By Gabriel Lazarin, MS, CGC
Gabriel is the Director of Genetic Counselors at Counsyl, a laboratory that offers expanded carrier screening.
Discussions about carrier screening inevitably center around disease severity. Is the disease severe enough that it is worth offering screening? Who defines severity and then who decides whether that category of disease severity merits population screening?
These questions are easily recognized, but subjectively answered. Both sides of a complicated equation must be balanced. Physicians and public health officials desire screening protocols that address pressing medical concerns knowing that any screening program comes with costs, financial and otherwise. Parents-to-be have an interest in knowing what daily challenges they may face. Unsurprisingly, these sometimes competing interests result in conflicting perspectives on disease severity.
The focus on severity has increased as carrier screening panels have expanded the list of potential diseases for which a person may be screened. Despite the lack of consensus on definition of the word, severity is nonetheless cited in literature and referenced in conversations about carrier screening. In the ACMG’s statement on expanded carrier screening, the first criterion for consideration is, “Disorders should be of a nature that most at-risk patients and their partners identified in the screening program would consider having prenatal diagnosis…” Setting aside for the moment the stipulation that prenatal diagnosis should be considered (I, and many prenatal GCs, have many times encountered the patient that changes decisions once a hypothetical scenario becomes real), a paraphrase is that a disease should be severe enough so as to be “worth” screening.
The ACMG statement references severity again, saying, “The inclusion of disorders…associated with a mild phenotype should be optional…” A physician offering the test (and the laboratory supplying it) can reasonably question which specific disorders have a “mild” phenotype. Is hearing loss a mild phenotype, and who has the authority to make that decision? The recent joint statement on expanded carrier screening notably excludes commentary on severity, which further highlights the difficulties of its use in panel design.
In December, PLoS ONE published a study conducted by myself and others at Counsyl that is a first attempt at defining severity. ACMG provided the backbone of this approach: severity was one characteristic assessed when developing a universal newborn screening panel recommendation. Nearly 300 people participated in this significant endeavor, including at least 3 experts for every disease. While successful, replicating that process — laboratories have been updating their screening panels at least once a year — is prohibitively labor-intensive. We aimed for a process that was easily replicated and did not require convening experts of rare diseases.
Our results validate an algorithm that incorporates easily identifiable characteristics such as shortened lifespan or sensory impairment, and places that disease into one of four categories (also derived from ACMG): mild, moderate, severe, and profound. This avails the following advantages: more consistency among laboratories for selection and presentation of screening panels, and a common vocabulary among providers for describing diseases (like the singular language offered by a tumor staging system). Furthermore, the survey was completed in just under 6 minutes on average, making it much more practical for frequent use.
The study population included GCs and physicians, the majority working in reproductive settings. We intentionally did not attempt to identify experts on the diseases surveyed. Instead, commonly known diseases (e.g., cystic fibrosis) and lesser-known diseases (Bardet-Biedl syndrome) were concurrently assessed. All were evaluated in a consistent manner, indicating that familiarity does not affect severity categorization. In addition, the algorithm is completed by identification of disease characteristics not disease names. Even if an evaluator was not familiar with homocystinuria per se, she would certainly understand a list of its characteristics, such as intellectual disability and shortened life expectancy.
So, what’s next? A status check on current expanded screening offerings seems reasonable – Counsyl GCs applied the algorithm to 63 diseases that are common to three commonly-used commercial panels and determined that 25 have profound severity (e.g., Herlitz junctional epidermolysis bullosa, Tay-Sachs disease and metachromatic leukodystrophy) and 38 are severe (cystic fibrosis, ataxia telangiectasia, primary hyperoxaluria). All being in the two most impactful categories, many providers would likely agree on their inclusions.
However, another reasonable next step is to identify and reconcile differences that might be discovered by surveying the reproductive-age patient population. We, the medical community, also need to determine the desired aims of a screening program and apply those aims with consistency and objectivity. It could very well be that expectant parents and obstetricians agree with the ACMG’s statement that interest in prenatal diagnosis should be an influencing factor in a screening panel (what patients want has historically been an absent consideration in constructing guidelines).
But what about those who are not yet pregnant? Without the pressures of pregnancy, is it reasonable to allow the opportunity to consider a wider range of diseases? Obstetricians and GCs are more accepting of pre-pregnancy expanded screening. In pregnant women, decision-making can be influenced by interests in reducing stress and delaying information until after birth in order to reduce anxiety. A carrier screening protocol should serve the interests of pregnant and non-pregnant women, perhaps utilizing different severity thresholds for each scenario.
Through this study and blog post, I hope to open the conversation about what diseases should be screened, who should be screened for them and when that screening should happen. Without a standardized, objective vernacular, these discussions are colored by personal beliefs (which may not align with patient beliefs) and assumptive interpretations of important criteria. This is but a first step that needs to involve all stakeholders – providers, patients and professional societies. By first developing this standard language, we can begin this important discussion.
4 responses to “Guest Post: Starting a discussion on severity and the merits of carrier screening”
Regarding carrier screening or any genetic testing that exits in the context of reproductive decisions, I think it is important to really step back and try to get at what information matters most to the individual patient. It is also incredibly important that we take great care to consider carefully the words we use when describing and defining genetic conditions. As you point out, measures of severity lie in the eye of the beholder, and as the JAMA article you reference points out, healthcare providers tend to rate conditions more severely than individuals living with the conditions in many cases. This was the case for me when as a recent GC grad I met a couple for preconception counseling in which the male had delta-F508/delta-F508 cystic fibrosis. After years of learning about how “severe” CF was, I was humbled to learn that he didn’t view his condition that way. From my experience, a check list of health and development issues and physical features is not usually the primary information that patients want to know. The central question often is, what might life be like for an individual with this condition? The answers to these questions are also not objective, however I think we as genetic counselors can strive to try to do better in this area by learning from individuals living with genetic conditions and their families and then try to provide an honest portrayal of these conditions from lived experiences of those who know best. I appreciated reading in the conclusion of your PLoS study and this article that incorporating patient input is desired. A link to a commentary well worth reading on this topic by Sharon Terry and Natasha Bonhomme from the Genetic Alliance: http://www.geneticalliance.org/sites/default/files/expectinghealth/NothingAboutUsWithoutUs052013.pdf We should keep this perspective in mind as we consider the development of any carrier screening program.
My discsusions around carrier screening also center on detection rates. While many conditions included in expanded carrier screening are considered severe, many also have less than 10% detection rate outside of specific ethnicites. Are we doing a disservice to our patients by providing a false sense of reassurance by ordering testing with such low detection rates? Should carrier screening panels shift the focus from severity to increasing detection rates?
On that note, it can also be complicated for patients to understand the difference between SNP versus full sequencing (which would increase the detection rates). What about microdeletions??
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