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•WORK FOR EVERYONE•GENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSGENOMICSMAKING

THE QUARTERLY eBOOK OF BIO-IT WORLD’S MOST TRENDING ARTICLES

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MAKING GENOMICS WORK FOR EVERYONE

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The Quarterly eBook of Bio-IT World’s Most Trending Articles

Note from Allison Proffitt

Seven Bridges Unveils Cancer Genomics Cloud, Takes on Private Funding

Illumina Spinoff GRAIL to Trial Liquid Biopsies for Early Detection of Cancer

Citizen Sequencers: Taking Oxford Nanopore’s MinION to the Classroom and Beyond

Speed Heals: The 26-Hour Diagnostic Genome

HudsonAlpha, Kailos Ge-netics, & a Plan for Popula-tion-Wide BRCA Screening

PrecisionFDA to Test Accuracy of Genomic Analysis Tools

Yaron Turpaz on Human Longevity’s Big Plans

What Comes Next for Direct-to-Consumer Genetics?

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Allison ProffittWhat if a child with a mysterious rare disease could have her whole genome sequenced, and a diagnosis found, in a single day? What if our health records were stored alongside our ge-nomes, with a battery of lab and clinical test results, to create complete medical avatars? What if we could all sequence DNA ourselves, on the go and with a minimum of training? These vi-sions may be closer than you think. Over the past year, Bio-IT World has covered a remarkable array of ambitious projects from private companies, government, and individual researchers, to ex-tend the benefits of genomics as widely as pos-sible. These stories were some of our favorites.

Allison ProffittEditorial Director, Bio-IT World and Clinical Informatics News


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This morning, Seven Bridges Genomics announced the opening of its Cancer Genomics Cloud, an online platform for accessing and analyzing public data from The Cancer Genome Atlas (TCGA). The release comes fifteen months after Seven Bridges was chosen by the National Cancer Institute (NCI) as one of three developers of these pilot clouds, which are intended to make the vast tumor sequencing data in

SEVEN BRIDGES UNVEILS

CANCER GENOMICS CLOUD, TAKES ON PRIVATE FUNDING

BY AARON KROL | FEBRUARY 16, 2016


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http://www.bio-itworld.com/2014/11/3/nci-awards-contracts-cancer-genomics-cloud-pilots.html



TCGA easier for scientists to ac-cess, without downloading reams of raw data or writing their own scripts to search through the Atlas.

“The TCGA project has lasted over a decade,” says Andrew Gruen, Product Marketing Di-rector at Seven Bridges. “It’s a massive investment, with 11,000 patients and 33 different tumor types and subtypes. Making it usable, and efficiently usable, has been a high priority [for the NCI].”

Seven Bridges is a creator of cloud environments for managing genomic data at an industrial scale, primarily for pharma companies and large research collaborations. Its customers include Genomics England, a state-owned compa-ny working to sequence 100,000 whole human genomes within the UK’s National Health Service. Nev-ertheless, the scale of TCGA, which contains over a petabyte of data, made building the Cancer Genom-ics Cloud a major endeavor.

Brandi Davis-Dusenbery, Senior Scientist at Seven Bridges, led the project, collaborating regularly with representatives from the NCI. The platform can be accessed at www.cancergenomicscloud.org.

The Cancer Genomics Cloud is similar to Seven Bridges’ standard commercial product, in which popular open source informatics tools―including BWA, the GATK suite, and the Tuxedo suite―can be arranged into reproducible pipelines for custom analysis of sequencing reads. Users can also place their

own tools in these pipelines and transfer them across projects.

“Someone who’s used the Seven Bridges Platform in the past will find it very familiar, but there are a number of cancer-specific tools, especially on the visualization side,” says James Sietstra, President of Seven Bridges. His company has previously unveiled specialized tools for cancer analysis that take into account known onco-genic variants, tumor-normal com-parisons, and pharmacogenetics.

Seven Bridges also worked with the NCI to create a metadata schema in which genomic data from TCGA is labeled with detailed clinical informa-tion, such as the type of tumor that was sequenced, and the patient’s demographics and treatment his-tory. With this system, users of the Cancer Genomics Cloud can search the entire TCGA database for tumors that meet highly specific criteria, something that has been difficult and time-consuming for research-ers working directly with TCGA.

“We’ve allowed you to create really detailed queries visually,” says Gruen. “You can very easily define the cohort of folks you’re looking for in your experiment.”

The NCI had other requirements for its partners on the Cancer Ge-nomics Cloud pilots, including that all TCGA data be co-located with the analysis platforms, to minimize bottlenecks associated with trans-ferring data. Seven Bridges, whose commercial platform can be deployed in either the Amazon or Google clouds, worked with Amazon Web Services to meet these requirements within a virtual private cloud. Users can also upload their own data to analyze alongside TCGA data.

While the Seven Bridges Cancer Genomics Cloud is the first pilot to go live, the Broad Institute of MIT and Harvard and the Institute for Systems Biology in Seattle are actively working on their own solutions for expand-ing access to TCGA data. All three organizations have worked together on containers to transfer custom informatics tools across systems, so that users will be able to recreate their pipelines inside each platform.

The NCI has earmarked $1 million to pay for the use of Amazon Web Services compute time inside the Cancer Genomics Cloud, a portion of which can be claimed by any scientist with plans to conduct studies using

“The TCGA project has lasted over a decade. It’s a massive investment, with 11,000 patients and 33 different tumor types and subtypes”

— Andrew Gruen, Product Marketing Director at Seven Bridges


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TCGA data. Additional credits will be made available to groups who upload their own data or analy-sis tools, with no responsibility to make those resources public. “Any researcher with an Internet connection, including the small academic lab that potentially can’t afford to store TCGA on their local cluster, can access public data at the click of a mouse through the Cancer Genomics Cloud,” says Sietstra.

At the same time the Cancer Genomics Cloud is going live, Sev-en Bridges has also announced the completion of a Series A funding round totaling $45 mil-lion, led by Kryssen Capital.

For a biotechnology firm, Seven Bridges has waited a remarkably long time to bring in private funding. The company was founded by CEO Deniz Kural in 2009, and now has 200 em-ployees across four offices in Cam-bridge, Mass.; San Francisco, Calif.; London; and Belgrade, Serbia. Until now, Seven Bridges has relied for its operating expenses on revenue from its platform, and occasional grants from government partners―such as a

$6 million commitment from the NCI for the Cancer Genomics Cloud pilot.

“We took the long view with Sev-en Bridges,” says Sietstra. “Before taking on institutional capital, we really wanted to build the compa-ny into something long-term and stable, and that takes a while.”

Sietstra says the new funding will go toward hiring additional engi-neers, and ongoing development of the core Seven Bridges Platform.

“Any researcher with an Internet connection... can access public data at the click of a mouse through the Cancer Genomics Cloud”

— James Sietstra, President of Seven Bridges

Queries in the Cancer Genomics Cloud can be defined using over 140 clinical and biospecimen properties. Image: Seven Bridges Genomics


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ILLUMINA SPINOFF

GRAIL TO TRIAL LIQUID BIOPSIES FOR EARLY DETECTION OF CANCER

BY AARON KROL | JANUARY 11, 2016

Illumina, the dominant manufactur-er of DNA sequencing technology, has formed a spinoff company called GRAIL to experiment with a simple blood test for early de-tection of all types of cancer.

Illumina, whose instruments ac-counted for more than 90% of all DNA data collected worldwide in 2014, already has its fingers in many of the most lucrative medical uses of genomics. The company’s line of verifi tests, acquired with Verinata Health in 2013, tap into the fast-grow-ing market for non-invasive prenatal tests, which detect fetal disorders

through a blood draw from the preg-nant mother. A collaboration with several large pharma companies has also produced a panel test called TruSight Tumor 15, which searches for mutations that could present new treatment options in cancer cases.

GRAIL, however, will be the first independent business Illumina has created to pursue a still-nascent clinical program. Its goal, said Illumi-na’s former CMO Richard Klausner, now an executive at GRAIL, on a conference call yesterday, will be to develop “a universal, direct measure of cancer,” far more accurate than 250 First Avenue, Suite 300

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proxy tests like mammograms or PSA tests for prostate cancer.

The technology involved is liquid biopsy, in which DNA and RNA molecules shed by tumors are picked up circulating freely in the bloodstream. By extremely deep sequencing, or by isolating tumor nucleic acids from other genetic materials in the blood, researchers in both academia and private indus-try have shown it is possible to find telltale signatures of cancer in simple blood draws. Companies including QIAGEN, RainDance, and Genomic Health are all working to commer-cialize liquid biopsies as alternatives to more invasive cancer testing.

None, however, have demonstrated that liquid biopsies can accurately predict the emergence of malig-nant cancer at an early stage.

GRAIL will have access to enormous resources to experiment with liquid biopsy as a preventative test in stage one and two cancers. The company has raised more than $100 million at launch from ARCH Venture Part-ners, Bezos Expeditions, Sutter Hill Ventures, and Illumina itself, which remains the majority owner. GRAIL may also find it cheaper to do ul-tra-high-throughput sequencing than other companies in the liquid biopsy space, virtually all of which buy their instruments and reagents from Illu-mina―and given the multi-billion-dol-lar opportunity for an early stage pan-cancer test, and the clout that comes from its Illumina ties, GRAIL will likely have little trouble raising new rounds of funding if necessary.

The bar for releasing a test of this nature, however, is daunting. Early testing of any kind is more likely to

pick up benign cancers, never des-tined to cause health problems, than young malignant tumors that demand prompt treatment. For GRAIL’s liquid biopsy to benefit patients, the com-pany would need to uncover genetic markers that can distinguish harmful cancers from benign ones with exqui-site specificity―and find these mark-ers in datasets where tumor DNA may represent as little as one out of every 100,000 sequencing reads.

