Working Group Meeting May 7-8, 2012
EGAPP Working Group members present:
Jonathan Berg, MD/PhD, FACMG; Ned Calonge, MD, MPH, chair; Doug Campos-Outcalt, MD, MPA; Ben Djulbegovic, MD; Ted Ganiats, MD; Roger D. Klein, MD, JD; Ken Offit, MD, MPH; Stephen Pauker, MD, MACP, FACC, ABMH; Margaret Piper, PhD, MPH; Sue Richards, PhD, FACMG; Ora Strickland, PhD; Sean Tunis, MD, MSc; Marc Williams, MD, FAAP, FACMG; and Doris Zallen, PhD
Welcome and Opening Statement
Ned Calonge welcomed the EWG and meeting attendees. The attendees introduced themselves and informed the group what latest projects each are working on.
Status Updates and review of briefing book materials
Dave Dotson welcomed the EWG to meeting 24 and provided the staff update. He provided a status of:
- Evidence review in progress
- Recommendations in preparation
- Manuscripts in Progress
- Handouts were reviewed
- EGAPP Web site statistics
The EGAPP FY2012 activities will include:
- Peer review and submitted recommendations
- Begin work on potential recommendations
- PCA3/prostate cancer
- Submit methods update paper, lessons learned paper, and binning manuscript
- CRC collaboration work.
A selection of 2 new EWG members will be ongoing – public health (2 nominees qualified and interested), pharmacogenetics (1 nominee qualified and interested). What are the next steps?
Muin Khoury welcomed the EWG Meeting attendees. He focused on the need to start up the production of more recommendations and methods. The status and activities of the Office of Public Health Genomics (OPHG) for 2012 were reviewed, including followup to stakeholders meeting and budget concerns.
The priorities of the office continue to be:
- Honest broker
- Technical assistance to CDC state public health
- Policy and communications
- Continue horizon scanning and online knowledge bases.
The OPHG Weekly update has changed significantly with the blog being very active on a weekly basis. The most recent blog is on the 3 tiers of evidence.
PLoS currents: Evidence on Genomic Tests – 23 genomic tests quick reviews are available.
Lynch Syndrome screening network – 71% of NCI-designated cancer centers screen tumors while only 15% of small community based centers. March 22 was Lynch Syndrome Awareness Day.
NHGRI 2012 – results of consortium, clinical sequencing exploratory research, genomic medicine pilot implementation projects, binning: ClinVar and ClinAction – An EGAPP-like process?, and Question: how should EGAPP coordinate WGS binning efforts?
OPHG’s NCI connections and include:
- Support of KSC
- Support for CISNet modeling
- Comparative effective research
- Cofounding of CSER
- Precision Medicine Discussion – Harold Varmus-workshop
- Planning for the next generation genomics and epidemiology research (December 2012 workshop)
Muin Khoury presented OPHG’s Evolving thoughts for EGAPP moving forward
- Focus on prevention and screening
- Explore unique EGAPP role to complement USPSTF on preventive services stratified by genomics/family history – 20+ that include family history as a contextual issue.
- Use of colorectal cancer screening as first example
- Integrate value research, modeling and rapid reviews
Next Generation Sequencing: Standardization of Clinical Testing
Ira Lubin presented his office’s work on Next Generation Sequencing (NGS) standardization of testing. He outlined his presentation to include:
- New analytic paradigm
- Enhanced sequence analysis
- Guidance in development
- CDC’s role to assure the analytic validity
General workflow is similar to that of other testing processes. However, several factors complicate the results: What do you do with incidental findings? What information do you want returned? And What’s relevant to family members?
The main focus of NGS is for atypical clinical presentations & rare diseases. A lot of promise in terms of advancing clinical care. Price point for hardware is coming down but the price for interpretation remains high.
Amy Gargis presented additional information on the work of their office. She outlined her presentation.
Sanger sequencing is very well understood and considered the Gold Standard. The accuracy approaches 100%. Next Generation Sequencing technologies are based on massively parallel sequencing of DNA fragments. The processes by technique/corporation are all different.
Bioinformatics pipeline for NGS include three stages of sequencing analysis:
- Primary – image capture/processing
- Secondary – sequence read files, variant calling/filtering of data by target
- Tertiary – variant interpretation
As part of the secondary stage, the depth of coverage, has not been established and varies from platform to platform. There is a need to establish this for target positions because reads are not uniform across genome.
