, 23andMe performs the genotyping first on its full database, and then stratifies by disease. It is groundbreaking science like this that serves as a swift rebuttal to those who insist on maligning the consumer genomics company as merely “recreational genomics."

What if we broaden the criteria slightly and consider papers focusing on NGS? Of the papers that stood out to me, several focused on the introduction of exome and genome sequencing and analysis in the clinic. Pride of place goes to the landmark report in Genetics in Medicine by Elizabeth Worthey, Howie Jacob and colleagues at the Medical College of Wisconsin in ending the diagnostic odyssey surrounding Nicholas Volker, a 7-year-old boy with a mysterious intestinal disorder who was successfully treated following the discovery of a rare genetic mutation. The peer review paper was formally published in 2011, a couple of months after a Pulitzer Prize-winning series of articles ran in the Milwaukee Journal Sentinel. 

Two papers in the Journal of the American Medical Association from the Washington University team led by Timothy Ley, Elaine Mardis and Richard Wilson illustrated the potential of whole-genome sequencing analysis in cancer patients. One revealed a cryptic fusion oncogene in a patient with acute promyelocytic leukemia with therapeutic implications; the other identified a novel p53 mutation in a patient with increased cancer susceptibility. 

Also of note was the sequencing of a pair of teenage twins with Dopa-responsive dystonia, by Matthew Bainbridge, Richard Gibbs and colleagues at the Baylor College of Medicine that pinpointed the causative gene mutation, and was published in Science Translational Medicine. 

From China, BGI published twenty NGS papers in 2011, including the genomes of the naked mole rat and the hybrid Escherichia coli strain responsible for several fatalities in a food poisoning outbreak in Germany last summer.

So what were your favorite, most impressive NGS papers of 2011?

Call for Entries: The Sequence Squeeze Competition

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Editor’s Note: Richard Holland is chief business officer and co-founder of Eagle Genomics Ltd, a UK-based bioinformatics services company that is partnering with the Pistoia Alliance to administer the Sequence Squeeze competition. 

January 6, 2012

Richard Holland :
Capitalizing on next-generation sequencing requires as much attention to technology and computer science as life science. The biggest players in the life sciences have also realized that no one will get ahead by “going it alone.” Instead, they are working together pre-competitively to develop open solutions that will benefit the entire industry. The Pistoia Alliance has succeeded in building a unique coalition of industry players - the world’s top pharma companies, life science information, services, and technology suppliers, and academic researchers - to resolve common barriers to R&D innovation, such as the handling of “big data”.

An exciting example of a Pistoia Alliance-led project of particular interest to the NGS community is the Pistoia Alliance Sequence Squeeze Competition, which will award a $15,000 cash prize to the developer of the best new, open-source algorithm for compressing NGS data.

Currently available compression technologies, which enable labs to store data from sequencing runs, are faltering under the data volumes produced by NGS. Pistoia Alliance members recognize that compression solutions may well come from computer scientists or mathematicians - hence the Alliance’s willingness to put forward a generous monetary incentive to encourage anyone to develop a better algorithm.

The judging panel further highlights the importance of this issue to the sequencing community: BGI, the Broad Institute, and the Wellcome Trust Sanger Institute have all put forward staff to judge the competition.

The competition is open to ANYONE, because it recognizes that life scientists may not necessarily have the expertise to resolve this “big data” problem. The answer may lie in statistics, mathematics, computer science, physics, or other non-biological disciplines, so the Alliance is spreading the word as widely as possible in order to encourage entries from previously untapped sources.

Entries can be submitted via the contest website at http://www.sequencesqueeze.org, which also contains details of the functional requirements for entries and some sample code to use as a starting point. Judging of entries takes place within the Amazon EC2 cloud and so we require entries to be submitted using Amazon's S3 file system.

As an incentive to have a go and enter the contest, Amazon is generously offering the first 40 entrants a $20 voucher for use with their cloud services. The competition closes to new entries at 5:00 pm GMT on March 15, 2012. Winners will be announced at the Pistoia Alliance Conference in Boston on April 24, 2012 (held in conjunction with this year’s Bio-IT World Conference & Expo).

The Sequence Squeeze Competition is just one of the projects the Pistoia Alliance is sponsoring. We also have an active effort underway to develop shared cloud services for storing and analyzing NGS data, which we call Sequence Services. The Alliance website at http://www.pistoiaalliance.org has full details of this and other ongoing projects.

I-Study: Genomic Interpretation - Who Will Pay?
During this webinar, members of the study review team present preliminary findings of the I-Study, conducted at the Harvard Medical School's 2011 Personalized Medicine Conference.
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