To demonstrate the accuracy of such a test, GRAIL will need to mount clinical trials on a scale normally reserved only for post-market studies of ultra-common medications like statins or aspirin. In the conference call announcing the launch of GRAIL, José Baselga, the current President of the American Association for Cancer Research, Physician-in-Chief at Me-morial Sloan Kettering Cancer Center, and now Chair of GRAIL’s Advisory Board, said that the company plans to launch an “unprecedented, large population-based study” in which hundreds of thousands of healthy patients may be enrolled. Each participant would be regularly tested with GRAIL’s technology over a period of months or years, until enough had developed cancer to gauge the test’s real-world specificity and sensitivity.

This massive trial is likely the only form of study that could satisfy the FDA that an early pan-cancer test is accurate and safe. As Illumina CEO Jay Flatley acknowledged, a liquid biopsy of this nature will

need to have an “extraordinari-ly low false positive rate.”

That’s something Illumina itself has struggled with, as some researchers have raised concerns about false positives in non-invasive prenatal tests like verifi. These tests, like liquid biopsies for cancer, seek out signals from low-abundance free-floating DNA in the blood; their specificity has not been assessed in formal clinical trials in the U.S., because they are sold as non-diagnostic screening tests through a non-FDA-regulat-ed laboratory testing structure.

Illumina has worked successfully with the FDA in the past, winning a historic clearance in 2013 for its MiSeqDx sequencer and associat-ed tests for rare genetic disease. However, the FDA did not demand a prospective clinical trial for that instrument. More recently, Illumina has begun co-sponsoring clinical studies with Memorial Sloan Ketter-ing for liquid biopsies in breast and lung cancers, but these studies are still in very early stages. They will now be merged into GRAIL’s larger effort.

GRAIL will spend the duration of 2016 choosing a panel of genetic markers that the company feels have the best chance of identifying malignant cancers early. “There is no more powerful vision for reduc-ing cancer mortality around the globe than early detection,” said Klausner on the conference call.

The company hopes to be-gin clinical trials in 2017.

The company plans to launch an “un-precedented, large population-based study”

— José Baselga, Chair of GRAIL’s Advisory Board


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CITIZEN SEQUENCERS: TAKING OXFORD NANOPORE’S MINION TO THE CLASSROOM AND BEYOND

In February 2005, Karen James was attending the first International Barcode of Life Conference at the Natural History Museum in London. The meeting had convened to spread the word about DNA barcoding, a novel idea at the time, which would let scientists quickly identify species of plants and animals from small pieces of biological material―a leaf clipping, a scat sample, a strand of hair.

Speaking at the conference was Dan Janzen, a specialist in species con-servation in Costa Rica, who had an eccentric vision for how his field work would be done in ten or twenty years’ time. “[He] posted a Photoshopped picture of a flip phone―that’s all we had back then―cobbled together

BY AARON KROL | DECEMBER 9, 2015


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with Sanger sequencing data from a photo on the Internet,” James remembers. “And he said, ‘One day we’ll have a DNA sequencer in our pocket.’ A lot of people laughed.”

Last week at the New York Ge-nome Center, James retold that story at the first MinION Community Meeting, held about a year and a half after the first pocketsize MinION sequencers were shipped through the mail to scientists around the world. There are now hundreds of these se-quencers in circulation, manufactured by Oxford Nanopore Technologies in the U.K.; plugged into a laptop’s USB port, they can read the whole genome of a virus in a matter of hours.

It’s not quite field sequencing, James says, but “it brings us closer to being able to imagine what that would look like.” At the community meeting, Oxford Nanopore showed off prototypes of a device called the VolTRAX, around the size of a very thick credit card, which automatical-ly prepares DNA samples to be fed into the MinION. “You can imagine a MinION attached to a VolTRAX, attached to a smartphone, pow-ered by maybe the phone’s battery or an external battery case,” says James. “That would be the device.”

In her own work, based at the Mount Desert Island Biological Laboratory next door to Acadia National Park in Maine, James has found the MinION so simple to use that she’s trained high school students to run experiments on it during summer courses. And the sequencer is so inexpensive that it’s reshaping her plans for a larger program in Aca-dia, where she hopes to recruit

thousands of visitors to the national park to collect biological samples. Sequencing these samples as they come in, James could soon enlist her volunteers to help track which species are coming to the park, how healthy their populations are, and whether their seasonal patterns of movement are changing―especial-ly as climate change disrupts the natural rhythms of the Maine coast.

“It does change the sorts of ques-tions I can ask,” she says. “I can imagine asking my citizen science collaborators to collect a water sam-ple, or reach down from their kayak and get some sediment from an eel-grass bed, and using the MinION to sequence that cheaply and quickly.”

Users like James are helping Oxford Nanopore reach audiences who could never before have had such direct encounters with the science of DNA. That’s not just exciting; it’s also a unique business opportu-nity for Oxford, the first sequenc-ing company that can realistically look at colleges, high schools, and community labs as potential cus-tomers. With James’ help, the com-pany is starting to test the waters for the MinION in education.

COMMUNITY INPUTAt the New York Genome Center, while other members of the MinION

Community were showing off projects from the Sierra Leone Ebola outbreak and the International Space Station, James was presenting the first trickle of results from a survey she’d an-nounced a few days earlier on Twitter.

James and Oxford Nanopore want to know how educators might use the MinION in their classrooms and community projects, and what kinds of equipment and support they would need. A few dozen people have already replied to the survey: mainly teachers in universities and high schools, but also a smattering of “biohackers” and interested amateurs from outside the academy. James hopes to eventually collect at least 150 responses, enough to get a feel for the applications where Oxford Nanopore could offer a first port of entry into the practice of genetics.

“The thing I’m most excited about is just getting DNA sequencing into the hands of more learners,” she says. “I want more high school students and college students and citizen scien-tists to have an experience of DNA se-quencing that helps them to learn and understand it. It’s going to continue to be an increasing aspect of their lives.”

A handful of institutions, includ-ing the New York Genome Center in partnership with Columbia University, are already figuring out how to offer training on the MinION in a classroom setting. While the laboratory proce-

“I want more high school students and college students and citizen scientists to have an experience of DNA sequencing.”

— Karen James, Mount Desert Island Biological Laboratory in Maine


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dures connected to the MinION are simpler than with other sequencers, students still need instruction on isolating DNA from cells, shearing it, and treating it with enzymes that help control the flow of DNA through the instrument’s sensors. For students without experience working in labs, that might not be straightforward.

Then there’s the backend pro-cess of dealing with genetic data. If the aim of bringing the MinION into classrooms is to familiarize students with the ways genetics touches their lives, the long strings of DNA letters produced by Oxford Nanopore’s core software are far too abstract to have much value.

The company is just now piloting more approachable tools that place DNA data in a real-world context. This November, it released a pro-gram called What’s in my Pot?, or WIMP, that matches DNA sequences to known strains of bacteria and other microbes. Students could use programs like WIMP to explore the complex microbial ecosys-tems living in soil, water, or even their own bodies. (See, “Oxford Nanopore’s Software Side.”)

“I wouldn’t be interested in an educational program that operates like a black box, where people are just producing data and aren’t get-ting anything out of it,” says James. For her own projects in Acadia, for instance, she would much prefer if volunteers could go online and follow the samples they collect in the park all the way to species matches, giving them a tangible stake in the pro-gram’s results. And even the scien-

tists coordinating a project like this will need more user-friendly software, to understand the growing amounts of DNA data they might soon be collecting with help from the public.

“WIMP, or something like WIMP, is essential to being able to do large-scale citizen science assist-ed by MinION sequencing,” James says. “You need to be able to get a rapid answer without spending hours and hours gazing at your data, trying to understand it.”

MOVING MINIONSFor the time being, educational projects with the MinION are most-ly restricted to things like James’ summer courses, engaging a handful of students at a time. But Oxford Nanopore is looking into ways it can support a much larger number of ed-ucators and amateur biologists who see in the MinION their first oppor-tunity to work hands-on with DNA.

Most of these users won’t have the resources of Columbia University and the New York Genome Center. While the MinION is an order of magnitude less expensive than any other sequencer on the market, it’s still a pricy piece of equipment for a high school science department or community college―and a teacher might need five or ten to get a large number of students involved.

James says she’s discussed a few solutions with Oxford Nanopore to lower this barrier to entry, like writ-ing grants jointly with teachers, or creating a lending program that gets MinIONs into classrooms without

making schools buy them outright. Oxford Nanopore could also try connecting teachers with crowdfund-ing; the organization DonorsChoose, for instance, lets donors chip in to buy educational materials for public schools. Oxford Nanopore is also weighing whether classrooms might need a specialized kit alongside the MinION, with equipment that custom-ers in research labs take for granted.

To bring these ideas together, James is consulting with Oxford Nanopore on an online education portal. (She is reimbursed for her time working on the site.) In addition to gathering together any funding plans or special kits, the portal is expected to give early adopters a space to submit feedback, and share sample projects and lesson plans.

It’s a felicitous moment to think about the role of DNA sequencing in education. At a time when health-care providers are just beginning to consider genetics as a part of normal care, and companies like 23andMe and uBiome are trying to connect DNA information to people’s everyday lives, genetic literacy is becoming a relevant skill far outside the university lab.

“I think of this on a more general level of connecting people to sci-ence,” James says. “There’s a fair amount of research showing that hands-on experiences are more effective learning experiences. The alternative is that you’re in a class-room and you hear a lecture about DNA sequencing―that’s a lot less effective than spending an afternoon doing some DNA sequencing.”250 First Avenue, Suite 300


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SPEED HEALS:THE 26-HOUR DIAGNOSTIC GENOME

BY ALLISON PROFFITT | SEPTEMBER 29, 2015

Stephen Kingsmore and his colleagues at the Center for Pediatric Genomic Medicine at Children’s Mercy in Kansas City, announced 26-hour diagnostic whole genome sequencing in a paper published today in Genomic Medicine, an improvement over the 50-


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hour whole genome sequencing the group published in 2012.

The paper is published just one day after Kingsmore took his new post as President and CEO of the Rady Pediatric Genomics and Sys-tems Medicine Institute at Rady Children’s Hospital in San Diego.

