Achieving clarity in cancer genomics

Approximately 3 years ago, we held a clinical bioinformatics summit to discuss with international leaders in genomics, genetic testing and clinical laboratory procedures what it would take achieve clinical grade whole genome sequencing (WGS). That is to make WGS a safe and useful component of routine diagnostic assessments in the clinic. Among the mechanisms we chose to accelerate the advent of clinical grade WGS was a competition where 3 families contributed their genomic sequence and clinical histories.  Then multiple teams assembled and competed to produce the most accurate, most clinically useful diagnostic report. The competition resulted in a lot of learning and multidisciplinary team formation but also, even though we had not dared count on it, several breakthrough diagnoses. A good lay summary can be found here from Bio-IT World and an in-depth scientific summary here. Also, the cake presented by one of the mother’s to her child, who had gone for years without a diagnosis until the leading teams converged on the same mutations in the same gene, is shown below. With generous funding from Rob and Karen Hale, we kicked off the next round of the CLARITY competition as described below.

In addition to rare undiagnosed diseases, perhaps the most clinically impactful area of genomics, in the near term,  is that of precision diagnostics for cancer. However, the analytic challenge is far deeper as it requires analyzing tumors that are often heterogeneous (i.e. different clones), comparing it to germ line sequence (i.e. non-tumor DNA). Then, how are we to determine which of the mutations found are relevant to the diagnosis or therapy selection? Integrating information from RNA sequence and epigenetic modifications (e.g. DNA methylation) may help and there are several good ideas being proffered by several researchers.  Yet, how do we begin to bring all the data together systematically and meaningfully for patients with a malignancy? Given how early we are in this new realm of medicine, we decided to first hold a workshop where several national leaders in cancer genomics gave thoughtful assessments of the best way forward. After we we synthesize the learning from this meeting, we will announce a new CLARITY challenge for patients with recurrent cancers. Shown below are some of the speakers at the meeting which included Gad Getz, Rick Wilson, Peter Park, David Sweetser, David Margulies, Isaac Kohane, Judy Garber, Sharon Plon, Steve Chanock, Marian Harris, Heidi Rehm, Levy Garraway, and Katie Janeway. Another small but important step forward in the development of a data-driven, computationally-enabled medicine.

Hungry for DNA Games?

Thirty teams world-wide are apparently hungry enough and willing to contribute to making genomic medicine possible. Their efforts will help reduce to practice a game that to date is only within reach of star teams. May the odds be ever in our favor.

The passing of clean taxonomies.

Among the most productive constructs of the enlightenment are the modern taxonomies. These have been helpful in bringing order to the chaos of signs and symptoms and other clinical findings and were central tools in achieving our 20th century understanding of pathophysiology. They have also have an influential role to play in reimbursement for medical services. With the dawn of high-throughput molecular diagnostics many of us recognize that we are going to be able to be far more precise in our diagnostic and therefore therapeutic approach to diseases and their prevention.

Nonetheless, as we approach the systematization of medicine, we will be reminded often that nature may not hew to the simplified models that we are developing. This recent study in the New England Journal of Medicine, just does that by demonstrating directly that within a "single" tumor there exists a large multiplicity of tumor types, each with its own genomic characteristics and therefore particular therapeutic responsiveness (or lack of it). It can be argued that this is another instance of the tension between the "neats" and the "scruffies" but perhaps it is a foreshadowing of the decreased effectiveness of taxonomies as a cognitive tool for biomedical discovery and clinical care. If indeed, the underlying substructure of physiology is best represented by a probabilistic network model that can only be best grasped and managed through the use of computational tools, we have to seriously re-evaluate both our approach to disease definition and biomedical education.

Ancestral betrayal

We share many things with our ancestors, including a fraction of their genetic code. This genetic link to the past has further invigorated an already large industry and hobby in the exploration of genealogy and historical provenance. This piece from today's news, shows how these same records can be used to leverage your ancestors to identify you. In this instance, a murder suspect is potentially fingered by his ancestors from the Mayflower.

Hat tip: Ben Reis

Genome-wide clinical-grade interpretation

We are getting very close to the point that genome-scale sequence is available for clinical use. But will we know how to process and interpret it for such clinical applications?

