Comments on "NHGRI Long-Range Planning"

Given the mission of the NHGRI, these are appropriate questions that need to be answered and can be used for future direction. One most important issue that should be integrated throughout is a comprehensive content/information on ELSI (Ethical, Legal and Sociocultural Issues) on genetics data collection and testing for front line health practitioners. This content should include well-developed and consumer-tested evidence-based talking points for consumers and health practitioners. Another issue is the cost factor. In a market-driven economy, private and government sectors should drive the cost of genetics testing down. If we truly value genetics testing as a hope for the future globally we should make it available, accessible, and affordable. In addition, general health care providers, not just physicians or few limited specialized professionals, can understand and explain the results to the public in an understandable way. Information technology can be harnessed such as virtual practice including genetics informed consent, ELSI, collection, recording, chain of custody, testing, analysis, reporting of findings to the consumer, etc.

(184) Tuesday, February 24, 2009 5:20 PM

A critical factor in implementing genetic testing is convincing people to participate in such testing. Recent legislation may help, but there is still reluctance to provide genetic data that people believe could be used to deny insurance, employment or other opportunities. The public needs to be convinced that genetic testing is risk free. A discussion of this issue could be added to Paper 1 or Paper 3.

The impact of these important White Papers could be increased by good editing. Some of the writing is crisp and lucid. Some, frankly, is not.

(185) Tuesday, February 24, 2009 5:34 PM

In the NICHD Collaborative Pediatric Critical Care Network, we have had very open and collegial relationships with NHGRI staff who have attended our Steering Committee meetings, and expressed an interest in our work. We are a 10,000 annual-admission collaborative research network with unique ethnicity and geographic distribution, and with a great interest in candidate genes, as well as triggers and patterns of gene expression in critically ill and injured children. While all of our NIGRI contacts have been positive about our work, they have made it clear that their mission really focuses on whole genome analysis studies in large populations, on problems that affect large populations of adults (e.g., colon cancer). So, the ability to support, for example, our look at candidate genes in sepsis (or critical asthma, critical pertussis/pulmonary hypertension, MRSA following influenza, or many other critical conditions) is not present. This means that an important scientific opportunity is being missed, i.e., to look at pathogenesis in the young, at stages in the developmental trajectory before adulthood where such suggested research, in pediatric morbidity and the development of disability, might truly lead to research to improve the health of all children with special needs and chronic illnesses.

(186) Tuesday, February 24, 2009 5:36 PM

For the points made involving the target individuals/patients, it seems important that the identification of research needs, the research interpretations and clinical applications of genomics, and the education/training of all stakeholders, should acknowledge more strongly the changing dynamics of a person over the lifespan. These dynamics include not only changes during development (e.g., pediatrics as addressed by some comments) and aging, but also after a life-changing list of medical conditions. Those conditions should also include disabilities, not found in any of the papers.

(187) Tuesday, February 24, 2009 5:37 PM

February 27, 2009

The Association for Molecular Pathology (AMP) is an international medical professional association representing approximately 1,600 physicians, doctoral scientists, and medical technologists who perform laboratory testing based on knowledge derived from molecular biology, genetics, and genomics. Since the beginning of our organization we have dedicated ourselves to the development and implementation of molecular diagnostic testing, which includes genetic testing in all its definitions, in a manner consistent with the highest standards established by the Clinical Laboratory Improvement Act (CLIA), the College of American Pathologists (CAP), the American College of Medical Genetics (ACMG), and the United States Food and Drug Administration (FDA). Our members lead and work at the majority of clinical molecular diagnostic laboratories in the United States as well as in laboratories in many other countries. We are frequently involved in the development of novel molecular tests, and in the validation of laboratory developed or commercial assays.

Thank you for the opportunity to comment on the White Papers in Phase 1 of NHGRIýs Long-range Planning project. Our comments are as follows:

White paper 1:
Applying Genomics to Clinical Problems-Diagnostics, Preventive Medicine, Pharmacogenomics

Q1, additional questions:
- How do we integrate of the vast amount of information becoming available through genomic medicine, into the constraint practical environment of clinical practice?
- How do we sort actionable (vetted) information from early results and when should we consider findings at a genomic level ready for implementation, especially in the absence of an understanding of functional or epigenetic effects?

Q2, additional questions:
- It is important to ask how the cost of testing can be kept low, but also to determine how the cost of interpretation and education can be kept within reasonable limits (and what these are). The technology is expected to allow mass data generation, but QA and reliable interpretation of raw data is lagging behind.