The second generation STATseq pipeline comprises 18-hour whole genome sequencing on an Illumi-na HiSeq 2500 in rapid run mode; read mapping, alignment, and vari-ant calling with the Edico DRAGEN pipeline; and a trio of softwares for analysis: VIKING, RUNES, and SSAGA.

The 26-hour clock runs from blood sample to provisional diag-nosis. Of the four samples run with the new pipeline and published in the Genomic Medicine paper (DOI 10.1186/s13073-015-0221-8), the shortest total time was 26:08 and the longest two were 26:47.

Although the time has been cut in half, Kingsmore is particularly pleased with the increased sensi-tivity. The analytics sensitivity and specificity are both 99.5%. “That’s a significant improvement over the 2012 marks,” Kingsmore told Bio-IT World. “But also it’s actually a pretty significant improvement over what you might call the research standard of BWA-mem plus GATK. It really is a much more sensitive platform.”

In fact, Kingsmore added, “The new variants that we’re seeing tend to be rare, deleterious variants, so that the filtering mechanisms that were being employed with the standard pipeline tended to have a bias against delete-rious rare variants, which of course are the only thing you’re really inter-ested in if you’re doing diagnostics.”

Kingsmore and his former team at Children’s Mercy have been working closely with Illumina on the problem of quick and accurate diagnoses for babies in the NICU for years. The 50-hour pipeline was published in con-junction with Illumina’s team in Essex, UK, and the current work has been on-going since then. In fact, Kingsmore said he’s had data from the Essex team for, “well over a year,” though he wanted to wait to publish, “be-cause we felt it was important to be able to transfer the technology from Essex at Illumina’s own shop so that it actually worked in our hospital.”

The sequencing speed improve-ments—26 hours to 18—were done by “tweaking the recipe,” Kingsmore said. Cycles were run faster, which then required calibration of heating and cooling, and other specifics. First run by Illumina in Essex, Kingsmore said that the ultra-fast run wasn’t seamlessly transferrable to the

hospital setting. “We did have a lot of missteps initially in deploying that in Kansas City. We actually had to have some of the guys come over from Essex and spend a week in our lab working on things like ramp rates and heating and cooling and pump set-tings before we were happy with it.”

DRAGEN SPEEDThe most speed gains were made in alignment, variant detection, and genotyping. What took 15 hours in the first generation of the STATseq pipeline took Kingsmore’s team only 40 minutes with Edico’s DRA-GEN aligner and variant caller. Maximum analytic sensitivity was achieved by combining variant calls of both the DRAGEN pipeline and GSNAP/GATK 3.2-VQSR pipeline.

Kingsmore—much like Shawn Levy at HudsonAlpha—wasn’t lukewarm on Edico’s DRAGEN

The most speed gains were made in alignment, variant detection, and genotyping. Image: iStock


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pipeline; he twice used the word “solved” to describe its impact:

“DRAGEN technology solves one of the larger bottlenecks, which was up until now everybody has had to spend increasing money ei-ther on cloud compute or on super-computing,” Kingsmore said. “Now the major driver for that, which was alignment and variant calling—that problem has been solved.”

Both Kingsmore and Levy report that the DRAGEN pipeline takes about 40 minutes to process a genome. “Much to our surprise, DRAGEN not only gave us speed but it gave us improvements in analytic perfor-mance,” Kingsmore said. “That was something we had not expected. It was a nice bonus to have not only a faster result, but a better result.”

INTERPRETATION TOOLKITThe final step at Children’s Mercy might be the most challenging: coming up with a clinical diagnosis.

Three software tools developed by Neil Miller, Director of Informat-ics and Software Development at Children’s Mercy, were used in the pipeline. Slightly older (and slower by about 30 minutes) versions of SSAGA (Symptom and Sign Associ-ated Genome Analysis) and RUNES (Rapid Understanding of Nucleotide variant Effect Software) were al-ready part of the 50-hour pipeline.

The phenotypic analysis of a patient (or trio if possible) is done in parallel with the sequencing, Kingsmore said. While blood samples are progress-ing through DNA isolation, library prep, and sequencing, clinicians are teasing apart symptoms that may

have no relation to one another.“For some of the babies the clini-

cal picture is very, very simple. The babies has seizures and that’s it. But for other babies maybe have been in the unit for a while and they have a rather complex clinical picture. And you do need to read through the record and extract what’s relevant and meaningful. It is a bit subjective, because many of these babies have more than one thing going on… There is a little bit of an art there to know-ing whether you’re dealing with one thing or two concurrent diseases.”

SSAGA is a web-based software that help with that, providing a differential diagnosis from diseas-es listed in OMIM, Orphanet, and DECIPHER (Database of genomic variation and phenotype in humans using Ensembl Resources) based on Human Phenotype Ontology terms that a clinician enters for the patient.

RUNES identifies known dis-ease-causing variants and uses predictive tools to estimate variant consequence. RUNES then assigns a score that estimates how likely the variant is to be disease-causing.

Previously, the outputs of the two programs were compared via spreadsheet. But in the new 26-

hour pipeline, outputs from both programs feed into VIKING (vari-ant integration and knowledge interpretation in genomes). VIKING allows dynamic filtering of variants based on clinical features, disease genes, ACMG-type pathogenicity category, allele frequency, geno-type, and inheritance pattern.

The three-software package can, “automate much of the downstream analysis and interpretation, meaning that a single lab director can relatively rapidly interpret and report results. So much of the heavy lifting is done in terms of analysis and interpreta-tion,” said Kingsmore. “It’s not fully automated. But it’s at the point now where a lab director can make a diag-nosis anywhere from three seconds to three hours depending on how tricky and elusive that diagnosis is.”

Though proprietary to Children’s Mercy, RUNES, SSAGA, and VI-KING “are on a journey,” Kingsmore said. “By the end of the year, I’m hopeful that they will be available as freeware because the mission is to see this technology provided to kids all over the country. I know the Neil Miller and others are also talking about providing that on a software-as-a-service basis.”

“It is a bit subjective, because many of these babies have more than one thing going on… There is a little bit of an art there to knowing whether you’re dealing with one thing or two concurrent diseases.”

— Stephen Kingsmore, Center for Pediatric Genomic Medicine at Children’s Mercy in Kansas City


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But while Kingsmore calls the par-ticular softwares used in the pipeline “incredibly useful,” he praises anal-ysis software built by Liz Worthey at HudsonAlpha, Ingenuity’s Variant Analysis Suite, and NextCODE’s GOR system. “I think there are a number of commercial and noncommer-cial systems that are evolving.”

FDA AND VALIDATIONAll of the testing reported in the paper was research testing. The protocol hasn’t yet been validated for CLIA and CAP guidelines, though much of the software has been validated inde-pendently. Whether or not a diagnosis from the STATseq pipeline should undergo confirmatory testing will be up to the lab director, Kingsmore said.

The first generation pipeline was granted a “non-significant risk” status by FDA. “They said that where a delay in returning a result was life-threatening, they gave us NSR—non-significant risk status—for return of a provisional result to a neonatologist,” Kingsmore said.

He views the 26-hour test as the next generation of the original test, but regulatory waters are murky

right now for laboratory-developed tests. “[The 26-hour test] is a more accurate and sensitive test. It would seem to me that if they were will-ing to do it [i.e. grant NSR status] for a less-accurate and sensitive test it should be a no-brainer.”

CALIFORNIA CHAPTERHaving just completed the sec-ond generation pipeline, King-smore’s move to California was the logical next step to scaling the pipelines he’d worked to develop at Children’s Mercy, he said.

“Genetic diseases are the leading cause of death in infants, they’re the leading cause of death in the NICU, in the PICU. They’re respon-sible for 15% of pediatric hospital-izations. Across the nation we’re looking at literally hundreds of thousands of kids who could bene-fit from this technology,” he said.

And for the technology to ever reach those children, it needs to be not only quick, but scalable.

“A key ingredient for the break-through application of genomic medicine is speed at scale. In medi-cal practice, the value of information

is proportionate to its immediacy relative to the acuity of the clinical situation,” Kingsmore wrote in a Genome Medicine opinion in July (and from where this title is bor-rowed: Genome Medicine 2015, 7:82 doi:10.1186/s13073-015-0201-z)

Rady and San Diego are the perfect spot to facilitate this scaling, King-smore believes. The Institute was cre-ated in April 2014 with a $120 million gift from the Rady Family and a $40 million investment from Rady Chil-dren’s Hospital and is affiliated with the University of California San Diego. “[The hospital has] got all of the clinical stuff in place that you need to do something truly significant. And then we’ve got companies like Illumina and Edico Genomics right in our backyard!” Kingsmore adds.

Kingsmore is planning a close relationship between Rady and the team that has stayed in Kansas City. “The big Insight grant that we had that I won at Children’s Mercy is mov-ing with me to San Diego, and then we’re going to send half of it back to Children’s Mercy so we’ll be able to collaborate,” he said. He envisions Rady as being one of the earliest users of SSAGA, RUNES, and VIKING on a software-as-a-service model. “I think that’s one that will work well for many children’s hospitals,” he said.

Kingsmore is also working to set up a consortium of children’s hospitals nationwide to trans-form pediatric care using genom-ics. He hopes the first members will be announced this fall.

“Genetic diseases are the leading cause of death in infants... Across the nation we’re looking at literally hundreds of thousands of kids who could benefit from this technology.”

— Stephen Kingsmore, Center for Pediatric Genomic Medicine at Children’s Mercy in Kansas City


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HUDSONALPHA, KAILOS GENETICS, & A PLAN FOR POPULATION-WIDE BRCA SCREENING

BY ALLISON PROFFITT | SEPTEMBER 9, 2015

It’s one of her most consistent talking points. Mary-Claire King, the 2014 Lasker Award-winning scientist who discovered the BRCA1 gene implicated in breast can-cer, has issued several public challeng-es to make BRCA1 and BRCA2 testing available to all 30-year-old women.

Last October, King made her case at the HudsonAlpha Institute for Biotech-nology in Huntsville, Alabama, where she

spoke at the annual breast and ovarian cancer awareness event and fundraiser.