Whole Genome Sequencing Discussion
Katrina Goddard reviewed an outline of the presentation on Whole Genome Sequencing. In framing the questions there are two returns (i.e. results to the physician and/or patient/consumer): Mandatory vs. voluntary.
A high bar is set on what is to be returned to a patient.
There is a need to systematically and efficiently evaluate the evidence about incidental findings using the following concepts:
- Actionability (Clinical Utility or equivalent)
- significance (Variants of unknown significance)
Implementation Approach: Overview
Rule in and rule out of Bin 1. Posted and if evidence is available for whatever reason, it would be made available.
Actionability – is there a practice guideline(s) for the genetic condition? Does the practice Guideline indicate that the result is actionable in one or more ways? Patient management and Surveillance? Family management? Circumstances to avoid? Is the result actionable in an undiagnosed adult with the genetic condition?
- What do we define as a practice guideline vs. and evidence-based practice guideline?
- Is a genetest review enough of a guideline?
- Do the practice guidelines normally reserved for children apply to adults?
Penetrance – Controversial cutoffs for penetrance (>40% or >2.0 in any population)? What sources are acceptable to use for penetrance? Need to be transparent about methods and guidelines.
Significance – Is the condition an important health problem?
Proof of principle methodology to complete the effort.
In comparison of methods to rule in/rule out with Green Method the results are pretty much in congruence with the exception of a few. The primary reasons for incongruence are: No guidelines, childhood onset disease, guideline only for child not adult.
Prostate Cancer SNP panels – review and recommendation
Julien Little presented an overview of the report Prostate Cancer SNP panels report. The EWG made edits to the recommendation statement and will circulate the recommendation for comments.
CRC Collaboration Planning
Ann Zauber and Muin Khoury opened the discussion on CRC collaboration risk stratification. The funding has been secured, option for a meeting. The need to know what role EGAPP wants to play.
EGAPP feels the role of family history in the process would be important. Additionally, how would EGAPP add to CRC screening? Can we add family history thru modeling and then bring to the task for to collaborate or independently? The EWG is interested.
The EWG volunteers would participate in a monthly conference call in preparation for a meeting in November.
The interested parties include KSC members, CisNet team, Ned Calonge, Marc Williams, Ted Ganiants, Cecile Jannsens, and Doris Zallen.
CYP450 Update Discussion
Dave Dotson reviewed the overall selection of articles from the original review. Dave repeated the search for using Pedmed using a similar search criteria and found 336 articles. Abstracts were classified into clinical validity or utility.
Summary of results:
- 336 total
- 302 abstracts reviewed
- 34 No abstracts
- 268 excluded
- 68 included
- Rx Decision – 1
- ADR – 11
- Clinical Response – 13
- SSRI Level – 33
CDC Library replicated the search string for the original review from September 2005 to 2012. 402 citations were found. The overlap between pubmed and the OVID search was 8 citations.
KRAS Recommendation Update
Roger Klein has added the CAP data to the recommendation in the analytic validity section for KRAS marker.
Add comments regarding the indeterminate results based on the proficiency testing in solid tumor samples versus blood samples for KRAS data analytic validity.
No comments on the inclusion for BRAF data analytic validity
Accept changes and give EWG ability to provide comments for a week. We then will submit to GIM – thoughts on reviewers to suggest? Kara Eng, Sharon Klein, Randy Burt, ? Samowitz, check NCCN prior reviewers for colon cancer, Glen Saltz, Stan Hamilton, Gary Lyman
T2D review/recommendation comments
Michael Douglas presented the current status of the T2D review and recommendation. The review and recommendation should be sent to EWG for specific comments due back at the end of May. When submitting for publication send list of suggested peer reviewers to GIM for the recommendation.
Lessons Learned Paper
The EWG discussed the Lessons Learned paper. A few comments were made:
- List current recommendations in a table.
- List the lessons learned in a table. This is probably not useful because the discussion around these lessons learned is needed from a contextual purpose.
- Why is the “decrease in funding” missing from the manuscript? The manuscript has been edited to balance this as a component but not the main focus. Efficiency in funding use.
- Liability Issue should be included especially in light of the “binning” of all the tests.
Wrap up and adjourn
Ned Calonge thanked the EWG meeting participants for their time and service. The meeting was adjourned at 11:30am.
The next EGAPP Working Group Meeting is scheduled for Monday & Tuesday,
September 10 -11, 2012 in Atlanta, GA.