What, how much and when – the conundrum of genetic testing!

With the conclusion of one of the largest global research effort in modern times by the end of April 2003, the Human Genome Project (HGP) took 20 years with over $5b in funding and produced scientific results which were of equally significant proportions. Researchers were able to sequence about 92% of the human genome with a 99.99% accuracy in all of the euchromatic regions of the genome and it opened up exponential possibilities for early detection of diseases through genetic variations and precise targeted therapies.[1] Since then, continuing efforts in the field of gene editing, high throughput sequencing and artificial intelligence methods such as deep learning have expanded further possibilities.

But how real and tangible are the benefits for patients and physicians in current day’s practice of medicine? Or, are these words just replete with just promise, hype and promise that will take years and possibly a decade to come real for larger applicability? 

Let us peel the layers to examine it deeper from multiple dimensions across health policy and implementation, technology advancements, emerging research, practice of medicine and patient.

Health Policy and Implementation

It has been determined that genomics plays some form of a role in the 9 of the top 10 diseases causing highest mortality in the US, which are heart disease, cancer, chronic lower respiratory disease, stroke, Alzheimer’s disease, diabetes, Influenza and pneumonia, nephritis and nephrosis and intentional self-harm.[2] The US Office of Disease Prevention and Health Promotion has now included Genomics as part of the Healthy People 2020 program star with initial focus on women with high-risk family history patterns for breast, ovarian, tubal or peritoneal cancer through BRCA1/2 testing methods. Secondary focus is on preventing genetic-related diseases that are backed by evidence-based recommendations and the Center for Medicare and Medicaid Services (CMS) and few private payers have now started covering reimbursement for many of these tests.[3]            

In parallel, the National Human Genome Research Institute has established a program to define a Genomics 2020 vision with focus on genomic technology advancements, genomic variations and interactions of genome with environmental factors.[4] This effort is expected to set the larger framework for public, private and public-private industry initiatives to break new ground in genomics.

To many who were skeptical of the genomics and HGP, the scientific value and larger impact to human health has now become clear. Studies that investigated the economic impact of HGP have reported every dollar invested in this project returned anywhere from $66 to $140 to our economy.[5] Even if that is a wide range, any investor would take a 1 to 66 return going by conservative estimates, or even half of that at 1 to 30. Considering the average stock market return is ~5-7%, that is fantastic ROI by any standard highlighting the potential of this field and how much genomics could drive our future economic development.

Technology Advancements

The area of human genetics and genomic sequencing has seen such explosive growth that even the overused cliché of its development outpacing Moore’s law appears pale compared to the current trajectory. To get an idea of how much activity is ongoing, look at the following statistics – in an August 2017 study from NCBI, just in the area of Human Genetic testing alone, there are over 80,000 tests available in the market with 10,000 unique modulations growing at a rate of 10 new tests being added every 4 days for the next 4 years.[6]  With a projected trillion dollars plus in economic market potential and a CAGR of 9.5%, technology is driving genetic advancements across individual tests such as BRCA1/BRCA2 panels, mitochondrial, human genome and whole exome, pharmacogenetics, Comparative Genetic Hybridization, single gene, cancer/somatic and others. The number of commercial direct-to-consumer and business-to-business vendors that offer an exhausting plethora of testing services is so disorientating it’s like stepping off the incredible Hulk and Kingda-Ka roller coasters both combined in a single ride that takes half the time. Now, once we manage to regain our balance from this paroxysmal positional vertigo, let us start to make sense of this phantasmagoria by segregating current genetic testing along three tiers: 1) ones that are prescribed based on clear synthesized evidence of benefit and efficacy such as BRCA, 2) those that may be prescribed for informed decision making on existential evidence or family history such as in primary care, cardiovascular or hematological disorders, and 3) direct to consumer genetic testing kits that you can pick off the shelves in any pharmacy or order online that lack any synthesized evidence or therapeutic benefit for clinical prescription/usage. This classification also aligns with the CDC’s classification of genetic testing as part of their tiered approach of integrating genetic testing into routine medical practice.[7]

From a $99 genetic testing kit to a $1,500 comprehensive genome sequencing report, the choices are varied and even physicians are at odds on how to utilize the testing reports in a practical manner that benefits the patients.