HudsonAlpha has accepted the challenge.Starting on October 30, 2015, every

30-year-old woman in Huntsville and Mad-ison County, Alabama, will be eligible for a free cancer screening panel thanks to the Information is Power initiative of the HudsonAlpha Institute. Kailos Genetics, a six-year-old diagnostics company that


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https://www.kailosgenetics.com/



spun out of HudsonAlpha and is still headquartered in the same building, is partnering with Hud-sonAlpha on the initiative and will conduct the testing using its 23-gene Women’s Health Panel.

Women who are 30 years old at any point between October 29, 2015 and October 28, 2016 and live in Madison County, Alabama, are eligible to participate. Individuals older than 17—male or female—and living in Madison, Morgan, Limestone, Marshall, or Jackson County, Ala-bama, qualify for a $99 discounted rate on the Women’s Health panel.

The initiative is a bold step forward for population-wide genetic testing. While King and others have called for such testing, some researchers and ethicists have warned that we are not yet ready to take that step.

Kimberly Strong, director of the Ethics and Genomics Program at HudsonAlpha and the faculty mem-ber leading the initiative, has heard the objections before. “I acknowl-edge that an initiative like this is not universally accepted as something that should be done at this moment in time,” she said. Currently, genetic testing for genes linked to breast and ovarian cancer is offered to individu-als who have already been diagnosed with cancer, or are from a family that is considered high risk. “But these types of testing scenarios do miss out on identifying some people who are unknowingly at increased risk,” Strong said. “Our initiative aims to conduct larger population-lev-el testing to raise awareness of genetic and traditional screening methods and identify additional

individuals at increased cancer risk who may not have had access to testing through other avenues.”

Identifying patients who are at in-creased risk will allow their healthcare providers to create a new screening plan, Strong said. “Genetic testing never takes the place of traditional screening, of mammograms and colo-noscopies,” she emphasized. “What it does do is give another piece of the puzzle as to what might be going on, what someone’s risk might be.”

But risk is a tricky thing to understand.

Matt Yurgelun, an oncologist at Dana-Farber Cancer Institute and Harvard Medical School, recently published an article in the Journal of Clinical Oncology (doi: 10.1200/JCO.2015.60.8596) warning of some of the risks associated with popu-lation-wide BRCA1/2 screening.

Yurgelun is not familiar with Hud-sonAlpha’s plan, and so declined to speak about the specifics, but he called population-wide screening projects “a very laudable idea.”

“It’s been a great talking point to get discussion about genetic medicine into the mainstream public discourse, finding ways to improve access to

genetic testing, and improve the public awareness of genetic testing,” Yurgelun said. “At the same time, there are aspects of genetic testing that need to be kept in mind when you go from using it in a high-risk setting, which is how it’s classically used now, to using it as a screening test for the general population.

Yurgelun and his coauthors high-lighted variants of unknown sig-nificance, genetic counseling, and discrimination as hazards on the way to population-wide screening.

“Population-based BRCA1/2 screen-ing would be intrinsically different from high-risk genetic testing in ways that will likely accentuate the limitations, particularly for minority women, while also reducing potential benefits,” the authors wrote. “Poten-tial effects of false-negative results, including the possibility of false reassurance that might lead some women to forego appropriate care, are of concern. Although profession-al genetic counseling can mitigate these risks, the volume generated by population-wide BRCA1/2 screen-ing would mandate that traditional informed consent and counseling models be completely overhauled.”

“Our initiative aims to conduct larger population-level testing to raise awareness of genetic and traditional screening methods and identify additional individuals at increased cancer risk”

— Kimberly Strong, director of the Ethics and Genomics Program at HudsonAlpha


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COUNSELING AT SCALEHudsonAlpha is taking the need for genetic counseling seriously, while exploring ways to do it at scale. Par-ticipants in the HudsonAlpha initiative will begin the process by visiting the Information is Power website and ordering a test kit (once the program launches on October 30). In order to proceed, people will watch a video outlining how genetic testing works and what it can—and can’t—tell you.

“We are trying to simulate some of the traditional things that occur, so that at the very least the topics that are discussed in a traditional genetic counseling process would be included in that pre-test video,” Strong said. “It will give a description of what a test can tell someone, and probably more importantly, what it can’t tell them. [A test is] not going to diagnose cancer, for instance. Even a positive result for one of these gene changes doesn’t equal cancer, and a negative result doesn’t mean one would never get cancer.”

The video will explore what one’s test results might mean for bio-logical family members and touch on GINA—the Genetic Information Nondiscrimination Act—highlighting that GINA does not provide protec-tion for life, disability, or long term care insurance. Each section of the video will be short—just a handful of minutes per topic, Strong said. She’s not sure how long the entire video will be when it’s completed.

Importantly, the Information is Power initiative is not a clinical or re-search study. There has been no IRB approval, and Strong and HudsonAl-pha are not collecting data on the par-ticipants or the process. While every-one who receives the test must check a box stating that they have watched the video to proceed, this isn’t clin-ical informed consent. Participants aren’t tested on their understanding, and while they can opt in to an email list for a possible future study, no such study is currently planned.

After watching the video, partic-ipants move forward with testing.

And at this point, the initiative shifts into Kailos’ domain.

A DISSATISFYING MODELKailos Genetics’ Women’s Health Panel screens for 23 genes associat-ed with breast, ovarian, uterine, colon, and pancreatic cancers, including BRCA1/2, PALB2, TP53, and more. For Kailos, the initiative launch will come just months after the com-pany started offering its genetic tests for sale online to patients.

The consumer-facing product marks the next step in an ongoing business model evolution, Troy Moore, Kailos’ Chief Scientific Offi-cer, told me during a visit to Kailos headquarters. The company’s founda-tional technology is the product of a HudsonAlpha Ph.D. student. It was li-censed into the company and offered first to research and academic labs, before the company morphed into a more traditional diagnostics com-pany business. But after just a few years, Moore said, Kailos was “some-what dissatisfied with that model.”

Late in 2014, the company de-cided to no longer offer testing for insurance reimbursement and instead focus on a consumer-direct-ed approach. “We would remain a CLIA-certified laboratory, work on our CAP certification, our New York certification, all that good stuff—still bring that level of testing—but allow consumers to order the tests from us directly,” Moore explained.

Kailos currently offers a menu of pharmacogenomics tests exploring the genetics related to patient re-sponse to antidepressants, tamoxi-fen, pain management medications,

Marie-Claire King discovered BRCA1. Image: hudsonalpha.org/information-is-power.


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Plavix, oral contraceptives, and stomach acid reducers. The tests are regularly $149 to $299 each, but are currently listed at $99 each.

More tests are being announced regularly, said Randy Bachmeyer, Kailos CTO. A cardiology test is coming soon, and several risk-based panels will be introduced, including a wider release for the women’s health panel as well as men’s health and eye health panels.

Kailos isn’t the only company anxious to cut out the insurance middleman. Invitae, Color Genom-

ics, and Pathway Genomics all announced products this year that are sold through variations on the same approach. In Kailos’ case, when a customer orders a test, she types in the name of her physician who should receive the test results. Kailos faxes that doctor an explana-tion of the test and the requisition.

“Several of them come back to us and say, ‘I’m not the appropriate physician for this. They are asking about Plavix testing and I’m their GP. It really should be their cardiologist,’” Moore explained. “In which case, we’ll reach out to the cardiologist or go back to the patient and explain the situation. If they don’t have a physi-cian available to them, or one that will order the test for them, then our medical director will look it over and sign off on the ordering of the test.”

The process seems a bit cum-bersome compared, for example, to Color’s model of instantly con-necting customers to an ordering physician through their online store. Moore acknowledges that the approach might slow them down a bit, but he’s unconcerned.

“That’s okay. Part of the goal here is physician education, for them to know this type of testing is available and it’s available without the nor-mal hassles of reimbursement.”

Kailos views the physician’s role as very important, explained Bach-meyer. “It’s [the patient’s] physician that either has put them on drugs, or will put them on drugs, so if we can’t engage that patient or that custom-er’s physician, we’ve left it all up to him to talk to his doctor. We want him to be able to talk to his doctor—we want him to have a report to look at

as well—but it’s very important that he works with his primary physician.”

“If their physician won’t take [the reports] seriously, I hope they look for another physician,” Moore add-ed. “They should take it seriously.”

The same requisition process will be in place for the Information is Power initiative, and both Kailos and HudsonAlpha are working on edu-cational outreach to doctors locally. “We’re doing active outreach to physicians in the area,” Strong told me. “We’re having face-to-face meet-ings. Lots of emails are going out.”

“OBGYNs understand BRCA1 and BRCA2 testing and its relationship to breast cancer and ovarian cancer, but they’re not all comfortable with a list of 22 other genes and how that will impact them,” Moore says. “Until it’s put out there, and they have to deal with it, [adoption] is going to be really, really slow, which means people aren’t necessarily going to get the best healthcare they could get.”

The Information is Power initia-tive is meant to force their hand.

SAMPLE PROGRESSWhile doctors are signing requisi-tions, the patient’s sample moves through the normal Kailos pipeline.

All Kailos customers receive cheek swab kits in the mail and return them to Kailos’ laboratory in the HudsonAlpha building. Samples undergo targeted sequencing, a hybridization method with limited PCR. Panels are designed on Kailos Blue, the company’s design-to-re-ports platform. The design process was honed during the company’s years serving research customers,

Troy Moore, Kailos CSO (top)Randy Bachmeyer, Kailos CTO (bottom)


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explained Bachmeyer. “We’ve prob-ably done over 100 different panels for different research customers.”

To precisely target genes, Kailos Blue suggests where to put down primers from a reservoir of about 4,000 options, Bachmeyer said.

“When we produce the panel for the very first design, we get probably about a 90%-95% success rate. Of course we are doing clinical test-ing, and that’s not good enough. That’s where you can really go in and start tweaking the individual design until you’ve got the 100% you need to do that particular test.”