Q3, additional questions:
These are excellent questions. What types of studies will be needed and what is the necessary scope to provide answers?
- Should we consider development of an educational track for a medical subspecialty under molecular pathology (ýapplied genomicsý, with many interdisciplinary components)?

Q4, additional questions:
- Where will clinicians find support for their questions about newly discovered information? Should this be centralized?

Q6, additional questions:
- How do we plan for clinician education and translation of identified risk factors into actionable information?

Q7, additional questions:
- How do clinicians ensure that information obtained through recreational genomics/DTC testing is analytically and clinically valid?


White paper 2:
Applying Genomics to Clinical Problems ý Therapeutics
(IS: No comments: my comments were addressed in the reviews already posted promote integration of genetic, genomics, functional pathways, research and clinical disciplines to distill the most powerful data)

Q3. additional questions (Simhan Nagan):
§ How do we weigh in practical factors such as the high costs associated with conducting genome-wide association studies, and the elaborate IT-infrastructural support needed to analyze the computationally intensive data generated.
§ How can processes that streamline ethics committee approvals and obtaining informed consent documents for genome-wide association studies in the global environment of a typical drug trial be established.

White paper 3:
A Vision for the Future of Genomics: Education and Community Engagement

Q3, additional questions:
Who is going to provide the infrastructure and resources to educate health care providers. And how are such resources curated?

Q11, additional questions:
How can we best inform the public of the risks associated with freely sharing their genomic information with others (relatives, friends, companies)?

(191) Friday, February 27, 2009 9:55 AM

When targeted vectors are able to modify a viable line of stable stem cells the medical needs of small percentage dependent genetic disabilities may be used to help increase the medical chances for success. Orphan diseases may be used to herald dicoveries or to justify funding if there is a known probable outcome that is scientifically justifiable.

(222) Monday, March 23, 2009 8:51 AM

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(225) Thursday, March 26, 2009 12:50 AM

I've written columns about this but here's a summary of my thoughts:
I think the genome-wide association studies need to be thought about differently. My argument about such fishing expeditions is that we ought to be fishing where we know there are fish to catch. I think that, rather than throwing money and resources at ever larger "random" studies trying to associate common variants with disease, we ought to look at the association between rarer, but disease-associated, variants with other diseases.
For example, it's established that carriers for the rare autosomal recessive lysosomal storage disorder Gaucher Disease are about 10x more likely to develop Parkinson's Disease than are non-carriers (the carrier frequency is about 1 in 100 in the general population but 1 in 20 among Ashkenazai Jews). One possible interpretation for this correlation is that lysosomal dysfunction is a significant risk factor for Parkinson's. If that were true, then one would expect that carriers for Anderson-Fabry Disease, Niemann-Pick Disease, Tay-Sachs Disease, and Pompe Disease should also be at increased risk for Parkinson's. It would be easy to test for such a correlation.
There are a huge number of inborn errors of metabolism and many are recessive diseases, so the carriers represent, I believe, a fascinating source of candidate genes for the kind of rare variant-disease connection study that I have in mind. My suspicion is that there is more haploinsufficiency out there than is generally believed, and that a significant number of "sporadic" diseases are actually genetic disorders with low penetrance.
In short, I would like to urge the NHGRI to incorporate studies of the connections between diseases into its long-range policy. It is uniquely positioned to take the lead in such studies, which are difficult throughout the rest of NIH due tot he balkanization of biomedical research by phenotypically-described diseases.

(250) Wednesday, April 29, 2009 7:36 PM

Genome wide functional experiments are now possible, even in challenging primary cells such as neurons. The development of systems to integrate the results of phenotypic screens of the sort done via High Content Screening (HCS), with other assays and public data sources is essential. The lack of established standards within given fields, such as HCS, prevents an easy integration with orthogonal experiments and public data sources such as PubChem or Kegg. The lack of standardized statistical methods to analyze HCS data is also problematic. Developing comprehensive solutions to these problems will require a community effort and workshops including bioinformatics experts, chemical biologists, end-users, equipment manufactures and software providers are likely to be essential. From a business perspective of instrument and software manufacturers, the risk of investing into developing and adopting standardized nomenclatures that will not become the community standard needs to be minimized. Even simple naming conventions of HCS analysis parameters will require some software development effort. This is another reason why a community effort is required. There are many examples of successful community and industry standards. One of the main driving forces and success criteria will be the enormous gain of productivity resulting from the ability to integrate various internal and external data sets and public data sources. This will ultimately improve our ability to development of novel therapeutics for complex indications for which there is no cure or treatment today.

(251) Wednesday, April 29, 2009 11:17 PM