Author Archive for Luke Jostins

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Debating the future of genome sequencing in medicine

This is a cross-post from my more technical blog, Genetic Inference. However, I thought that it might be of interest to non-specialists who like to keep up with the ongoing debates about the role of genomics in health and medicine.

Last week many of us at Genomes Unzipped (along with over 7000 other geneticists) were at the International Congress of Human Genetics in Montreal. A highlight of the meeting was a large debate entitled “Current and Emerging Sequencing Technologies: Changing the Practice of Medical Genetics”. The panel and the audience were both packed with research scientists, clinicians and industry researchers (you can see the full list of panel participants here), and as you’d expect the discussion was at times pretty lively.

Different perspectives

Joris Veltman described his exome sequencing of 500 individuals with intractable disease, and noted that there has been much success, and very little evidence of harm. Ségolène Aymé mentioned NIH targts that hope to see almost all genetic diseases diagnosed by 2020, and new treatments for rare diseases to be developed simultaneously. There seemed to be a solid consensus across the panel that sequencing should be rolled out as a standard tool in the diagnosis of genetic diseases, provided that the approach is a targeted one, restricted to finding the pathogenic mutation(s) causing the disease.

More controversial was the role of sequencing of healthy individuals, and the general return of data to patients or doctors for any reason other than directly diagnosing a genetic disease. Rade Drmanac, chief scientific officer of Complete Genomics, was obviously strongly in favour of everyone having their genome sequenced, and made it clear that Complete Genomics intends to start offering sequencing to doctors in the future. In his vision, genomes are sequenced at birth, and an initial analysis of immediately actionable results (e.g. potential genetic diseases) is passed to the doctor and patient, with further analyses being carried out if and when they are required.

Michael Hayden immediately dismissed this as hype. He pointed out how unable the US is to handle medical sequencing, with no good systems of reimbursement, a massive shortage of genetic councilors, and a general lack of training in the medical profession.While more positive in general, Louanne Hudgins also expressed worries about the lack of knowledge of genetics among doctors, with some truly scary examples of MDs failing to understanding even the most basic concepts in genetics.

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Friday Links: Studying association studies, and success at last in psychiatric genetics

In PLoS Genetics this week there is a viewpoint article on data sharing in disease genetics. The authors systematically looked at 643 genome-wide association studies published between 2002 and 2010, to see how easily available the results of the studies are now. They found that the availability of full study results has gone down over time, and many groups that do share data have put more restrictions in place on its use. They put this down to fears over the privacy of research subjects, and in particular to the Homer et al study. The Homer et al result is somewhat complicated, but in essence it says that if you have stolen someone’s genotype data, you can use it to figure out if they have participated in any given research study by looking at the full results of the study.

It certainly seems possible that worries about privacy are reducing the free flow of information within the research community. However, whether on balance the decrease in information flow is worth the increase in security is an open question. For my own view, I feel that having the genome-wide results of genome-wide association studies freely available is very important to the field, and is more important than the the rather esoteric risk of someone stealing someone’s DNA and using it to figure out that they once took part in a research study of inflammatory bowel disease. [LJ]

Genome-wide association studies have been hugely successful in identifying dozens of common genetic risk factors for a large number of common diseases. However, one area that GWAS has not had much success in is the field of psychiatric illness, where finding common risk factors that replicate across studies has been consistently difficult. However, it looks like this is starting to change. The current issue of Nature Genetics has two papers from the Psychiatric GWAS Consortium, detailing some of the largest meta-analyses of schizophrenia and bipolar disease ever published.

The schizophrenia study robustly replicated two previously implicated variants, and discovered five new ones, and the bipolar disease study replicated one and discovered a new one. The new variants give us some pretty startling insights into the genetics of the diseases, in particular revealing the importance of a non-coding gene micro-RNA 137 in regulating a wide range of genes expressed in neurons. As always, these variants explain only a small proportion of the total genetic effect, but they show that psychiatric genetics has now truly entered the GWAS arena, with all the scientific benefits that this can bring to medical research. [LJ]

The images above, in order, are taken from the paper Temporal Trends in Results Availability from Genome-Wide Association Studies, and from Wikimedia Commons.

Genetic risk prediction in complex disease

I thought I’d point out a review article in Human Molecular Genetics that just came out in (open access) preprint form by Luke and myself on genetic risk prediction in complex disease. In it we discuss some of the strengths and weaknesses of genetic and risk prediction compared to classical epidemiological predictors, different statistical modelling considerations, and the effect of GWAS on prediction. Readers of this space might find the conclusion of some interest, where we consider some of the societal aspects of trying to bring the interpretation of genomes into mainstream medical practice.

