Wednesday, May 27, 2015

NEJM Publishes Six Papers on Genomic Testing (May 27, 2015)

On May 25, 2015, the New England Journal of Medicine published six policy papers on genomic sequencing applications, policy, and challenges.

Links after the break.

Precision Medicine - Personalized, Problematic, and Promising.
LJ Jameson & DL Longo.  Here.

The FDA and Genomic Tests - Getting Regulation Right.
BJ Evans, W Burke, GP Jarvik.   Here.
(See previously by Evans, here and here.)

The FDA and Genetic Testing.  [Response to Evans et al.]
ED Litwack, E Mansfield, J Shuren.  Here.
(On the FDA's flexibility see also here).

Three articles circle the topic of clinical variant databases and the expansion in a rolling basis of genes tested:

Gene Panel Sequencing and the Prediction of Breast Cancer Risk.
DF Easton et al.  Here.

ClinGen - The Clinical Genomic Resource.
HL Rehm et al.  Here.

Curating the Way to Better Determinants of Genetic Risk.
EG Phimister.  Here.

For a discussion of the six articles in Genomeweb (subscription), here.

An observation -
NEJM sometimes must shorten the titles of longer articles for the "splash pad" on its home page that represents the article.  In the case of Easton's article, they add a striking editorial spin in rephrasing the title - by parachuting in the banner "Caveat emptor" which does not appear in the Eaton article.

A follow-up: JAMA (June 3, 2015)

A week later, JAMA publishes a pair of two-pager op-eds on precision medicine, focused on the President's Precision Medicine Initiative (here).

The Precision Medicine Imitative: A New National Effort
Ashley EA [Stanford]  JAMA 313:2119, here.

A Public Health Perspective on a National Precision Medicine Cohort: Balancing long term knowledge generation with early health benefit.
Khoury MJ [CDC] & Evans JP [Duke]  JAMA 313:2117, here.

Khoury's article delves into some of the complexities of the million-person sequencing cohort that has been proposed.  For example, what would you do if you find occult cases of carriers of the fatal disorder Huntington's disease?  Khoury and Evans write:

A unique feature of the proposed cohort is whole-genome sequencing of the participants.4,5 Although this will inevitably lead to numerous discoveries and possible interventions, it will take time to yield dividends. In the meantime, there is a real opportunity for near-term benefit by focusing on conditions for which evidence-based applications are already available. The Centers for Disease Control and Prevention has created a 3-tier classification schema of genomic applications based on the methods of evidence-based medicine. REF 5   Similarly, a “binning” strategy for the human genome was proposed based on clinical validity and utility of genes and genomic variants.  REF 6    
Tier 1 (bin 1) genes and their variants are those with sufficient evidence for clinical validity and clinical utility to provide meaningful and actionable information to consumers and health care practitioners. Tier 2 (bin 2) genes and their variants are those with established evidence of validity but insufficient evidence of utility to support a recommendation for medical action. Tier 3 (bin 3) genes and their variants are those with either sufficient evidence for a lack of utility or presence of clear risk of harm, or those with insufficient evidence for both validity and utility.Adoption of tier 1 applications in the proposed million-person cohort could provide a path toward obtaining immediate benefits for thousands of participants and their families. 
Examples of tier 1 conditions for which preventive interventions are already available among persons with a predisposing mutation include hereditary breast and ovarian cancer syndrome (BRCA mutations), Lynch syndrome (associated with increased risk of colorectal cancer), and familial hypercholesterolemia. An estimated 2 million people in the United States have one of these conditions and most are not aware of their risk for cancer or heart disease. Once these individuals are identified, evidence-based interventions are available that can reduce their risk of adverse health outcomes. The challenges include how to best obtain consent, educate, identify, and deliver results to such individuals in the population because the implementation of any public health measure also carries risks and costs, as well as potential benefits. For example, although most would agree that identifying individuals at high risk of a preventable condition is desirable, important questions, such as the true penetrance of these conditions when ascertained via a population-based approach, remain to be answered.

This cohort of a million or more people would be expected to include many thousands of undiagnosed, unrecognized patients with a high risk for breast/ovarian cancer, colorectal cancer, or coronary heart disease, identified through genomic sequencing. If identified and properly educated, these individuals and their relatives could leverage established interventions to reduce their risk—an immediate potential benefit from this endeavor. Just as important, the cohort could inform many critical questions that need to be answered before implementing genomics at the population level. Other potential targets may include a carefully selected subset of highly actionable genes that the American College of Medical Genetics and Genomics7 has recommended be analyzed when individuals undergo genome-scale sequencing for other reasons.
The references 5 and 6 on "bins" are:
Dotson  WD, Douglas  MP, Kolor  K,  et al.  Prioritizing genomic applications for action by level of evidence: a horizon-scanning method. Clin Pharmacol Ther. 2014;95(4):394-402.
PubMed   |  Link to Article
Berg  JS, Khoury  MJ, Evans  JP.  Deploying whole genome sequencing in clinical practice and public health: meeting the challenge one bin at a time. Genet Med. 2011;13(6):499-504.
PubMed   |  Link to Article

For a journalist writing on genomics "hype," see here at Mendelspod commenting on a Buzzfeed article here.

For a June 22, 2015 article in JAMA on hype in personalized medicine, see:
Joyner MJ & Paneth N (2015) Seven Questions for personalized medicine. JAMA (epub), here.

Writing in part:  The average annual cost of new targeted cancer drugs frequently exceeds $100 000 per year. The authors of a recent trial of ivacaftor and lumacaftor for CF pointed out that these new medicines had effects on FEV in the first second of expiration “in the range of the magnitudes of change seen in studies of other cystic fibrosis therapeutics.”These include azithromycin, hypertonic saline, and ibuprofen. [But] Ivacaftor costs $300 000 per year, whereas a 1-year supply of ibuprofen costs approximately $30, and unlike ivacaftor, it can be used by all patients with CF. [refs omitted]
Joyner wrote a NYT op-ed last January, "Moonshot Medicine Will Let Us Down," here.

To discuss how the changing healthcare system and Medicare policy affects your company, association, or investments, contact Dr Quinn through FaegreBD Consulting