Genome sequencing--how are results reported?

What kind of data should be provided to those who have their genome sequenced?

This is the first issue raised by McGuire, Caulfield, and Cho in their Nature Reviews Genetics article, Research ethics and the challenge of whole-genome sequencing. In the following, I have taken their text and added some text of my own. The authors' text is in quotes or indented.

 "Should participants simply be given their raw sequence data?"

"James Watson received a miniature hard drive with his entire genome sequence. For most individuals, this form will be meaningless." Most of the rest of us are unlikely to be able to interpret a raw-data presentation. "People who consent to have their genome sequenced," whether for research or personal use, "are likely to want to learn more.""

"An annotated listing of potentially relevant genes would provide more information." This is like the presentations delivered by companies offering genome-analysis, where they provide the data for interpretation but also highlight specific "genes" and analyze them for you. You can see examples of these types of analyses at Hsien Hsien's blog, Eye on DNA.

The authors of the Nature Reviews Genetics article contend that

. . . this level of analysis would require validation in an approved clinical laboratory (at least in the United States). Such a process would be expensive and, without the appropriate expertise, the results could be subject to misinterpretation. These concerns will be exacerbated if whole-genome sequencing is offered in the commercial or clinical context, where appropriate research protections might not be present.

What is the process of disclosure and is there follow-up care?

Inevitably, the significance of the generated data will vary — from clearly clinically relevant (for example, monogenetic disease information), to potentially relevant (for example, risk information), to data of unknown clinical significance. Expertise is needed for interpretation and to ensure an adequate understanding of the health and social implications of the identified genetic variation, both in the present and in the future. At present, there is no standard mechanism for disclosing research results, and there are an inadequate number of physicians who are specially trained to interpret and communicate this information and to provide follow-up information and clinical care when new research findings are reported. This suggests an expanded role for geneticists and genetic counsellors, as well as physicians; we therefore recommend that further training for primary-care physicians in genomics should be provided to facilitate the communication of research results, and to provide follow-up information and clinical care as new research findings are reported.

Furthermore, genetic results of uncertain clinical validity will nevertheless generate potential concern about disease risk among otherwise healthy individuals. This concern may potentially lead to increased demand for more invasive follow-up diagnostics such as magnetic resonance imaging (MRI) or computed tomography (CT) scans, raising questions about who should pay for such services, and placing pressure on already stressed clinical providers. Even if wealthy individuals choose to pay for themselves, issues of justice and equity arise as personal genome sequencing will consume limited resources such as scanner, technician and physician time. Before whole-genome sequencing is integrated into routine clinical care, the potential effects on an already strained health-care system must be carefully considered.

How will the data be stored? How will data be integrated intoa person's clinical record?

Several groups are actively working on developing policy regarding the integration of genetic and genomic information into the electronic health record. This work should continue, and those involved must think progressively and preventively about data generated from human whole-genome sequencing. A process to determine what constitutes validated and clinically relevant data will be difficult to implement. However, national advisory committees, such as the US Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS), can provide useful guidance and set standards for determining what the terms ‘validated’ and ‘clinically relevant’ mean. Whole-genome sequence data should not be integrated into the health record until such detailed guidance, appropriate security measures and comprehensive policies are developed and ensured. Of course, individuals retain the right to refuse genetic testing and can request that individual research results are not included in their health record.

The examination of these issues led to the recommendations given in the first blog entry on this topic:

 Returning research results

Recommendation 1.1. All human whole-genome sequencing initiatives should be conducted under a formal research protocol, and ought to include the development of a data return and counselling policy that can be evaluated by the relevant research ethics board.

Recommendation 1.2. Further training for physicians should be provided to facilitate the communication of research results, and to provide follow-up information and clinical care as new research findings are reported.

Recommendation 1.3. Only validated data of known clinical relevance should be integrated into the health record. Practice guidelines should be developed for determining what constitutes validated and clinically relevant data. A process should be developed to update an individual’s health record with additional genetic information as research progresses and new knowledge about the clinical relevance of specific gene loci is gained.

This topic will continue tomorrow, with an examination of issues relating to relatives of the person whose DNA is being sequenced.

Marie Godfrey, PhD





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