Whole genome sequencing is now routinely applied to uncover the causes of rare diseases. However to benefit a larger population and to prevent the onset of disease, it is suggested that sequencing additionally needs to be carried out on healthy people as part of normal clinical practice. Greg Gibson from the Georgia Institute of Technology, USA and Atul Butte from Stanford University, USA explore how such sequencing can be integrated with clinical profiles and used to develop individual health action plans. Their findings, published in a recent article in Genome Medicine, describe the whole genome sequences and longitudinal clinical profiles for eight middle-aged Caucasian participants from the Center for Health Discovery and Well Being at Emory University, USA. Gibson and Butte told Biome more about the importance and impact such insights may have for health and wellness.
What led to your interest into research in genomic medicine?
GG: I worked as a fly quantitative geneticist for 15 years. When the revolution in human genomics came in the late 2000s, I decided the time was right to pursue a new challenge and to see whether my perspective might translate to human biology. I started with some basic genomic anthropology and did not expect to have a clinical focus so quickly, but when I moved to Georgia Tech in 2009, their partnership with Emory on development of a Predictive Health Institute provided the perfect opportunity to establish a genomic medicine program.
AB: I started my research career as the Human Genome Project was just picking up steam. It seemed obvious ten years ago, and even more obvious now, that the high-throughput measurement of molecules, whether proteins, RNA, and now especially DNA, was going to influence how we medically diagnose and treat individuals.
What are the main goals of the research at the Center for Health Discovery and Well Being?
GG: The Center for Health Discovery and Well Being (CHDWB) was initially conceived by Dr Ken Brigham to support the evaluation of innovative medical care models that place the emphasis on wellness and patient self-knowledge. It combines unusually deep annual clinical evaluations with a health partner model, where participants develop personalized health action plans focusing on those aspects of their health that need attention to prevent the onset of chronic illness. There are almost 700 healthy adults involved and this cohort provides multiple opportunities for long-term profiling of changes in clinical parameters with age.
Personalized medicine has largely focused on disease. However, your study focuses on sequencing healthy individuals. Can you tell us why this is so important?
GG: Our core belief is that if individuals can be encouraged and empowered to be involved in their own medical care, they may adopt more healthy behavior patterns before they start aging. We are thus interested in using whole genome sequencing, in combination with annual CHDWB clinical profiling, and functional genomics profiling (so called transcriptomics and metabolomics), to generate individual profiles of health. Our pilot data suggests that people are hungry for this information, and our next step is to evaluate how they deal with it, whether it does encourage lifestyle changes, and eventually whether it improves quality of life. The idea is that common genotypes in the genome can be used to classify which aspects of a person’s health may have the highest risk for disease, and to combine this with their clinical profiles to make informed decisions.
AB: As far as medicine has advanced in recent years, we still haven’t found any way to avoid dying! And today, you just can’t die without having something wrong with you or even being labelled with a disease, at least on your death certificate. So not to be too morbid or flippant, but we will all be patients someday. If there is a chance that genome sequencing can yield reasonably accurate predictions at increasingly lower costs, and if those predictions suggest low-cost interventions for health, then I would argue that the use of DNA sequencing in healthy individuals should be studied.
We use tools like colonoscopy, mammography, and prostate-specific antigen in preventative medicine, each of which is well known to have pluses and minuses in costs, reliability, and accuracy, and so it seems obvious that DNA sequencing will play a role in prevention eventually. I do fully acknowledge that it is still a hypothesis (a testable hypothesis!) as to whether patients are more likely to follow age-old advice about weight loss and smoking, with genomes in hand.
What was most surprising or interesting when you started looking at the results of combining sequencing data and clinical records?
AB: It was surprising that predictions for future disease can be made in an automated way across individuals, and it was surprising that these predictions could yield preventative measures.
GG: Given that we know that the genotypes discovered so far only explain a small fraction of risk for common diseases (such as asthma or diabetes), it is remarkable that there was something like a two to one ratio of concordance between genetic classification and clinical profile to discordance. This will only get better over the next five to ten years.
What resources will be needed in practice to translate complex personalized sequencing data into clinically relevant actions that promote health and well-being?
GG: Money, desire, and proof of principle. We’re a long way from a clear funding model for this in a healthcare environment that tends to focus on curing illness rather than preventing its onset. The cost of genotyping is no longer prohibitive, but good clinical profiling is several thousand dollars a year, and the two need to be performed hand-in-hand. Next we need participants to stay engaged and not lose interest as the initial benefits and novelty wear off. We hope that genetic information will be a part of the solution, but of course we need to be able to provide it in an informative manner, not just as a report delivered to their iPad. Both of these things are of course more likely if we can generate clear examples where this approach makes a difference: perhaps people who recognize that their hypertension is probably behavioral rather than genetic or who pay more attention to diabetes risk or discover the cause of their propensity to gain weight. We’re definitely interested in partnerships to help make this model a reality.
AB: I think current physicians might be concerned about the amount of effort and diligence it will take to obtain and interpret genomes. I think we will eventually have tools to help them, in the same way we have visualization tools that represent radiological images in such a way to enable diagnosis. But it could be that specialists take on this role, the same way radiologists perform mammograms or gastroenterologists perform colonoscopies for preventative care.
How do you think your findings could affect clinical practice in the future? What do you think the benefits and challenges will be?
GG: I’m under no illusions that this will happen overnight, but very optimistic that many people definitely want it to happen. I think we need to overcome the deterministic view of genetics and claims that we can use genetic profiles to predict disease, and instead measure success in terms of positive behavioral changes. Economic models suggest that it does not take a lot of improvement in general health to reduce absenteeism, the costs of prescription drugs, and to delay the onset of chronic disease, for this type of program to pay for itself. Since the benefit is more to the group than the individual (perhaps only a minority will actually respond) it is not clear who will pay. Then there are the scientific challenges: n=1 genetics is in its infancy and it is never easy to establish causality or even validate classifications and predictions. So patience is also going to be essential in the midst of the great excitement over genomic medicine.
AB: It is important to test many forms of prevention, and this is just one step of many needed to improve preventive care using genomics. If future studies also demonstrate the utility of this kind of work, and show improvements in quality-adjusted life years (QALYs) with maximum accuracy and at minimum cost, then I can see that this type of genomics can reach clinical care.
What’s next for your research? Are there plans to expand your pilot study?
GG: The next two challenges for us are to actually begin giving people their genomic profiles and evaluate whether it makes a difference, and to incorporate transcriptome and metabolome analyses into our genomic assessments. We’re planning on engaging tech-savvy students at Georgia Tech for the latter, and to work with a variety of physicians at Emory on the former. Then perhaps a third challenge will be to see if the whole approach can be used to help with long-term recovery from chronic illness. So much of genomics is focused on who will get disease, not enough on what to do to prevent it or to promote full recovery.
AB: We have ideas to run future studies with increased numbers of individuals, as well as increasing the number of ‘omic’ technologies to be run.