Sequencing happens in-house on one of five Illumina MiSeqs or one NextSeq instrument. Kailos Blue includes its own LIMS system to move samples through the pro-cess. Analytics run on the Amazon Cloud using a core pipeline of BWA and GATK, modified for targeted sequencing, Bachmeyer said. After

25-30 quality checks on each sample, results are stored in Amazon S3.

At this point, if the requisition paperwork is not in order, the test and its results are discarded (and paying customers get a refund). If the requisition paperwork is in, reports are generated. Pharmacog-enomic panels are reported based on PharmGKB guidelines; oncology reports rely on ClinVar. Test results are returned in both a patient-facing report and a physician-facing report.

For Kailos’ pharmacogenomics tests, the practical results might be specific dosing recommendations. The patient might be told that their test results warrant discussing a decreased medication dose with their doctor; the physician report might recommend cutting the dose by a more-specific 50%. Both reports were developed specifically for their in-tended readers with an emphasis on usability and clarity, Moore explains.

For the HudsonAlpha Informa-tion is Power initiative, any panels positive for mutations will be re-turned to a genetic counselor and the ordering physician several days before reports are sent to the pa-tient. The genetic counselor will touch base with the physician first, then reach out to the patient.

“We want to give the physician the opportunity to be the one to con-tact the patient,” Strong explained. “But regardless of whether the physician has contacted the pa-tient or not, the genetic counselor will be contacting the patient.”

THE CANADIAN PROJECTHudsonAlpha calls the project groundbreaking, but as I sat in the Kailos conference room, the whole thing sounded vaguely familiar.

Mohammad Akbari, an assistant professor in the Dalla Lana School of Public Health at the University of Toronto, presented plans for a similar project at The Clinical Genome Conference* in June of last year. I reached out to see how that effort was progressing.

Akbari, too, advocates for universal screening.

“Right now, we’re seeing people waiting until they are diagnosed with breast or ovarian cancer… and completing their [first] course of treatment—a year or two after their diagnosis!—[before they have genet-ic testing],” Akbari said. “The other problem is that when offering genetic testing we use so many different criteria: their family history, having a certain number of breast or ovarian cancer cases in their family, age of diagnosis. It’s believed with all those different criteria we are still missing a significant proportion of the carriers.”

A study from Akbari’s group sup-ports the theory (doi: 10.1038/bjc.2013.309). Researchers at the University of Toronto screened for BRCA mutations in about 6,000 Jewish women in Ontario from 2008 to 2012 who did not otherwise qualify for BRCA screening. “Of those 6,000, we found more than 1% of them—93—had a mutation,” he said.

*The Clinical Genome Conference—TCGC—is an annual event held each June in San Fran-cisco and run by Cambridge Healthtech Institute, the parent company for Bio-IT World.250 First Avenue, Suite 300


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Those findings prompted a larger vi-sion: the Universal Population-Based BRCAness Screening project. Akbari and his colleagues wanted to target women 30 to 60 years old in Ontario, Canada—about three million women. They planned to offer BRCA1, BRCA2, and PALB2 testing and had partnered with WaferGen for target enrichment.

That was the plan Akbari present-ed at TCGC a year ago. “Because of so many different reasons, we were not successful in implement-ing it,” Akbari told me last week when I checked in for an update. “But we are still working on it.”

The major challenges are funding and regulations around direct-to-con-sumer genetic testing in Canada. Akbari’s hope now is to collaborate with one of the large hospitals in To-ronto that is already offering genetic testing and launch universal testing in the first or second quarter of 2016.

Then he’ll be left with only the funding issue.

“We have been working in the last couple of years to find a source of funding to cover such genetic testing,” he said. “Un-fortunately, so far we have not secured any funding for it.”

Akbari hopes to offer the testing for about $150-$230, and to edu-cate and advocate for women to buy the test themselves. That, too, will be a challenge. “Especially here in Canada, people are so used to not paying for their health services, it’s really hard to convince people to pay for such a thing,” he said.

In the meantime, Akbari has been modeling cancer in Ontario. “We showed in our modeling of Ontario’s

population that if we can do pop-ulation-based genetic testing for BRCA1 and BRCA2, we can decrease the incidence of breast and ovarian cancer significantly in the popula-tion.” (A paper with more details has been accepted for publication.)

With enough data points, Akbari hopes to prove that genetic screen-ing should be universal, and he hopes eventually such tests will be covered by the Canadian healthcare system. “Our ethical responsibility as a group of academic scientists is to show the benefit of such popula-tion-based genetic testing,” he said.

THE NUMBERS GAMEHudsonAlpha’s initiative might overwhelm its organizers as well, but the smaller, better funded project has fewer obstacles to success.

HudsonAlpha has calculated that there are 1,500 women who would qualify for free screening in the Huntsville area covered by Information is Power. In the sur-rounding counties, there might be about 600,000 individuals (esti-mated from 2013 numbers) eligible for the discounted rate of $99 per test. That’s a lot of tests, but far fewer than Akbari’s three million.

Kailos is donating the testing for 30-year-old women and offering the discounted price to the rest of the eligible participants. The lab can currently run about 2,000 samples a month with four tech-nicians, a testament to the ease of the protocol, said Bachmeyer.

There are also various overhead costs: the website, the educational

materials, and the genetic counselors’ time. HudsonAlpha is assuming those costs, explained Maureen Mack, Senior Director for Marketing and Communications at HudsonAlpha.

There are several genetic counsel-ors committed to the project thus far—three from HudsonAlpha and two more that can be contracted in if needed, said Moore. Currently, genetic counseling will be offered to everyone whose tests reveal mu-tations. Strong declined to predict how many people that would be, but did say, “We are expecting numbers to be small.” For non-Ashkenazi populations, studies have estimat-ed that 1 in 400 women carries a BRCA mutation. Troy Moore expects the rates for the other genes in the Kailos panel to be even lower.

The project will kick off at the Tie the Ribbon fundraiser on October 29. Everyone who attends the lun-cheon will receive a kit, though not everyone will be eligible for free screening. Tickets to Tie the Ribbon are $60 each. Once the initiative has launched, HudsonAlpha will be doing community outreach and education. “Evaluation of the initiative and com-munity consultation is going to occur over the coming year,” said Strong.

Mack didn’t share a budget for the project, but said HudsonAlpha has been fundraising since last October, and the cities of Huntsville and Madison, and Madison Coun-ty have also committed funds.

We are committed to every woman who is eligible, Mack said. “Would we be surprised if 1,500 women took advantage of it? Maybe. But we will keep our commitment.” 250 First Avenue, Suite 300


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PRECISIONFDA TO TEST ACCURACY OF GENOMIC ANALYSIS TOOLS

BY AARON KROL | AUGUST 27, 2015

As the FDA prepares to take a more active role in the oversight of genetic tests, the agency is finding itself in un-familiar territory: regulating software.

In the past, reviewing new diagnostics rarely involved stepping far outside the wet lab. Tests might involve finding a patho-gen under the microscope, or detecting an analyte through a chemical reaction in a test tube: simple yes or no questions that just had to be checked to make sure they reliably gave the right answers.

In genetics, however, data has to go through a lot of checkpoints before it gets to yes or no. Can a new computational pipeline crawl through a string of DNA code to find genetic variants? Does it always call those variants correctly―and are they really linked to the disease you want to diagnose?

These are questions that even professional bioinformaticians have sometimes strug-gled to answer. The trouble is, virtually all DNA data is delivered and mediated through computer programs, making it hard to


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know what the ground truth is. Even if workflows consistently give the same answers, it’s difficult to be sure they’re telling us what’s really in our genomes, and not just falling victim to the same common biases and errors.

With the federal government’s dis-mal reputation for handling IT proj-ects, you might think the FDA is the last organization we’d want trying to tackle this complex issue, especial-ly with the safety and accuracy of our medical testing on the line. But in fact, the FDA has a record of suc-cess and flexibility in IT. Last year, the agency formed a new Office of Health Informatics under Chief Health Informatics Officer Taha Kass-Hout, who has moved swiftly to transition to more reliance on cloud computing and more agile and open software development. His office’s first project, openF-DA, was widely praised for making it easier for the public to get useful information out of FDA databases covering drug side effects, product recalls, and medical device defects.

Now, the Office of Health Informat-ics has embarked on a new project called precisionFDA, in which the FDA will try to better understand how accurate computational pipelines really are at interpreting genetic data. An initial research and devel-opment grant to build the platform has been awarded to DNAnexus, a company whose cloud-based service has set records for rapid genomic analysis at a huge scale.

The first goal of the precisionF-DA project is to fulfill its regulatory mission. The platform will be loaded

with extremely well-curated “truth sets” of DNA data, such as those produced by the Genome in a Bottle Consortium―genomes so thoroughly studied that we can say with high confidence whether computational pipelines are getting the right an-swers out of them. The platform will also include “reference pipelines,” standard sets of computational tools

that represent the state of the art in analysis. Combined, these ma-terials will let users compare their custom workflows against common standards, scoring their accuracy and identifying areas where they fall short. Eventually, the FDA will be able to use this platform to gauge whether new sets of tools can be trusted to make diagnoses in real patients.

But precisionFDA also serves a second purpose. Since the FDA an-nounced its decision to fold labora-tory developed tests, including the large majority of genetic tests, into the same regulatory procedures it uses for mass market diagnostics, the companies and hospital labs who deliver this testing have worried that the agency will stifle innovation

in the burgeoning field of genomic medicine. By building precisionFDA on open source software, and actively seeking input from the institutions who will be regulated, the FDA is hoping to offer transparency in its regulatory process and win some community buy-in for its standards.

“This really is something we view as a community effort,” says Da-

vid Litwack, a policy advisor on personalized medicine in the FDA Office of In Vitro Diagnostics and Radiological Health. “It is an open platform, and it’s a chance for people who are developing and working in this space to really have an effect on how FDA looks at genomics.”

The experience of building openF-DA has also taught the agency how an open and inclusive development process can create powerful new functions for big IT projects. “The initial intention for openFDA was to provide easier access to already publicly available data, but we’ve seen how further innovation hap-pened from the marketplace and from users, especially the researcher community,” Kass-Hout tells Bio-IT

“This really is something we view as a community effort. It is an open platform, and it’s a chance for people who are developing and working in this space to really have an effect on how FDA looks at genomics.”

