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CDC - Blogs - Genomics and Health Impact Blog – When Should We All Have Our Genomes Sequenced?
Genomic Screening of Healthy Individuals? Not Yet
New CDC blog post: When should we all have our genomes sequenced?
Improving genome understanding. The cost and accuracy of genome sequencing have improved dramatically. George Church asks why so few people are opting to inspect their genome, Nature News, October 2013
CDC blog post: How can we use genetic testing in population screening for common diseases?
Reflections on the cost of "low-cost" whole genome sequencing: framing the health policy debate
Caulfield T, et al. PLoS Biol 11(11): e1001699 Nov 2013
Genomes of 100 000 people will be sequenced to create an open access research resource
Torjesen I BMJ 2013;347:f6690
Open-access genome project lands in UK, by Ewen Callway, Nature News Blog, Nov 7
The UK Personal Genome Project could provide a massive free tool for scientists to further understanding of disease and human genetics, by James Gallagher, BBC News, Nov 6
October 31st, 2013 1:58 pm ET - Muin J Khoury, Director, Office of Public Health Genomics, Centers for Disease Control and Prevention
Recently, George Church, a prominent genomics researcher and leader of the Personal Genome Project asked why so few people are opting to inspect their genome. The cost and accuracy of genome sequencing have certainly improved dramatically. He clearly sees the health benefits of whole genome sequencing. He states “we should avoid being judgmental of people who practice genomic modesty or who choose not to act on genome information, but we should also ask if we are providing adequate and equal access to education about the benefits and risks of genome information.” Will access and education be sufficient to do the job? Or do we also need additional evidence on the interpretation, utility and value of our genome in health care and disease prevention?
More than a decade after the completion of the human genome project, the genome sequence has reached the clinic. We are now the era of Next Generation Sequencing (NGS) which includes many platforms for sequencing the exome or other large components of the genome, eventually culminating in whole genome sequencing (WGS). These technologies are increasingly utilized to identify genetic causes of rare, mysterious diseases, particularly childhood conditions. In addition, tumor-based genomic screening, family history–directed decision support, and pharmacogenomic applications all show increasing promise in the practice of medicine.
But how about genomic sequencing of healthy individuals? Over the past few years, an increasing number of healthy individuals have had their genomes sequenced, analyzed, and published. The Personal Genome Project has been dedicated to creating public genome, health, and trait data resources and is based on willing participants that agree to publicly share their personal data for improving the health of many. Recently, the Empowered Genome Community initiative was launched to help people who have had their whole genomes sequenced make their genomes more scientifically useful, by exploring and sharing them with each other and with researchers.
But is the routine use of WGS beyond research any different from the use of screening tests in clinical practice? One can argue that WGS is part of the unique characteristics of each person (age, gender, ancestry, ethnicity) and can be used for a variety of purposes other than clinical practice, such as genealogy, recreation, forensics, and health literacy. When it can be measured correctly and the price is right, should it be exempt from evidence-based principles? In fact, many researchers and genomic tests developers are convinced that “consumers want their genomes sequenced, and that they have a right to have them. The only question is the price. When the price comes down far enough, it will just happen. Everyone will get their genomic data and know what to make of it. We will be living in a kind of genomic utopia.”
Nevertheless, if we want to use WGS in the course of regular preventive care and health promotion, research should be conducted to evaluate its benefits, harms and added value to what we are currently doing. The widespread use of cholesterol screening in the population in the prevention of heart disease and prostate specific antigen in screening for prostate cancer are just two examples that have been subjected to years of rigorous studies (the latter is still controversial) and evidence-based guidelines. The idea of screening healthy individuals has been around for more than 100 years and has captured the interest of health-care providers, public health professionals, and the general public. The main purpose of screening is early detection of asymptomatic disease or risk assessment for future disease to improve health outcomes. Today screening is well established in clinical practice and public health and includes many diseases such as cancer, diabetes, heart disease and infectious diseases. Scientific and implementation principles for screening have been discussed by many organizations, most notably the 1968 criteria from the World Health Organization [PDF 7.25 MB], and have evolved over time. These principles ensure that the benefits of screening outweigh potential harms and reach equitably throughout the population. Generally, however, we tend to overestimate the positive health impact of screening and underestimate the potential for harmful effects such as overdiagnosis, inappropriate interventions, and anxiety.
While WGS in healthy individuals has the potential, using genetic risk stratification, for improving health and preventing disease, it can also lead to potential medical and psychological harms, cascading or inappropriate healthcare interventions and increasing costs. Given the myriad of weak associations between genetic variants and many diseases, it is not currently clear what the added value of genomic information is in screening and disease prevention [PDF 641.24 KB]. As stated by Evans and colleagues in a recent commentary: “Efforts that aim for genomic risk stratification often are justified by the hope that simply informing individuals of their genetic risks for disease will induce beneficial behavioral changes. Thus far, this notion is largely contradicted by available evidence. Although we already know how to lower risks for most common diseases, getting populations to eat properly, exercise, and give up unhealthy behaviors, especially without major policy changes, is challenging, and there is little evidence to suggest that genetic tweaking of risk will meaningfully augment these efforts.” The bottom line is that we still do not understand the balance of benefits and harms of WGS and how to ensure that benefits can be distributed equitably across the population. The importance of conducting research on WGS before widespread use in practice cannot be over emphasized.