Friday Links: New genes for multiple sclerosis, and a new list of DTC genomics companies

This week sees the publication of a large study of the genetics of multiple sclerosis. A consortium of 23 research groups gathered together data on nearly 10,000 MS suffers, and discovered 29 new genetic variants that contribute to disease risk. Overall, genetic variants for MS can now explain around 20% of the overall heritability of the disease, and these genetic variants highlight pathways that are likely to be important in the disease (such as T-helper-cell differentiation). Notably, this study is published in Nature, which is pretty rare for genome-wide association studies such as this. Perhaps related to this is the wonderful degree of detail included in the figures, such as in the ancestry plots of individuals in the study (see left). It is also surprisingly readable, containing just 4 pages of main article, with the nitty-gritty relegated to 100 pages of supplemental text. [LJ]

The Genetics and Public Policy Center have released an updated version of their list of direct-to-consumer genetic testing companies. You can view the list as a rather user-unfriendly massive PDF matrix of companies versus diseases tested here. The list is certainly not as useful as it could be – for instance, there are no indications of test price or quality, and whole-genome sequencing companies are shown as not testing for any disease, rather than (effectively) testing for all diseases – but it would be a good starting point for a crowd-sourcing project to produce a more comprehensive database. Hmmm… [DM]

A case study in personal genomics

I have no strong family history of any disease, despite having 7 blood aunts and uncles and countless cousins. So when I sent my spit off to 23andMe at the start of the Genomes Unzipped project, I was expecting something very similar to Caroline’s experience: a 5% increase in risk here, a 2% decrease in risk there, nothing that would really tell my anything about my health.

However, this was not my experience. Along with a pretty interesting Y haplogroup, I also had three unexpected and potentially worrying health results. I am a cystic fibrosis carrier, a hemochromatosis compound heterozygote, and have a strongly elevated risk of age-related macular degeneration. This cocktail of genetic disease certainly was not what I came to the test expecting!

After some thinking, I decided to take my test results to my GP, and see if there was any advice or testing he would recommend. In the end, my GP referred me to a clinical geneticist, which started a cascade of appointments which in turn led to a number of important changes in how I treat my own health.

What was most interesting is how the whole experience got me thinking about my health as something I am in charge of. I have since made a number of important life-style changes, some of them directly related to my genotyping results, some more generally to improve my overall health.

The point of this post is just to go through some of the experiences, what I have learned about specific conditions, and what changes I have made to my life since. In some sense, I feel like my experience is a case-study in what good outcomes can come from personal genomics, both for specific conditions, and more generally for how genetic data can change your own approach to your health.

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DTC Genetic Testing and the FDA: is there an end in sight to the regulatory uncertainty?

Disclaimer: Genomes Unzipped received 12 free kits from Lumigenix for review purposes, and Dan Vorhaus has provided legal advice to the company. We plan to release a full review of the Lumigenix service in early July.

Last month three direct-to-consumer (DTC) genetic testing companies opened their mailboxes to find a slightly ominous but entirely expected letter from the FDA. The three recipients (LumigenixAmerican International Biotechnology Services and Precision Quality DNA) received substantively equivalent letters, with the FDA warning each company that its genetic testing service “appears to meet the definition of a device as that term is defined in section 201(h) of the Federal Food Drug and Cosmetic Act,” and that the agency would like to meet with company representatives “to discuss whether the service [they] are promoting requires review by FDA and what information [they] would need to submit in order for [their] product to be legally marketed.”

Translated from bureaucratese, that means that the FDA views these services as ones that may need to be formally reviewed by the agency and either approved or cleared before they can be legally sold. The FDA letter asks each company to describe its service and to explain either (1) why it does not require FDA approval or (2) how the company plans to pursue such approval.

This is a strategy that the FDA has pursued with a growing cadre of DTC service providers. These letters (currently 23 and counting1) represent the only public and company-specific actions the agency has taken to date with respect to DTC genetic testing. While many DTC letter recipients are engaged in dialogue with the FDA, those conversations have occurred beyond the public’s view. Until now.

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Genetics of CF severity, a survey of DTC customers and the value of a genetic diagnosis

In this week’s Nature Genetics there is a genome-wide association study of lung disease severity in cystic fibrosis suffers (or at least the subset who carry the ΔF508 mutation). The authors report a number of variants with “suggestive evidence”, and one with genome-wide significant evidence . The one genome-wide significant variant is rs12793173, with the C allele increasing the severity of lung disease. The variant is downstream of the gene EHF, which is also believed to play a role in asthma; the hope is that the function of this gene may shed some light on what causes variation in CF severity. As a CF mutation carrier with a CC genotype, any children that I have would be at a at slightly increased of having worse lung function. However, the variant only explains 1-2% of variation in lung function, so I won’t be worrying too much. [LJ]

A reader got in touch with us to inform of research he is doing into the response of personal genomics customers to genetic information. He is looking for users and potential users of DTC genetic tests to fill out a survey; you can find the survey here. If you have the time, this would be worth doing. Arguments about DTC genetics are too often based on hypotheticals or guesses, but there is a rapidly growing field that looks at how individuals really response to genetic data. This sort of data is exactly what is needed to make sensible decisions about the impact of DTC genetics on society. [LJ]