Emerging Research

Advancements in genomics are being combined with artificial intelligence methods to ascertain the pathogenicity of specific variations and its impact, including binding properties of proteins for genetic treatment. In addition, the potential to modify parts of the mutant genetic variation to a rectified baseline form through gene editing techniques such as ZFN, CRISPR and TALENs is gathering vast interest and applicability. Many of the monogenic diseases such as muscular dystrophy, hemophilia, sickle cell disease and others are already seeing practical interventions that may benefit the patient. For instance, Vertex and CRISPR announced FDA fast track designation for approval and progress in their gene-editing therapy CTX001 for beta thalassemia and sickle-cell anemia.[8] Other companies such as Novartis have advanced focused efforts in gene therapy in areas such lymphoblastic leukemia (childhood cancer) and spinal muscular atrophy that hold great potential for patients affected with these diseases.[9] In addition, the organization has partnered with Oxford University to establish a world-leading research alliance leveraging Artificial Intelligence and big data analysis to interpret early predictors of patient responses to treatments for inflammatory diseases such as multiple sclerosis and psoriasis.[10]

There are some other fascinating advancements by companies such as face2gene that enable facial phenotypes of genetic disorders using deep learning opening up possibilities for identifying genetic syndromes early on in as young as babies to target better therapies.[11] One more emerging area is Metagenomic analysis, which is study of genetic material from environmental samples. Genetic analysis of bacteria present in our gut, mouth, skin and other sites collectively labeled as the human microbiome or second genome may provide insights into digestive, skin and behavioral disorders. While the baseline for microbiome analysis is not as fully established and sequenced as the human genome, thanks to the HGP, it is still emerging as a supplementary diagnostic marker for physicians to detect health conditions and determine best interventions.

Practice of Medicine

Across many facets of healthcare - from primary care, diagnostics, acute care, chronic illness treatment to long-term care, genomic testing has the most profound impact when applied upstream for early detection of disease conditions and determining most effective drugs through pharmacogenomic matching. However, there are a number of practical limitations to this becoming mainstream in patient care. While for certain high-risk conditions, physicians are utilizing tier-1 genetic testing for diagnosis and evidence-based interventional therapies, adoption in preventative and/or primary care is still in adolescence. Primary reasons include lack of synthesized evidence for its efficacy in such a setting, reimbursement considerations from large payers such as CMS who may not support such extended testing, and a level of healthy conservatism in medicine that aims to eliminate false positives that arise from superfluous testing. Also, the lack of integration of analysis methods involving traditional panel biomarkers with genetic phenotypes, plus the need for a progressive diagnostic shift in primary care, all contribute to lower utilization of genetic testing in routine care regimen.

A recent survey of 500 primary care physicians in New York city found that only one-third prescribed a genetic test and most felt that they were handicapped to meaningfully interpret many of the results and integrate it into their practice.[12] In addition, the actual dialogue of broader preventative and diagnostic benefits of genetic testing between physicians and patients is not happening at the primary care setting as it is viewed as out of scope given that 90% of the visits are for reactive interventions or annual visits. But the situation is changing… many of the health systems such as Geisinger have started to incorporate testing for 77 genes for all of their patients that will enable the health system to take action based on genetic testing results.[13] Through this initiative called MyCode, Geisinger will absorb the estimated residual cost of $300-$500 for this test after any payer reimbursement and drive treatment that can avoid costly care down the line – this is a smart move! For it is geared to reduce overall healthcare costs for their population through early detection, intervention and prevention … and more evidence data of these benefits from these types of initiatives will only spur others to follow.

Finally, what does it means to the consumer/patient

Genetic testing may generate a range of feelings from excitement to paranoia depending on personality, needs, and level of awareness. The multitude of choices available combined with the downward spiral of genome sequencing cost certainly makes it more appealing to a consumer/patient than a well-made hot cappuccino on a cold winter NYC morning … but at the same time confusing the hell out of us in terms of what we can actually do with the outputs. A cursory search on the web will inundate us with links to hundreds of DNA testing companies that can track our ancestry and even relate us to all those famous personalities that we routinely dream of knowing and tracking down all those gene variant rascals that hold the potential for a myriad of disease conditions. In most cases, the reports provide a basic understanding of our genetic disposition and our risk factors, including the raw data.