— David Litwack, a policy advisor on personalized medicine in the FDA Office of In Vitro Diagnostics and Radiological Health


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World. “So hopefully some surprise will come from the community that we haven’t thought about. This is the beauty of making this open.”

A GROUNDSWELL OF ACTIVITY”Omar Serang, Chief Cloud Officer of DNAnexus, became connected with the FDA Office of Health Informatics when his company attended the rib-bon-cutting ceremony for openFDA. “Our jaws dropped to see a federal agency using GitHub, holding code hackathons,” he says. “It was a crazy collision of Silicon Valley culture and federal government culture.”

DNAnexus was already a party to industry discussions about collecting better reference material for test-ing out new genomic technologies. Serang says he’s spoken with testing companies like 23andMe and Coun-syl, DNA sequencing giant Illumina, academic institutes like the Baylor College of Medicine, and a group at the Centers for Disease Control and Prevention led by Lisa Callman about what kinds of DNA samples would make the best reference material, and how to make them universally accessible. Those conversations are now informing the construction of precisionFDA, as DNAnexus has taken on the contract for that project.

“We don’t have enough ground truth out there, covering enough ethnicities, covering enough ge-nomic makeups,” Serang says. “There’s a groundswell of community activity already taking place that precisionFDA can capitalize on.”

With help from various industry and academic groups, Serang and his team at DNAnexus are compiling a list of essential reference materials to make available in precisionFDA at launch. These will likely include the Genome in a Bottle assembly of a genome called NA12878; Illumina’s “platinum genome” assembly of the same specimen; and the “Lupski Genome” assembled at Baylor.

But this handful of resources will represent only a fraction of the ma-terial needed to accurately assess how pipelines perform across the spectrum of human genomic varia-tion. That will be especially true of pipelines used in diagnostic tests: users will want to see whether their tools can catch the thousands of different variants involved in rare hereditary diseases, for instance, or different subtypes of cancer.

To include enough material to satisfy all these requirements, preci-

sionFDA is taking three different ap-proaches. First, Serang says it’s very likely the precisionFDA team and its partners will collect new DNA data for specific niche purposes. “The initial pilot is focusing on carrier screening and Mendelian disease,” he says. As the project continues, it will also become important to collect more complex sources of variation, like DNA from the immune-related HLA region, or tumor-normal pairs that will test the ability of tools to detect large structural variants involved in cancer.

Second, DNAnexus is building programs to generate in silico data of high enough quality to mimic real DNA reads. Serang says this function will have two components. The first, a “FASTQ synthesizer,” will create artificial FASTQ files―a common for-mat for DNA data―that have similar characteristics to real data from a sequencer, including occasional er-rors. The second, a “FASTQ injector,”

“

It will become important to collect more complex sources of variation, like tumor-normal pairs that will test the ability of tools to detect large structural variants involved in cancer.Image: iStock


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will be able to take real or synthetic FASTQ libraries and spike them with a few artificial reads that users want their pipelines to be able to find. For instance, the FASTQ injec-tor might add some known cystic fibrosis mutations to an otherwise healthy genome, so that a diagnos-tic test for cystic fibrosis could be evaluated inside precisionFDA even in the absence of real disease samples.

Most importantly, however, users of precisionFDA will be able to add any data of their choosing to the platform. This can be done publicly, to share useful datasets with the FDA and the broader community, or in a private environment with-in precisionFDA purely for users to see how their tools perform.

“At this stage in the pilot, this is not about validation or approval,” says Serang. “This is all about vetting and analysis, and to be able to have the community feeling very safe work-ing in their private data spaces.”

NEW FRONTIERS FOR THE FDAPrecisionFDA will not be the first proj-ect to tackle comparisons between genomic analysis tools. Resources like GCAT (which has collaborated with Genome in a Bottle) exist to score pipelines and give a rough idea of which common tools are most reliable in which situations. But Serang thinks DNAnexus can not only give these comparisons a higher profile and a role in regulation, but also make them easier to use.

“What we’re finding is that the work that’s most advanced algorithmi-

cally is also sort of behind from a user interface perspective,” he says. “Our commitment is to bringing the best call comparator to bear with a more future-friendly front end.”

To that end, DNAnexus is building precisionFDA on top of the com-mercial DNAnexus platform. The new precisionFDA web portal will feature open APIs for running tasks and getting back comparisons with other pipelines, and will eventually be free to access for any users who want to assess their tools’ reliability. The FDA is aiming to make a beta release available this December.

“PrecisionFDA can at least offer people the necessary resources to validate their tests, and that itself we believe to be a huge way of bringing innovation to this mar-ketplace,” says Kass-Hout.

It’s a marketplace that is changing quickly, giving the FDA new and fluid responsibilities. Past forms of FDA review have generally focused on a single use case for each test, but genomic devices could easily give results across hundreds of different diseases areas. That makes it much more important to check their accuracy upstream in the testing process, rather than solely in terms of clinical results.

“We recognize that the way tests are being used, and almost certainly

will be used in the future, is almost use-independent, or use-blind,” says Litwack. “That’s a challenge we’re responding to with this technology.”

Although it will probably be a while before precisionFDA can formally be used to evaluate tests during new product reviews, even beta users will be playing an important role in defining future regulations. Right now, the standards for genomic software are often unclear; only a handful of genomic tests or testing platforms have been cleared by the FDA for clinical use, and their reviews had to be heavily negotiated. By testing pipelines within precisionFDA, the agency and the organizations it regulates will be able to reach some consensus on what aspects of genomic testing give computational tools the most trouble, and what metrics can best evaluate those pain points.

“There will be contributions from the community around reference materials, or adding their own pipelines or workflows to replicate results,” says Kass-Hout. “OpenFDA used a very similar model, this agile, dynamic way of implementing a platform where people were able to build applications or websites on top… For us at FDA, we’re breaking new frontiers in ways we’re adopting this for science.”

“What we’re finding is that the work that’s most advanced algorithmically is also sort of behind from a user interface perspective”

— Omar Serang, Chief Cloud Officer of DNAnexus


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http://www.bio-itworld.com/2015/2/26/gcat-team-publishes-methods-results-benchmarking-tests-aligners-variant-callers.html




YARON TURPAZ ON HUMAN LONGEVITY’S BIG PLANS

JULY 27, 2015

Human Longevity launched in March of last year, the latest of J. Craig Venter’s genomics start-ups, headquartered in San Diego. The vision was grand: se-quence 100,000 human genomes a year and “change the way medicine is practiced by helping to shift to a more preventive, genomic-based medicine model,” Venter said at the company’s launch. “Our goal is not necessarily lengthening life, but extending a healthier, high perform-ing and more productive life span.”

The company started with an $80 million initial investment that Ven-ter expected to last for about 18 months. On the eve of that milestone, Bio-IT World editor Allison Prof-fitt spoke with Yaron Turpaz, HLI’s Chief Information Officer, about the first year’s progress and the kind of knowledgebase HLI is building.

Turpaz joined HLI at the outset with experience leading R&D IT at AstraZeneca and Eli Lilly. He was tasked with building and growing


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the company’s genomic and phe-notypic database business; leading all bioinformatics/informatics and software engineering efforts; ex-panding informatics program at HLI’s California facility; and building HLI’s computing and informatics program and facility in Singapore.

It’s a daunting list, and one Turpaz wouldn’t mind some help with. The company lists 56 open positions for re-searchers, bioinformaticians, software engineers, and clinicians in San Diego, Singapore, and Mountain View, Calif. The goal for all of them is to build a million-genome database replete with phenotypic and clinical data. Then the fun will really get started.

Bio-IT World: Your mandate at HLI is vast. Tell me your take on the company’s vision in light of those responsibilities.

Yaron Turpaz: The umbrella goal of what we are trying to do is simply to transform healthcare. We would like to move from reactive medicine to preventive medicine, so basically not just go to the doctor when you get sick, but really [use] the different ge-nomics and other ‘omics elements to define the baseline, assess risks and track changes to identify peaks early enough so we can translate [data] to care from a preventative approach.

In addition, a lot of what we’ll do will be used for novel target discov-eries, biomarker discoveries, and patient stratification, including the rescue of failed clinical trials. The core of what we’ll do is to build this knowledgebase with hundreds of thousands of genomes that are then

linked to whole genome microbiome and metabolomics on a large scale and, when possible, a full body MRI imaging and other assays. We will try to integrate this information and do a lot of downstream analysis—kind of classic bioinformatics just with the right statistical power and with multi-dimensional data. In addition, we are using machine learning to explore the data without prior knowledge and try to understand what comes out.

What does the infrastructure look like to capture that?

We established the largest sequenc-ing facility in the world, and we have now a capacity of almost 40,000 whole sequenced genomes at a 30x coverage per year. We have 24 of the HiSeq X machines from Illumina, and this was a major effort initially just to put the lab in production and build the required IT and informatics systems to handle the vast amount of data in an unprecedented scale and speed. We are for the most part cloud-based, so we try to maximize the use of the cloud where possible.

Basically, as the data comes out of the sequencing machine, we have hot storage that takes the data right before we upload it to the cloud. We are using EMC Isilon platform as hot storage and then transfer

the packaged data to the Ama-zon Cloud for all of our production and downstream data analysis.

The projection is that we’ll expand our sequencing capacity based on the demands as we sign on more significant contracts. We landed an agreement with Genentech and we’re in discussion with other phar-ma. As we land more contracts with requirements for more [sequenc-ing] machines, we’ll increase the throughput. We’re building now the commercial HLI Knowledgebase that different companies can subscribe to, to extract the knowledge and mine for transformational discoveries.

The things that you’ve mentioned—whole genome sequencing, microbi-ome sequencing, full body MRIs and imaging—where do these data come from? The agreement you men-tioned with Genentech, for example, is only for de-identified genomes.