Continuing her series of interviews with people who have taken genetic tests, Elaine Westwick interviewed Jane Gregory, the mother of a child with a complex developmental disorder that was finally diagnosed by a genetic test. The interview raises a lot of the classical issues that you often see in clinical genetics cases, including the power of finding a genetic cause, even when knowing the cause doesn’t add any new treatment options. Well worth reading. [LJ]

The image at the top of the post, “65 Roses”, was made by Tanya Dawn

Cracking non-coding variation, carrying cystic fibrosis, and more Alzheimer’s prediction

Daniel and Luke attended the Biology of Genomes conference at Cold Spring Harbour last week. The talks did not have a huge amount of direct relevance to personal genomics, but did show some real quantum leaps in understanding the function of the non-coding DNA that makes up most of our genomes. Understanding mutations that lie outside of coding DNA is largely a prerequisite for transitioning to whole-genome sequencing for personal genomics, as most of the variation that drives genetic differences between people appears to lie there. As we’ve said before, one of the powerful aspects of sequencing is that it allows you to get at the aspects of your DNA that are unique to you, but that is only really useful (and a lot cooler) if we know what this unique variation does. Biology of Genomes showed us that that dream is closer now than it has ever been before.

For a (somewhat technical) account of some of the conference talks, you can read Luke’s blog posts over at Genetic Inference (along with a signficiantly less technical post about chipmunks and wood cabins), and Matthew Herper has a lay-friendly post on his Forbes blog. As has become standard, Twitter was an important way of disseminating knowledge live during talks, and Keith Bradnam and EpiExperts wrote about this aspect. [LJ]

Since GNZ started, Luke has actually been holding back writing about his many and varied genomics woes, and his resulting quest for bodily health, mostly for lack of time. However, one part of this has leaked out somewhat: he has recently given an interview to fellow blogger Elaine Westwick about being one of the two cystic fibrosis carriers in Genomes Unzipped. Read the interview at Elaine’s blog The Stuff of Life. [LJ]

On a similar subject to our recent post about calculating Alzheimer’s risk, over at Genomics Law Report Dan has written a detailed post about the regulatory challenges ahead for both direct-to-consumer and clinical tests for Alzheimer’s. [LJ]

Calculating your Alzheimer’s risk

For many diseases we have very little ability to determine who is at high or low risk; the risk factors are unreplicated, complicated, or understudied. However, for other diseases we can do much better. Alzheimer’s disease is a form of senile dementia that is characterised by abnormal clustering of proteins in the brain (right). We know a number of important risk factors for Alzheimer’s, and knowing your own risk factors may seriously change your estimate of the chance of developing the disease. But how can you calculate this risk?

This is going to be somewhat of an information deluge, as I go through everything to think about when you predict a complex disease, including how to calculate genetic and environmental risks, and how important these risks are, both individually and all together. I will demonstrate all of the calculations on the various GNZ contributors, and in particular how I have worked out my own risk.

I’ll measure the risks in terms of odds ratios; you may want to read the introduction to Carl’s post from earlier this year to refresh your mind on what this means. I will also use the disease probability; this is simply the chance of developing Alzheimer’s, or equally, the percentage of people with this set of risk factors who will develop the disease.

Also note that an important factor to consider is the baseline lifetime risk, the total proportion of people who will develop Alzheimer’s before they die. I am going to use a lifetime risk of 9% for men and 17% for women, taken from an Alzheimer’s Association report, but getting a good estimate of this is actually very difficult, and will vary from country to country.

If you want to know more about Alzheimer’s, including prevention, diagnosis and treatment, you can read about the disease on the Mayo Clinic or NHS Choices websites.

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Last chance to submit comments to the FDA about DTC genetics

Today is the last day to submit comments to the FDA about the future of regulation of direct-to-consumer genetic testing, and, by extension, the future of personal genomics. I would strongly urge anyone reading this blog to submit a comment; the FDA needs to hear the full diversity of opinions and facts on this subject to make an informed decision.

Have you or your family taken a DTC genetic test, and can explain your experiences, either positive or negative? Are you a scientist working on human genetics and have thoughts about the scientific merits of the tests? Are you a clinician, and have insights into how individual’s having direct access to their own genetic information will effect your practice? Are you an ethicist, social scientist or public health professional with opinions about the rights of individuals to access their genetic data, or the impacts such access will have on society or public health? Write a hundred words or so and submit them to the FDA.

You can submit comments via this form; remember, today is the last day before comments close. You can see the comments that have already been submitted here.

For more coverage on this round of comments, see posts by Dan, Daniel and Razib. You may also like to reread our consensus statement about the FDA’s recent investigations.

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