Given all of this, how can one make the right choice as to what, how much and when to undertake genetic testing?

If the interest in genetic testing is to satisfy one’s intellectual urge, then most of the basic testing services available in a kit form either at a local pharmacy or online should satiate that desire with colorful reports to match. However, for those that may want to do something practical with their health utilizing the testing results, one may want to look deeper. Just reporting genetic variants is only one part of the puzzle…the ability to link it to diseases, potential pathogenic variants and additional risk factors is where it gets more complete. These kind of testing services typically involve a high throughput sequencing utilizing a machine such as the Illumina HiSeq series and the results to be carefully curated across multiple databases and exceptions validated by qualified genetic specialists and bioinformatic professionals by going through published research such as PubMed and others. Reported genetic variations are of two kinds; one that are actionable and can be prevented, treated or modified, and others which are more for lifestyle adjustment. In addition, some of the reports provide pharmacogenomic analysis that will help physicians to tailor more targeted drug interventions. With so much DNA testing hovering around us and trying to grab our attention, it may be prudent to rely on the advice of a primary care physician or specialist to undertake the most relevant genetic testing. Many with autoimmune, terminal or chronic disease may also require it as part of their ongoing protocols.

The true value of genetic testing is only realized when the results can be leveraged for improving one’s health condition, through combined preventative and ongoing treatments. It will require progressive primary care givers and health systems to drive a higher level of collaboration in a more innovative care setting for us to realize the true potential and impact of genetic testing.   

Until then, let us be mindful of this conundrum, but be optimistic of the fantastic potential it holds for all us to improve our health and lead a higher quality of life. Amen!

References:

1.      All About The Human Genome Project (HGP). National Human Genome Research Institute. www.genome.gov/10001772/

2.      Leading Causes of Death. Centers for Disease Control and Prevention. https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm

3.      Genomics, Healthy People 2020. US Office of Disease Prevention and Health Promotion. https://www.healthypeople.gov/2020/topics-objectives/topic/genomics#5

4.      Establishing a 2020 vision for Genomics. National Human Genome Research Institute. https://www.genome.gov/27570607/strategic-planning-overview/

5.      Calculating the impact of Human Genome Project. National Human Genome Research Institute. https://www.genome.gov/27544383/

6.      Genetic Testing Registry. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/gtr/

7.      Evaluating Genetic Tests. Centers for Disease Control and Prevention. https://www.cdc.gov/genomics/gtesting/index.htm

8.      CRISPR Therapeutics and Vertex Announce Progress in Clinical Development Programs for the Investigational CRISPR/Cas9 Gene-Editing Therapy CTX001. Vertex. https://investors.vrtx.com/news-releases/news-release-details/crispr-therapeutics-and-vertex-announce-progress-clinical

9.      Delivering on the promise of cell and gene therapy for patients. Novartis. https://www.novartis.com/our-science/novartis-institutes-biomedical-research/delivering-promise-cell-and-gene-therapy-patients

10.  Novartis and the University of Oxford’s Big Data Institute to establish world-leading research alliance using artificial intelligence to understand complex diseases and improve drug development. Novartis. https://www.novartis.co.uk/news/media-releases/novartis-and-university-oxford%27s-big-data-institute-establish-world-leading

11.  Identifying facial phenotypes of genetic disorders using deep learning. Nature Medicine. https://www.nature.com/articles/s41591-018-0279-0?_ga=2.198226283.537041572.1551632897-88319242.1548432198

12.  Views Of Primary Care Providers On Testing Patients For Genetic Risks For Common Chronic Diseases. Health Affairs. https://www.healthaffairs.org/doi/full/10.1377/hlthaff.2017.1548

13.  MyCode Community Health Initiative. Geisenger. https://www.geisinger.org/mycode