Correct. In general, when we establish collaboration of large cohorts, we retain the rights to the data, as well as the de-identified phenotypic and clin-ical data. We are not a fee-for-service sequencing facility, so it’s not about sending us your sample, just to get your data back. We will only sequence when there’s high quality phenotypic and clinical data that comes with the

“The umbrella goal of what we are trying to do is simply to transform healthcare. We would like to move from reactive medicine to preventive medicine...”

— Yaron Turpaz, HLI’s Chief Information Officer


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samples, and they will be part of the HLI Knowledgebase. This is the main source of information for the hun-dreds of thousands of samples based on existing cohorts. Plus, we are now working with pharma to change the consents of the clinical trials, so mov-ing forward on any new clinical trial, this would be part of the collection. You can imagine in the future that every clinical trial will require full ge-nome [sequencing] on each patient.

Craig Venter has said that the company is going to begin to collect 3D scans of peoples’ fac-es as well. How does that fit?

We recruited 1,000 individuals to start with and we conducted the full face analysis and linked it to their genome and many other parameters. This is just the beginning. We are going to open this year our first HLI Health Nucleus in San Diego as an entry point for individuals to come in and go through a full whole-genome analysis, full body MRI, and other detailed phenotypic data that we are going to collect. At the first stage, our Health Nucleus will be estab-lished as a research use only, proof of concept of what can be done, and all information of individuals will always be communicated by physicians.

The volume of data will come from cohorts and collaboration with phar-maceutical companies, hospitals, and research institutes. At the moment, the healthy individuals or patients that will come [to HLI’s Health Nu-cleus] will not be the major source of samples compared to the hundreds of thousands of samples from clinical trials and [collaboration] cohorts.

Are you following these in-dividuals longitudinally?

Yes, that is one of the advantages of the Health Nucleus. For example, we can collect stool samples on multiple time points for microbiome analysis. We also consider to collect saliva or skin samples for the different sources of microbiome populations. We developed whole metagenome analysis of microbiome. While most microbiome offering out there by different companies only focus on the 16S gene for taxonomy, which we know is not sufficient—not for de-

tailed species analysis, and also not for downstream integrated pathway analysis that we do. We believe it’s important to follow up and contin-ue to learn about the microbiome population in integration with the whole human genome and then have better understanding of how it relates to triggering different diseases.

Some of the existing cohorts—for example the collaboration with Prof. Tim Spector from Kings College, the largest twin cohort in the world [TwinsUK]—have consented to follow up. Many of the cohorts that we collaborate with actually have this element. The process of follow up with cohorts participants to collect more samples is a bit slow but it’s possible to do it. And then, of course for any future studies that we’ll initi-ate with these institutions the studies will be designed longitudinally.

Is there a biobank? Are you keeping any tissue samples or everything is digital?

HLI focus is on the digital elements of individuals, and we may partner with different sources of samples, including biobanks that are interested in genomics characterization of their samples. The goal is to generate the data and do all the required analyses. We follow all the compliance and restriction of each study and either destroy samples or send it back.

So data are coming in from phar-ma collaborations as well as the private San Diego Health Nucle-us, and then your job is to store, analyze, and figure out what to do with all of that data?

HLI focus is on the digital elements of individuals. Image: iStock.


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Yes, pretty much, part of [our goal] is to generate the data in high quality, and then, as you say, store it, as well as develop solutions that will allow you to do the downstream analysis. The analysis can be processed in-house in a batch mode via our APIs or by pharma and physicians through a user interface when subscribing to the HLI Knowledgebase. We have diverse sources of data and are working closely with global phar-maceutical and biotech companies, hospitals, research institutes, aca-demia, government agencies, bio-banks and insurance companies.

As you build these solu-tions, what do you see as the biggest challenges?

In the first year, the main priority and goal was to establish the production lab and the production analytics as we continue to optimize it. What we focused on this year is the down-stream. So now that we have high quality genomes and high quality data stored on the cloud with highly opti-mized analysis workflow, it’s about the downstream multi-dimensional analysis solutions and biological in-terpretation. And as you can imagine, establishing the Health Nucleus also requires a major informatics effort.

What are your target numbers for the knowledgebase?

Our goal is to have at least a million genomes in the knowledgebase by 2020, and to reach those numbers in this timeframe, we obviously need to scale up in capacity and technol-ogy. The assumption is that capac-

ity needs to be increased, and also sequencing technology will change and get better in speed and quality.

We’re technology agnostic, so right now we have the Illumina machines and we also have two PacBio ma-chines. Our goal is to work with the best technology out there, for the best solutions, quality, capacity

and cost, and we will change and adapt as these technologies are being developed, so let’s assume that this will advance and progress in the next few years and we will continue to tap into that to reach to at least one million genomes.

You said one million genomes, but you also said you don’t want data that doesn’t have phenotypic and clini-cal data with it. So your goal is one million genomes with their accompa-nying phenotypic and clinical data.

Exactly. We believe that it’s essential for the downstream analysis and better understanding of the different elements we try to achieve towards transformation of healthcare.

As you’re gathering this data and you’re storing it on the cloud and running your analyses on it, how do you pick what to start work-ing on clinically? Are you going to just mine the data and see what

jumps out? Are you going to make decisions with your partners on what they want you to look at?

I think in reality, it’s a combination. Initial analysis is driven by the in-terest of our partners. The different questions that’ve been asked by the different cohorts, depend on the part-

nership and the type of data. Our goal is of course to enable our partners to get novel insight and focus on those studies. A key value that HLI brings to the table is the aggregated analysis across all genomes in our Knowl-edgebase so a natural next step in the analysis is to integrate the cohorts data with other relevant cohorts and generate or test new hypothesis.

In addition, there are specific studies such as the [3D facial scans] which addresses specific ques-tions of understanding the genome and how it relates to the physical traits in the face. Our approach with the machine learning is to let the data speak. We’ll identify as-sociations and links that relate to interpretation of phenotypic data that we didn’t even think of asking.

It is a bit too early for that. We need a critical mass of data to actually start to have such conclusion with enough statistical power, this ap-proach will add value as we’ll grow and build the knowledgebase.

“Our goal is to work with the best technology out there...and we will change and adapt as these technologies are being developed...”

— Yaron Turpaz, HLI’s Chief Information Officer


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WHAT COMES NEXT FOR

DIRECT-TO-CONSUMER GENETICS?

BY AARON KROL | JULY 16, 2015

“Mr. Obama’s regulators are chilling inno-vation and investment,” fumed the Wall Street Journal. “The FDA bureaucrats think they know better than you how to handle your genetic information,” Ronald Bailey protested on the website of the libertarian magazine Reason. At Slate, Gary Marchant punched out every adjective on the soda lid: “a shortsighted, heavy-handed, dou-ble-standard act of paternalism… a death sentence for direct-to-consumer genetic testing… unjustified and unwarranted.”

More than a year and a half after the FDA told 23andMe to take its genetic health reports off the market, Elizabeth Mansfield, the agency’s Director of Personalized Medicine, still sounds frustrated with the indignation the decision met with. “What a lot of people don’t understand,” she tells Bio-IT World, “is that FDA did not ban direct-to-consumer testing when it sent 23andMe a warning letter. It said, 23andMe, you in particular are out of compliance, and we’ve tried to work with you and it hasn’t worked


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out, so please stop selling your tests until you get into compliance.

“And that does not reflect any dissatisfactions with the mod-el or anything like that.”

This February, the FDA made good on that assertion, giving 23andMe the go-ahead to test cus-tomers for a single factor: whether their children are at risk for inheriting a rare genetic disease called Bloom syndrome. The FDA-cleared test uses the same spit kit and geno-typing panel 23andMe has always offered, albeit with more stringent labels and controls than customers may be used to. Mansfield thinks the process has cleared the air, and gives some assurance the FDA is not out to quash consumer genetics.

“I believe that [23andMe] have a much better understanding of what we’re looking for in terms of a regulatory submission,” she says. “We can move forward more easily with them.”

It’s an important precedent for the genetic testing industry, laying a straightforward path for a host of fu-ture tests. It’s also a far cry from the reports on 254 different health condi-tions that 23andMe once advertised.

A PATH FORWARDAt the time the FDA’s warning letter went out in November of 2013, 23andMe was the last major―certain-ly the last reputable―company letting people buy genetic health tests online, without going through a doctor or involving their health insurance. A large crop of “direct-to-consum-er” companies like Navigenics and deCODEme, formed in the mid-2000s

amid the optimism of the recently completed Human Genome Project, had all long since folded or changed their sales models. When 23andMe gave up the health reports that had once told customers their genetic risks for conditions from Alzheimer’s to Zellweger Syndrome, it seemed to critics of FDA policy that the last bul-wark for personal genetics had fallen.

Some of the doomsayers of late 2013 are probably surprised to see how 23andMe has thrived since. The company has crossed its long-an-ticipated threshold of one million customers, on the back of overseas sales and still-popular tests here at home for ancestry and non-med-ical genetic traits. 23andMe has penned lucrative deals with major pharma companies, started its own drug discovery business, and re-cently been valued at a market cap of over $1 billion, making it Silicon Valley’s first “unicorn” mega-com-pany in the field of biotechnology.

The clearance of its Bloom syn-drome test, however, has been the only tangible sign of progress on restoring 23andMe’s original di-rect-to-consumer business. The Bloom test doesn’t mean customers have access to any more information than before―the company is holding out for a more comprehensive panel of tests before releasing this one―but

it does lend some spine to 23and-Me’s optimism about its prospects.

23andMe is not speaking to the press about regulatory plans, citing ongoing discussions with the FDA about additional health tests. But a spokesperson for the company did tell Bio-IT World by email that they now expect to sell a larger direct-to-consumer product in the near future. “[W]e believe there is a regulatory path forward for di-rect-to-consumer genetic testing,” the spokesperson wrote. “Now that the parameters have been established for future submissions, we will have a health-related product that includes carrier status test reports on the market in the U.S. later this year.”