Harvard Medical School, Children’s Hospital Informatics Program, and Harvard Medical’s School Center for Biomedical Informatics, the Partners Center for Genetics and Genomics, and the Harvard Medical School Center for Computational Genetics will hold a working meeting on December 7th and 8th, 2010 at the Countway Library on the Harvard Medical School campus. The purpose of this meeting is to directly address the challenges of providing consistent and clinically useful information to physicians and their patients based on large-scale genome sequencing. This meeting will focus on developing a "pre-competitive space" where industry collaborates earlier and more often to accelerate the clinical benefit from next-generation sequencing. Attendees are from clinical laboratory, sequencing, electronic health record companies as well as governmental and academic groups. This is a free but limited attendance meeting so please contact me if you are interested.

Not so knotty genomes

Erez Lieberman, of the HST Bioinformatics and Integrative Genomics program has just published a provocative paper which uses moderate resolution mapping (1 megabase) of the 3 dimensional structure of the genome. The results are consistent with prior work suggesting that DNA maintains its function by packaging itself into a structure that is free of knots. Now, if I could only apply this to my collection of wires in my drawer.

Regulating Curators?

This article suggests that a new bill in introduced in California may regulate how the modern curators and interpreters of biomedical data (bioinformaticians) may end up being regulated and tarred by the same brush as direct-to-consumer genetics testing companies.

“This law doesn’t just cover companies, it covers what’s done in academic institutions, too,” Butte said. “Nothing in this bill blocks that.”

More evidence, in any case, of the centrality of information processing to the biomedical enterprise.

The alien within and other tales of curatorial genetic mishap

As reported by the New Scientist.

Another quality improvement challenge for the genomically-knowledgeable librarian.

Different cell, different story

A Swiss-American collaboration makes vivid just how specific the effect of cellular/tissue context is upon the impact of genetic variation. We have understood for several years that each tissue has a different (if highly overlapping) mix of expressed genes (mRNA). However this study shows, in a study of three different cell types in 75 individuals, that the variation in expression between individuals that is attributable to genetic variation in control elements (i.e. regulatory SNP's) is highly tissue dependent. That is, over half of the regulatory variants only have impact in particular tissues. This suggests that understanding the impact of human genetic variation will take a lot more detailed study and not only in one tissue (usually blood).

[Dimas, A.S., Deutsch, S., Stranger, B.E., Montgomery, S.B., Borel, C., Attar-Cohen, H., Ingle, C., Beazley, C., Arcelus, M.G., Sekowska, M., Gagnebin, M., Nisbett, J., Deloukas, P., Dermitzakis, E.T. and Antonarakis, S.E. (2009) Common Regulatory Variation Impacts Gene Expression in a Cell Type-Dependent Manner, Science.]

Disclosing to and educating patients about genetic risk

We've read a lot about direct to consumer disclosure of genetic risk. Here is an opportunity to learn from Prof Robert Green about what he has learned from the methodological study of the disclosure process of the genetic risk for a serious disease.

Translational Genomics Seminar Series
"Genetic Risk Assessment for Alzheimer's Disease: The REVEAL Study."
Robert C. Green, MD, MPH
Duncan Reid Conference Room Brigham and Women's Hospital on Thursday, March 19th at 5pm.

The Library of the Genome?

In this article in a new journal (GenomeMedicine), we learn of the current efforts at the Cardiff University Institute of Medical Genetics to annotate the clinical meaning of the human genome. This database (of "over 85,000 different lesions detected in 3,253 different genes, with new entries currently accumulating at a rate exceeding 9,000 per annum") is arguably the human genome project most relevant to medicine. It also seems quite akin to curation projects very familiar to librarians. Can we use the knowledge and experience of librarians to increase the quality and timeliness of such genomic annotations? Can librarians learn from the efficiencies of the relatively small team of curators at Cardiff?

Finally, in the spirit of open access, would public funding of the Human Gene Mutation Database enable full free access to all the annotations?

Can we understand genetics? Can you help?

In the context of the multitudinous business plans of various direct-to-consumer genomics companies, any informed analyst should wonder: Can we (healthcare consumers) understand the information communicated by the long-promised, now available, large personalized genomic data sets? This in the context of much evidence that doctors cannot correctly interpret genetic tests and can be readily influenced by genetic testing companies.

With funding from the NIH, we are trying to study how to have patients manage, control and understand their own genomic data. There are several ways you can help but perhaps most importantly it is those who have had experience as consumers of genetics counseling who could help by serving as study subjects to determine what works and what does not in web-borne computer interfaces for direct-to-consumer disclosure of genetic risk data.