It is important to remember that WGS is not one test. It is a conglomerate of numerous tests, millions of genetic variants, a few of them have been validated for use in specific practice scenarios (such as Lynch Syndrome and Hereditary Breast and Ovarian Cancer, but the vast majority of genomic variants are of unknown health or medical significance. Therefore, as part of “rolling out” the WGS in practice, it is crucial to put its various components into “bins” of increasing levels of evidence on validity and utility to ensure reaping the full benefits of this far reaching technology in improving population health.
We hope that current National Human Genome Research Institute genomic medicine implementation activities will assess whether and how to implement next generation sequencing (NGS) into clinical practice both in sick people as well as healthy populations. Currently, a number of academic centers are studying implementation of genomic medicine in various research projects. In addition, the National Cancer Institute funded several comparative effectiveness research projects in cancer genomics to evaluate the added-value of genomic tests and applications along the cancer care continuum.
Finally, it is worth noting that the NIH recently awarded grants totaling more than $25 million over four years to help three research groups to develop authoritative information on the millions of genomic variants relevant to human disease and the hundreds that are expected to be useful for clinical practice. This effort will lead the way towards an evidence-based integration of the WGS into medicine and public health.
For 7 years I led one of the teams registered to compete for the US$10-million Archon Genomics X Prize, and I was naturally disappointed by the abrupt cancellation of the competition in August. However, the confusion surrounding the X Prize does provide an occasion to reflect on the problems and misunderstandings in genomics. The first is that genomics is seen as expensive. In fact, sequencing costs have plummeted — from $2.7 billion for the first human genome in 2003 down to $1,000 today. That’s not much more than the cost of a decent laptop, and much less than a car. However, people are reluctant to pay to have their genome sequenced — many feel that health care should be provided for free by insurance or the government and, indeed, this is our not-that-distant goal, as there are many in our community who would not benefit from genome information if it were not free. However, for those today who can afford a genome sequence, we would argue that, overall, the cost of sequencing is expected to be recovered over a lifetime through the avoidance of unnecessary diagnostics and therapeutics and time spent in waiting rooms and hospitals.
“Those of us at the sharp end of genomics need to work equally hard at conversations with
Are the results uninterpretable? Even if we place the As, Cs, Gs and Ts in the right order, how does this help? Genome-wide association studies (GWAS) and studies of twins can give the impression that predicting traits from genomic sequence is a haphazard science. But since 1991 the number of highly predictive gene tests has risen from two to 3,000. Even ‘complex’ traits include components that can be identified and applied clinically to individuals who are not classed to be directly at risk. For example, height and diabetes GWAS have shown that a vast number of common variants have small effects, but the alternative of seeking rare variants reveals large effects by altering levels of growth hormone for height and insulin for diabetes. These hormones are effective therapies even for individuals who are not mutant in them. Too often the messy results of GWAS and twin studies are down to poor selection of subjects and neglect of confounding environmental factors.
Even if they are interpretable, are the results useful? Yes! Even if there is no cure for the genetic conditions identified, there are effective preconception and prenatal options that could have an impact on the family. For example, Ashkenazi communities already use genetic screening to make lists of suitable marital partners early in life to avoid their offspring developing painful Tay–Sachs disease and more than 20 similarly devastating diseases (which are not restricted to their community, by the way). Although we are tempted to restrict genomics to those with ethnic or family risks, the fact is that we are all at risk. Even the possibility of finding markers for one treatable disease (such as a cancer or cardiomyopathy) could, for some, be a sufficient reason to check one’s genome.
Perhaps most provocatively, some critics assert that genomics could be harmful. The US Genetic Information Nondiscrimination Act (GINA) prevents discrimination based on health insurance and employment; however, there is not a GINA in every country, and it doesn’t cover the military, life insurance or person-to-person discrimination. But the question is: do the overall benefits of genomics exceed the risks? Do the benefits of driving trump the one-and-a-quarter million traffic-related deaths per year? A growing number of bioethicists and researchers are worried that typical consenting practices do not inform patients of the likelihood of data escape and re-identification. Certainly, conventional consents served to protect the researchers, not the volunteers. However, the huge numbers of volunteers who are willing to share their genetic data make this a moot point. Why insist on recruiting those — and setting policy around those — who would be upset if their data escapes?
It is important for those of us at the sharp end of work on genomics to work equally hard at conversations with the public. We already share our (very revealing) faces, voices and opinions. And, as we share more of our genetics and as we develop genomic progress into precision medicine, researchers and the public alike need frank assessments of all of these tests and treatments. We need the Genomics X Prize more than ever.
George Church is professor of genetics at Harvard Medical School, Boston, Massachusetts, and founder of the Personal Genome Project.