That’s a swift turnaround for a company whose ability to sell any health product was up in the air as recently as the start of this year. Carrier testing is an interesting and relevant part of genetic medicine, and a sound floor to build a compre-hensive product on―as long as it’s not a ceiling on what genetic tests can get by in a regulated market.

PROOF OF PRINCIPLEBloom syndrome is a serious condi-tion. People affected by the disorder suffer from stunted growth, frequent rashes related to sun exposure, and

“I believe that [23andMe] have a much better understanding of what we’re looking for in terms of a regulatory submission. We can move forward more easily with them.”

— Elizabeth Mansfield, FDA Director of Personalized Medicine


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most importantly, a frighteningly high risk of getting cancer at an early age.

It’s also extraordinarily rare, with fewer than a thousand recorded cases. There’s a sound commer-cial reason 23andMe isn’t hustling to get its solitary FDA-cleared test onto pharmacy shelves.

“It’s sort of a proof-of-principle experiment,” says Hank Greely, a bioethicist and legal scholar, and Director of the Center for Law and the Biosciences at Stanford Law School. Greely is a longtime skeptic of 23and-Me’s health tests, which he regards as underpowered to give reliable information on most diseases, but even he sees the test cleared by the FDA as a pretty straightforward case.

“The thing I like about it,” Greely says, “is FDA applied the same kind of analysis they apply to over-the-count-er drugs and devices. Which I think makes sense. Before you can sell a painkiller or a decongestant or some other drug over the counter, you need to prove to FDA that the average con-sumer would be able to understand when and how they should use it.”

The question of understanding is an important one for any medical product, but it’s an especially vexed issue in genetics. “Genetics is not widely understood, we don’t think, among the public,” says Mansfield. “At some point we have to make sure that the way the company is presenting the information about the test, how it’s interpreted and so on, can be understood by the peo-ple who are expected to use it.”

That caution is reflected in the new labeling the FDA has required

for 23andMe’s Bloom test. If sold direct-to-consumer, the test would have to present users with warn-ings like, “this test is not intended to diagnose a disease, or tell you anything about your risk for devel-oping a disease in the future,” and, for those who test positive, “the positive result you obtained is very likely to be incorrect due to the rarity of this variant.” 23andMe also had to complete a user comprehension study with its customers, and must make certified genetic counselors available to guide users through the quirks of genetic testing—like the implications for family members if a disease-related variant is found.

Apart from the genetic counselor, these are standard parts of the FDA’s toolkit, as Mansfield is quick to point out. “We weren’t dealing with anything

in that Bloom syndrome test that we hadn’t encountered before,” she says. “We’ve done over-the-counter before, and we’ve done genetic tests before. It was just combining the two.”

Mansfield makes a convincing case that selling direct-to-consumer is not a deal breaker for the FDA. Much more relevant than your sales model is whether your product is reliable, comprehensible, and medically sound. In personal genetics, that’s where things tend to get murky.

THE BIG JUMPAt the height of its popularity, 23andMe took a comprehensive, cradle-to-grave approach to health testing. Alongside obscure early-on-set diseases like Bloom syndrome, 23andMe also gauged customers’

A 23andMe test can predict your ancestry using DNA markers. Image: 23andMe user post.250 First Avenue, Suite 300 Needham, MA 02494www.healthtechpublishing.com

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risks for everyday killers like diabetes and heart disease, and late-in-life specters like Alzheimer’s―diseas-es we all know and worry about.

“It’s a big, big jump from the Bloom syndrome test to most of the 254 medical conditions they were releasing information on,” says Greely. “And the farther away you move from what was actually approved, the fuzzier things get.”

Most of the genetic variants thought to play a role in common diseases have only marginal effects. We all carry hundreds of variants that have been linked to small changes in risk for things like breast can-cer and diabetes, often in studies that have been hard to confirm or replicate. 23andMe can try to ag-gregate all those variants together, but not only will those reports rest on shakier foundations than rare disease tests, they’re also unlike-ly to add up to more than a 10 or 20% change in total risk either way.

“I don’t know why anybody would want to know that,” says Greely. “I don’t know what you’d do with it.”

Problems of user comprehension are hugely magnified in this kind of health report. Customers are being asked to understand what a marginal change in disease risk means for their overall health; the type of evidence, from population-wide studies, that supports the effects of these low-impact mutations; how the test provider is compounding the effects of many variants together; and the difference between absolute and relative risk—the kind of statistical

thinking that says a 20% change to a 10% risk adds up to 12 and not 30.

That doesn’t mean direct-to-consumer genetic tests for common diseases are off the table. Mansfield, for her part, wants to keep an open mind. “It would be wonderful if people could actually understand their risk there,” she says. “To the degree that we can figure out how to do it, and that there actually is a reasonable genetic underpinning for a disease, I think it’d be interesting.” But she also

stresses that there are thorny issues in this area that the FDA’s review of the Bloom test never touched on.

“The known genetic component for common diseases is not very strong,” she says. “A lot of the risk comes from things that aren’t ge-netic, so how you convey the in-formation to users is much more complex.” Among Mansfield’s wor-ries is that a genetic test might lead users to downplay lifestyle factors like diet, exercise, and smoking, or standbys of preventative medicine like routine cancer screening.

Maybe the standard tools for over-the-counter tests can handle all

those layers of uncertainty; Mans-field isn’t ruling it out. But it’s hard to imagine all the labels the FDA would require for a test like that.

A WATERSHED EVENTMeanwhile, in the vacuum left by the mass exit of direct-to-consumer companies, other kinds of genet-ic testing have been expanding.

In 2008, Ramji Srinivasan co-found-ed a company called Counsyl, one

of many trying to make a go at direct-to-consumer genetics. Like many of its competitors, Counsyl quickly reinvented itself after ini-tial conversations with the FDA. It now sells tests for carrier status in more than 100 rare diseases―in-cluding Bloom syndrome―on a prescription basis, often through hospitals and doctors’ offices.

To Srinivasan, direct-to-consumer testing is just a means to an end: giving more people access to genetic information about their health. That kind of information can help people make informed decisions about fam-ily planning and preventative medi-

“It would be wonderful if people could actually understand their risk there. To the degree...that there actually is a reasonable genetic underpinning for a disease.”

— Hank Greely, Director of the Center for Law and the Biosciences at Stanford Law


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cine, but only to the extent that they’re aware of genetic testing and will seek out testing services. “Getting people to do preventative medicine is a very hard task,” he says. “Not that many people have heard of cystic fibro-sis, or Smith-Lemli-Opitz, or impact carrier screening. We and others are working to educate people about the value of carrier screening, but more work needs to be done on that basic education front to build that market.”

Now that the FDA has published clear guidelines for direct-to-con-sumer carrier tests, Counsyl is in an enviable position to get back in the consumer market. The compa-ny employs more than 30 genetic counselors and has a well-developed online consultation process, which should make it relatively painless to implement the education measures

the FDA has asked for. But Srinivasan says he has no intention of selling direct-to-consumer again, at least not for the foreseeable future.

“I’m not totally convinced that the market is there yet,” he says.

Genetic health companies have always faced a big challenge in pitching an opaque product like genetic testing as a lifestyle tool with mass-market appeal. “Ideas like [direct-to-consumer] that make carrier screening more widely ac-cessible I think are a net good,” says Srinivasan. But his years adapting Counsyl’s business to the existing healthcare system have given him new ideas about extending the reach of genetics, which focus less on making tests easy to buy and more on reaching people when they most need to learn about their genetic risks.

“There’s still a huge untapped opportunity in the OB office,” he says. “There are millions of women who are going every year to the office, and getting carrier screening. We don’t necessarily need to reinvent distribu-tion in order to reach those people.”

In fact, he adds, access to genetic health information has been steadily growing in recent years, even in the absence of any direct-to-consumer sales. Srinivasan’s favorite success story is non-invasive prenatal screen-ing, a method of testing a fetus for chromosomal disorders months before birth, using a small blood sample from the mother. Hundreds of thousands of these genetic tests are now performed in the U.S. every year, by Counsyl and many others, a pace of adoption that has led to a sharp decline in more invasive procedures.

“The growth of non-invasive prenatal screening has been ex-tremely exciting to watch, because that’s credible proof of momen-tum,” says Srinivasan. “It’s com-pletely changed the economics of maternal fetal screening. That has been a watershed event.”

Other companies that were once in the direct-to-consumer business might see things differently. The regulatory environment is certainly more inviting now than it was two years ago. For instance, the FDA has set the precedent, during its Bloom review, that it will happily look at scientific publications and professional guidelines as evidence that a genetic variant is involved in disease, rather than demanding new clinical trials. That matches past policies for reviewing genetic

“The growth of non-invasive prenatal screening has been extremely exciting to watch, because that’s credible proof of momentum,” — Ramji Srinivasan


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VISIT: BIO-ITWORLD.COM

tests in the hospital environment, and clears away one of the biggest expenses of approving a new product.

The FDA also decided that all genetic tests similar to 23andMe’s Bloom syndrome product, those that look for carrier status in rare, recessive diseases, should now be considered “Class II” medical devic-es. That classification exempts them from the highest level of premarket scrutiny―new manufacturers will only have to prove that their prod-ucts are “substantially equivalent” to the tests created by 23andMe.

“We cleared a test,” says Man-sfield. “We down-classified an entire group of tests based on that. I think it’s pretty clear that we see this as an okay model.”

But she’s also content to take it slow. Every new indication for genetic testing will call for a new review to tease out its unique risks and ben-efits, and few will be as clear-cut or easy to understand as carrier testing. If what we want is to reach the great-est number of people with important genetic information, we would be well advised to focus on more than where and how tests can be sold.

“I think right now,” Mansfield adds, “at the stage we are at in medicine and understanding, it’s not a ter-rible thing for there not to be a lot of direct-to-consumer tests that are purporting to provide very im-portant medical information.”

The FDA has not yet formally published its letter to 23andMe clearing the company’s Bloom syndrome test, and down-classifying similar “autosomal recessive carrier screening gene mutation diagnostic systems.” How-ever, the document can be read on Scribd.250 First Avenue, Suite 300


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