On A Day When Apple Sidesteps Healthcare Technology, Mary-Claire King Shows How To Confront It

Mary Claire KingThe most interesting healthcare news of this week was manifestly not Apple AAPL +3.06%’s new watch; I can only assume that the Cupertino-based company concluded, after meeting with the FDA and consulting with a range of experts, that it made far more sense to go down the path of nutritional supplements, and stay as far from regulators as possible — as many of their brethren here in the Valley have emphatically suggested.

No, the more substantive healthcare contribution of the week came from the latest issue of JAMA, where 2014 Lasker Award winner Mary-Claire Kingwriting with several colleagues from Israel, audaciously suggested that all adult women should be screened for defined categories of BRCA1 and BRCA2 mutations – specifically, on “unambiguously loss-of-function mutations with definitive effect on cancer risk.”

(Disclosure reminder: I work at a genomic data management company.)

Today, patients with a family history of breast or ovarian cancer may be referred for BRCA1 and BRCA2 testing, but King is suggesting something more: she wants every adult woman to receive this testing, based on recent research she and her colleagues have published suggesting that relying on family history may miss half of the families with relevant BRCA1 or BRCA2 mutations; these families without a known history of breast or ovarian cancer tend to be smaller, King says, but members carrying the mutations have roughly the same chances of getting cancer as carriers from families with an established history of the disease.

The questions to ask about screening are captured by the ACCE framework (which I recently highlighted in the context of data from wearables, but which was originally developed for genetic testing).

Analytic validity – do the tests reliably and consistently measure the mutations they say they measure?

Clinical validity – how well does a positive test predict the likelihood of a cancer due to BRCA gene dysfunction?  To what extent can a negative test be relied on to conclude that a patient is not at elevated risk of cancer due to BRCA gene mutation?

Clinical utility – does a positive test provide actionable information?  King writes that “Among women who carry mutations in BRCA1 or BRCA2, surgical intervention, in particular risk-reducing salpingo-oophorectomy, reduces risk of both ovarian and breast cancer and reduces overall mortality.”

Ethical, legal, and social implications: What are the implications of population-level screening?  For example, might a negative screening test provide a false sense of security, resulting in reduced vigilance, and an ultimately an increase in non-BRCA-related breast cancers?

Is population-based testing for BRCA1 and BRCA2 mutations warranted?  The New York Times discussed this with King:

“Critics may object that ‘women aren’t ready for this,’ [King] said. But she argued: ‘Why should women be protected from information that will empower them and allow them to control their lives? We don’t need that kind of protection.’”

This is really the essential challenge of the rapidly-growing field of genomic testing, and the question King is pressing all of us to contemplate: when are the data good enough to share with patients?

Set the bar too high, and it raises the ugly specter of paternalism (as King suggests), as well as the very real concern that regulators, with the best of intentions, may let the perfect be the enemy of the good, and make it more difficult (and more expensive) for patients to access important information that could impact their lives.

However, share too early (before analytic validity is established, for example), and you risk providing bad data to patients that could result in devastating, life-changing decisions; this is the logic behind the FDA’s drive to regulate high-risk laboratory developed tests, for example (nicely discussed on this Mendelspod podcast).

Similarly, if you share data you don’t understand (which is a fair characterization of many mutations that are found during genetic screening), you risk scaring patients without helping them.  King, according to the Times, feels “ women should not be told about other rare mutations whose significance is unknown.”  (Others feel even these data should be shared.)

As the molecular basis of cancer and other diseases becomes increasingly well-understood, and additional risk factors are identified and characterized, more and more genes are likely to enter the BRCA1 and BRCA2 category, and merit serious consideration for population screening.

Moreover, as the cost of sequencing plummets, and the amount of actionable data increases, we may start to ask (as some already have) whether it makes sense to offer newborn infants not a handful of biochemical tests, as we do today, but rather genetic screening – perhaps even sequencing of their complete genomes.

