Genome-based Personalized Medicine - a Letter
Dear Andrew,
We regret to inform you that your grandma passed away after undergoing ‘personalized’ treatment at our genomic medical facility. Our experts determined that she was reckless with her genome during her long life and accumulated too many junk DNAs. Study shows that over 80% of the genome is functional in normal people, whereas in her case, only 10% appeared to work properly.
The immediate cause of her death was a blast, by which we do not want to mean that she was having a good time in our hand. In fact she was in terrible pain, when she called one of our nurses. To determine the cause of the pain, the nurse ran a large blast search against the HUGO and NR databases. Unfortunately, by the time blast completed its run, your grandma stopped responding to any type of alignment, annotation or GO analysis. We later determined that she only needed help to go to the toilet and that was the cause of her pain. However, running blast is part of standard procedure in our personalized medical facility, whereas your grandma’s non-genomic need was exceptional.
In fact, our programs could easily determine her need to go to toilet, if our variant caller worked properly. We utilize open-source software from one of the top research centers in Boston, but sadly their cryptic codes do not come with too many comments. A few months back, our software intern on H7-visa incorrectly modified a C-macro to convert output format from begin=0 genomic coordinate to begin=1 genomic coordinate. We just found out that all if our variant calls made since then had been wrong. Your grandma had a short deletion on chr7:1729112-1729114, which is common in all women between age 90-95 with frequent need to go to restroom. Shift that by one base and you get the genomic marker for constipation !!
The only ray of hope in this whole saga was the ‘positivity’ treatment she received every Thursday, based on the highly cited paper - “Positive Affect and the Complex Dynamics of Human Flourishing”. During that positivity treatment, we tried to maintain a healthy ratio of 2.9 to 1 of positive comments, positive remarks and positive food habits and she seemed to enjoy it (as measured by marked improvement in vagal tone). At other times, we treated her like crap. In future, we plan to expand this positivity experiment-control treatment in combination with monitoring of gene expression profile of our patients. Please keep us posted, if you or other members of your family likes to enjoy top-notch genomic treatment at our center.
Sincerely,
Jonathan Clown, MD, PhD
Chief Bioinformatician and non-evolutionary Geneticist
Institute of Genomic Health, CA
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Above commentary is written in jest, but what is reality? Ans. - it is no better than above letter, based on a new study published in JAMA. (h/t: @dangraur)
Clinical Application of Whole-Genome Sequencing - Proceed With Care
A number of concerns have been raised regarding the downstream consequences of providing clinicians with interpreted genome scale data in an otherwise healthy individual.12-14 Oneof the most pressing in an era of health care cost containment is the concern that flagging potential risks in patients would lead to resource intensive secondary testing and interventions of unclear benefit. The yield of potentially clinically significant variations related to inherited disease reported by Dewey et al for each participant was fairly substantial (as reported in Table 2 of the article8). To explore the clinical consequences of returning the results defined by the research team as reportable from their 12 participants, the authors shared technical summary reports (online supplemental material Sample Report8) to a small group of volunteer clinicians (3 primary care clinicians and 2 medical geneticists) not involved in the process of genome interpretation and analyzed their suggested action steps. That the clinicians could make much sense of the variant reports likely indicates a higher level of genomics expertise than their average peer clinicians. The findings suggest, at least superficially, that concerns about expensive immediate downstream clinical actions in every sequenced individual may be unfounded.
On average, the panelists suggested an estimated 1 to 3 initial additional diagnostic tests or referrals per individual at a cost of US $351 to US $776; clearly those next steps could result in a cascade of interventions of unclear costs. Despite the apparently reasonable hypothetical initial cost estimates, an important finding was the fair to poor levels of agreement among physicians regarding what variations should be acted on, as well as the diversity of next steps recommended. Admittedly, both the patient and clinician sample size is small. However, lack of agreement regarding clinical actions raises the credible possibility that introducing WGS information into clinical encounters at this time may be premature. Significant work is needed to develop evidence- linked guidelines for clinical action. Education of physicians and other health care practitioners regarding the potential risks and benefits of obtaining WGS seems of paramount importance.
Medical decision making in the setting of an incomplete understanding of human biology has been a part of caring for patients for thousands of years. For better or worse, clinicians have developed skills to cope reasonably effectively with substantial lacunae in knowledge.Complete elucidation of the human genome sequence will undoubtedly be recorded in the annals ofmedical science as a major step toward filling voids in understanding the biological underpinnings of health and disease. In the near term, however, genome sequencing has unmasked substantial additional fragments of the complexity underlying health and disease.
Medical application of genomic and personalized medicine technologies hold out the real promise of improved decision making and patient outcomes by providing an increased knowledge of the determinants of health and disease at the level of the individual patient. Like the personal computer, Internet, smartphones, and electronic health records, turning back now from the use of genomic technologies in health care is inconceivable.15 Studies like that of Dewey et al provide a glimpse of what is possible but demonstrate that much remains to be learned about previously assumed to be known information as well as myriad known unknowns and unknown unknowns before truly successful widespread integration can occur. A question facing potential early adopters of genome sequencing as an adjunct to patient care is whether or not having WGS data, at this time, will decrease uncertainty and improve outcomes or merely exponentially increase the complexity of clinical care.
