Genetic testing is an increasingly common health intervention across numerous clinical settings and is recognised to hold vast potential for improving patient care. Genetic counselling is the process that surrounds the consideration of genetic risk, encompassing many aspects directly related to genetic testing. Genetic counselling can be performed by genetic counsellors educated at the post-graduate level and regulated by a professional body. Genetic counselling provided by genetic counsellors includes a number of aspects separate to whether a genetic test is undertaken, for example, facilitating understanding, providing individual and family support, and assisting clients with adjustment to genetic risk.(1) However, aspects of genetic counselling are also undertaken by a range of other health professionals involved in patient care. As the processes of genetic testing and genetic counselling are intricately entwined, so too are the health-related outcomes that are measured in research in this area. Most research in the field of genetics does not distinguish between outcomes of genetic testing and genetic counselling; therefore, both will be considered and referred to herein.
One of the most widely adopted genetic tests worldwide is reproductive genetic carrier screening (RGCS), which provides individuals and couples with information about their risk of having a child with a genetic condition before or during early pregnancy.(2) RGCS identifies carriers of recessively inherited conditions (autosomal recessive or X-linked), such as cystic fibrosis, spinal muscular atrophy, and Fragile X syndrome. These conditions often arise unexpectedly and carriers are, in most instances, asymptomatic. Since there is usually only an increased reproductive risk if a carrier chances to partner with a carrier of the same condition, most couples that have an affected child will not have an existing family history that could have forewarned of their risk. Recessively inherited conditions are individually rare but when combined, are estimated to affect at least 30 in every 10,000 or 0.3% of births.(3–5) Based on this birth prevalence, it is estimated that 1–2% of couples will be at risk for having a child affected with a genetic condition, and this number can be much higher in consanguineous populations.(6) Of those at an increased risk, the likelihood of having an affected child ranges from 25%-50% in each pregnancy, depending on the specific condition. The intent of RGCS is to provide couples who are at increased risk with information to allow them to make informed reproductive decisions. Those who are aware of their risk can choose to pursue prenatal diagnosis during pregnancy, opt for in-vitro fertilisation (IVF) with preimplantation genetic diagnosis or the use of a donor gamete, consider adoption, or pursue pregnancy without any intervention and diagnose postnatally if desired. For this protocol, individuals and couples undertaking RGCS will be referred to as patients, however we acknowledge that these will be largely healthy adults, most of which will not go on to require significant medical follow-up as a result of their carrier screening results.
Carrier screening programs have been implemented since the 1970s in populations that have increased carrier frequencies for certain conditions, with targeted testing of only the conditions relevant to that population. Such conditions include but are not limited to Tay Sachs disease in the Ashkenazi Jewish population, and thalassaemia and other inherited haemoglobinopathies across a range of ethnicities.(7–9) These programs pre-dated our ability to identify carriers through genetic testing, instead relying on biochemical assays, with cystic fibrosis being one of the first conditions to have a screening program based on molecular methods introduced in the 1990’s.(10) Early carrier screening programs typically focused on one genetic condition; however recent advancements in genetic technologies have enabled a shift in the breadth of RGCS. Next generation sequencing has facilitated the development of 'expanded' panels that analyse hundreds to thousands of genetic conditions in a single laboratory test. These expanded panels are broadly available to the general population, and whilst they have predominantly been commercial offerings to date, largely limiting their uptake to high-income groups, there are emerging efforts internationally to support equitable access to expanded screening.(11) There are now a range of ways in which individuals and couples may access RGCS, including community screening programs in increased risk populations, attending public or private prenatal services during early pregnancy, or accessing preconception care through general practitioners or genetic counsellors in the public or private sectors.
There is increasing support for RGCS to be offered widely. In 2016, the Society of Obstetricians and Gynaecologists of Canada Genetics Committee and the Canadian College of Medical Geneticists Clinical Practice Committee (SOGC-CCMG) released a joint practice recommendation supporting the discussion of RGCS with all women/families considering pregnancy or at their first prenatal visit.(12) This advice was closely followed by a similar practice recommendation from the American College of Obstetricians and Gynaecologists (ACOG) in 2017.(13, 14) These international organisations were amongst the first to support the widespread offer of RGCS outside of increased risk populations, with The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) following suit in March 2019.(15) With this building momentum, it is a pivotal time to address research efforts to evaluate the impact of RGCS.
As with other areas of medicine, one of the aims of research in the field of genetics is to understand the benefits and harms of genetic testing as a health intervention. This is most often achieved by measuring the impact of a genetic test on patient outcomes when it is utilised in clinical practice; however this is acknowledged to be challenging.(16, 17) There is an established literature aiming to demonstrate the effectiveness of clinical genetics services, genetic counselling, and genetic testing, and systematic reviews have overall demonstrated a modest positive impact. (1, 18–23) A problem that has arisen frequently in the genetics literature is comparability across studies, with heterogeneity in the choice of outcomes and method of measurement. Often studies measure the same or similar concepts, such as psychological impact, but vary in the specific outcome that they report within this broad domain, utilise different measurement tools, and measure the outcome at variable time points. When outcome heterogeneity exists, the ability to directly compare and contrast the results of studies is hindered, and combining results, such as in a meta-analysis, becomes unreliable. This issue has been highlighted in research and commentary on the outcomes of genetic testing and genetic counselling and is becoming a focus of many discussions within the field.(1, 18)
Another issue noted in genetics research is the propensity for observational study designs due to the challenges of including a comparison group in the clinical setting. Very few studies on RGCS are experimental in design, with only a handful of randomised controlled trials. Observational study designs are well-recognised to have a lower standard of methodological rigour, with a number of potential problems that may lead to biasing of results.(24) One such issues is that there is not a requirement or tendency to publish a protocol outlining the outcomes that will be measured. This introduces a risk of reporting bias as there is a lack of accountability for publishing all outcomes, regardless of whether they support the author's position or reach statistical significance. There is also a great deal of variability in the inclusion of patient-reported outcomes, which are important for ensuring that the results of the research are relevant to patients. A small number of systematic reviews have been conducted in the field of RGCS, focusing on carrier screening for specific conditions. Those reviews that address data analysis and risk of bias in their methods, identified issues with outcome heterogeneity, study design, and overall quality of evidence, whilst others that didn’t specifically address these issues performed narrative syntheses, which is indicative that a meta-analysis was not possible with the available data.(23, 25–28)
We propose developing a core outcome set (COS) for RGCS. A COS is an agreed minimum set of outcomes that should be measured and reported in all studies on a particular topic.(29) The development of a COS applies a rigorous approach to defining outcomes that are relevant to all key stakeholders of a health intervention. This approach aims to minimise the heterogeneity in outcomes that are measured by different researchers, and as a result, maximise the ability to compare and combine studies in meta-analysis or other data synthesis approaches. Defining a COS also reduces the likelihood of reporting bias by ensuring that, at the very least, the core outcomes would be reported in all studies on an intervention. The incorporation of individuals who have had RGCS, clinicians involved in their care, and researchers and policy-makers guiding practice in this area in the development of this COS will ensure that outcomes are relevant to all stakeholders.
The Core Outcome DEvelopment in Carrier Screening (CODECS) study will apply the methodology outlined by the COMET (Core Outcomes Measures in Effectiveness Trials) Initiative to develop a COS for RGCS. To our knowledge, this study will be the first example of a COS aimed at standardising the reporting of outcomes in studies on a genetic testing intervention.