In an era where many parents already bank cord blood (as my wife and I did), based on the slight chance that it might be useful one day, is it such a stretch to imagine parents might want to obtain the complete genomic sequence of their kids, in hopes that over time, and with ever-increasing annotation, it might prove at least as beneficial as cord blood?  Such testing would raise a host of thorny issues, as a group from McGill University discussed thoughtfully in Science Translational Medicine earlier this year.

In contemplating the astonishing complexity around bleeding edge medical technologies, including the very real operational challenges, and the attendant ethical issues that are appropriately raised, you can certainly appreciate why an incumbent consumer electronics company might elect to steer clear of controversy, and opt instead for a watch that occasionally reminds you to stand up.

DNA Day: Celebrating the Decades-long Unraveling of DNA

DNA day 2014

April 25th marks DNA Day. It’s on the calendar today to commemorate the 1953 publication of the structure of DNA by Francis Crick, James Watson, and others — but really, it’s a time to think about this special molecule and its role in what we do.

Just a decade after the completion of the Human Genome Project, it is truly amazing that it’s possible not only to sequence a human genome or exome, but to do so thousands of times and compare the results for a better understanding of human genetic variation. Studies comparing a few thousand exomes are becoming routine, and we are even seeing studies with 10,000-plus exomes. (Check out our Baylor CHARGE project as an example.)

These massive research and clinical efforts will be necessary to truly parse the meaning of our DNA. We are proud to be part of the community working on this challenge by providing cloud-based computational resources that let scientists run enormous analyses without crushing their local infrastructure. We also host great tools in our platform, so researchers have the option of porting in their own favorite pipelines or using our tools to create plug-and-play workflows in the cloud. And our insistence on enterprise-grade security means that you don’t have to worry about keeping your data safe; we take care of that for you. That’s cause for everyone to be optimistic about the future of these studies on DNA Day.

In case you were wondering, our data consumption isn’t just limited to As, Cs, Ts, and Gs. This week our team had fun looking back at the impressive results of writing contests associated with past DNA Days. Check out last year’s winners of the essay contest sponsored by the American Society of Human Genetics or by the European Society of Human Genetics (both groups are expected to announce this year’s winners today). And if you only have a coffee break to do some link-surfing, don’t miss these winning haikus from previous DNA Day poetry contests. Here’s our favorite:

A spiral staircase
Each step makes you what you are
But not who you are
dpasquantonio

AGBT Posters Featuring DNAnexus

DNAnexus was featured in a couple of posters at AGBT this year. DNAnexus scientist, Andrew Carroll, was in the poster hall, sharing data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium genomic analysis project. In addition, Narayanan Veeraraghavan, Lead Programmer Scientist at Baylor’s Human Genome Sequencing Center, presented a poster focused their own variant-calling pipeline, Mercury that was built on the cloud via the DNAnexus platform.

If you missed the conference, or you didn’t get a chance to chat with Andrew or Narayanan, here’s your chance to check out their posters:

Andrew presented never seen before data that was generated by Baylor’s Human Genome Sequencing Center using DNAnexus to run Mercury, its own exome and genome analysis pipeline. Interestingly, it was found as exome numbers increase, so do new variants found. Here’s a graph demonstrating that each new exome analyzed yielded novel genetic variation, rather than reaching a plateau after some critical mass of exomes:

variants sites vs exomes sequenced

 

For Andrew’s perspective on the poster, check out this short video:

The heart of Narayanan’s poster centered around Mercury on the Cloud Analytics (MOCA), an automated NGS pipeline HGSC developed, which upon being ported to DNAnexus was used successfully for novel gene discovery in two large-scale projects: CHARGE and Baylor-Hopkins Center for Mendelian Genomics (BHCMG). Some of the key features in this production pipeline cited in the poster include: zero setup, on-demand scale-up, version control, reproducibility, compliance with CAP/CLIA/HIPAA, and ISO 27001 data handling and security and compliance.

We look forward to seeing alternate workflows being built on DNAnexus by CHARGE commons to benchmark studies without the need to install or configure analysis tools.