Precision Medicine, Cardiovascular Disease and Hunting Elephants
Section snippets
What is precision medicine?
There is no clear definition of PM and this term seems to have drifted into use over the last several years and largely replaced its predecessor personalized medicine. From a CVD perspective several prominent authors have focused on the potential for genetic or genomic (DNA sequence variant) information to inform ideas about risk stratification, prevention, drug dosing and choices, therapeutic responses and ultimately outcomes.2., 3., 4., 5. This includes information about both rare and common
The Human Genome (HG) Project (HGP) and genetic revolution in medicine
So, where did the concepts that ultimately led to Fig 1 come from? Ideas about the genotype phenotype relationship are at least a century old and preceded by more general philosophical debates about nature versus nurture that date to antiquity.6 However, by the 1980s it became apparent that it might be possible to sequence the human genome. This possibility led to many bold predictions about the medical advances that would rapidly follow the reading of the so-called “book of life” as the
Disease with a genetic component
A key idea underpinning both the HGP, the genetic revolution in medicine and now PM is that for many if not most diseases (including common diseases) a limited number of common gene variants explain most disease risk. This is known as the common disease common variant hypothesis.14 In this context, gene variants that confer relative disease risks of 5–10 × would be highly predictive. These variants could then be identified via screening and then targeted with precision interventions could be
Diagnostics
If a few common variants associated with markedly increased risk did in fact exist for most common diseases then making diagnostic or predictive tests with high levels of sensitivity and specificity would be possible. However, to take T2DM, for example, the receiver operator curve (a composite analytical approach that considers both diagnostic sensitivity and specificity) for gene risk scores in a number of studies has been only marginally better than predicting heads and tails from a coin flip
Preventive medicine
Given the general lack of predictive power of gene variants and gene scores, the obvious question is prevention of what? However, there are important questions about how patients respond to information about health risk that need to be considered in the context of genetic risk information. This holds especially true if the information is speculative or about a gene variant or risk score associated with minimal increases in relative risk that are dependent on or interact with a host of
Pharmacogenomics
Pharmacogenomics (formerly called pharmacogenetics) has a long history with a number of success stories related to drug metabolism and drug safety.33 It is also an area of precision medicine that can be combined with drug ordering and genetic testing regimens in the clinical setting to provide “decision support” and reduce the chances of patients receiving drugs that might evoke rare life threatening complications and reactions.34 However, for common conditions like HTN, there is no convincing
Gene therapy
There are currently no approved gene therapy treatments for CVD. This contrasts to the optimistic projections from the 1990s and early 2000s.44., 45. Along similar lines there are no approved stem cell therapies for CVD most notably heart failure (HF) and there are questions about the utility of this approach.46 Finally, there are a number of biological limitations and regulatory hurdles to xenotransplantation for the treatment of end stage HF.47., 48. For gene therapy and xenotransplantation
Drug therapy
The idea that therapeutic targets might emerge from gene variants associated with a disease or other phenotype has been a major “selling” point for those who advocate large scale sequencing of populations. The idea is that when a gene variant is associated with a phenotype, even if that association explains only a tiny fraction of phenotypic variance or has limited predictive value, it might still identify biological targets that could be useful in drug development.56 While this is an
Reduce costs
Projecting how wide adoption of PM, or any sweeping technological change, might affect health care costs is a daunting task. This task is made more difficult in the case of PM because it is so broad based and rests on assumptions about the ability to predict likely outcomes and either preempt or intervene in them effectively. What is the evidence for such assumptions? In addition to reliable “precision” data that can be acted on with confidence, a highly debatable proposition as outlined
Potential successes
The one potential success I have highlighted for PM thus far is preemptive decision support to avoid serious drug reactions frequently based on drug metabolism. Parenthetically, most of the reactions that can currently be flagged for attention come from genetic variation in a limited number of metabolic pathways (frequently liver or kidney) that were established long before high throughput sequencing and modern “omic” tools. The understanding of very rare diseases, frequently in children, is
Concluding thoughts and questions
It is said that all good stories have a set-up, conflict, and resolution. The set-up of this story was about the parable of blind men and the elephant and the related problem of the elephant in the room. The conflict has been about the mismatch between the optimistic projections made by PM advocates and what the data actually show. The fundamental point integrating my multifaceted critique of the genetic revolution in medicine and its policy child PM is that the advances from brute force
Statement of conflict of interest
The author declares no conflict of interest.
Acknowledgments
My work on individual variability and blood pressure has been supported by HL-83947. The opinions expressed in this essay are my own. I would like to thank Denis Cortese, MD, David Warner MD and Nigel Paneth MD, MPH for their helpful comments on this manuscript.
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2018, Genetics in MedicineCitation Excerpt :The appointment of precision-medicine proponent Francis Collins to the role of director of the National Institutes of Health, the announcement of President Obama’s Precision Medicine Initiative, and the emergence of numerous direct-to-consumer genetics-related health companies such as 23andMe, have all played a role in this rise of media discourse. Although the terms “personalized medicine” and “precision medicine” (PM) have become the most commonly used in this context, they still lack singular, concrete definitions.1,2 Many other terms have been used in similar contexts, including “stratified medicine,” “P4 medicine,” “genetic medicine,” and “personalized genomics.”2,3
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Statement of Conflict of Interest: see page 657.