Providing accurate risk assessment and anticipatory guidance are key functions of comprehensive genetic counseling. Providing accurate risk assessment for recurrence in the setting of a complex genetic trait, such as NSCL/P, is currently difficult. Providing preconception risk counseling to individuals with a personal or family history of NSCL/P is less than precise; the only risk figures available to provide are empirical in nature, and generally based on large prospective studies of mostly Caucasian cohorts (Grosen, Chevrier, et al., 2010). It is known that not all families with isolated cases of NSCL/P have the same recurrence – some cases may be truly sporadic or environmental, while others have increased risk due to an underlying genetic predisposition (Crawford & Sofaer, 1987). The ability to separate these two situations would allow for individualized risk assessment, not solely reliant on positive family history. If a predictive model could be built using risk factors in addition to family history, genetic counseling has the potential to improve for recurrence risk assessment in NSCL/P. The present study takes an important first step in the development of such a model.
A model is only clinically useful if it has an acceptable trade-off between sensitivity and specificity; highly sensitive tests allow practitioners to more confidently rule out disease if a highly sensitive test is negative (Trevethan, 2017). Conversely, a test which is highly specific will rarely result in a false negative, so a positive result provides reasonable confidence that a condition is truly present (Trevethan, 2017). Even the model with the best performance in the present study, Model 3, would result in a large number of false positives. The sensitivity was 87.1% and the specificity was 33.8%. This test performance means that nearly 30% of positives would be false
positives and nearly 50% of negatives would be false negatives, making it of little use in clinical practice.
Clinically useful methods of assessing risk can only be developed in the setting of robust research on the genetic and environmental risk factors. The present study evaluated only a handful of the many proposed risk phenotypes, finding cause for further consideration. Many more risk factors have been proposed in the literature that may be worth focusing on for developing a risk assessment tool with greater predictive ability, possibly even with the addition of a PRS component. Adding other risk factors may have the potential to improve model performance.
Providing accurate risk figures to couples in the preconception stage could allow for family planning, education, and preparation (both practical and emotional) for parenting a child with NSCL/P. Prenatally, risk assessment could provide cause for more careful ultrasound evaluation, plus the same ability to prepare, allowing parents to seek out resources and meet with cleft craniofacial centers to create a plan.
Predictive models can also serve an important public health service at the population-level, if they are able to aid in identifying subgroups of individuals at increased risk for recurrence (Agopian et al., 2012). Identifying those at increased risk to have a child with NSCL/P prior to conception could provide the opportunity to facilitate risk reduction steps (e.g. smoking cessation, folate and vitamin A supplementation) in an effort at primary prevention. Furthermore, the process of model development has the potential to reveal novel risk factors with significant predictive ability, providing new avenues for designing public health interventions. Research, such as that undertaken in the present study, is an essential component of public health services, as it allows for evidence-based policy development for population screening.
Additionally, one of the most critical points in laying the foundation for effective long- term care of a child with NSCL/P is in the first few days to weeks of the child’s life (Cleft Palate- Craniofacial Association, 2009). There are effects on physical, mental, and emotional health for individuals with NSCL/P and their caregivers; some of these effects can remain long-term issues without proper treatment (Sischo, Wilson-Genderson, & Broder, 2017). In the newborn period, infants with NSCL/P are at risk for failure to thrive without the proper feeding interventions; babies seen earlier in life by a cleft craniofacial center are more likely to have the right feeding support from the beginning (Kaye et al., 2017), they are also less likely to be admitted to the NICU.
It is important that caregivers have the support of providers who are adept at facilitating successful navigation of the surgical and therapeutic interventions for the OFC, specifically, and also of the mental and emotional difficulties they may feel along the way. Additionally, children with OFCs need access to emotional support through their families and the medical team to adapt to potential differences in their facial appearance and speech and to cope with the many surgical procedures and therapies they made need over the course of their lives. Cleft craniofacial centers are an invaluable resource in every life stage and step in treatment of an OFC. However, there may not be a center available immediately in certain areas of the country, as there are only about 175 centers in the U.S. Knowledge of risk status prior to delivery could help in coordinating with the nearest center, with the goal of an early visit with the team to plan for immediate needs (e.g. feeding), pre-surgical interventions, and initial surgery. In this case, predictive modeling could better the ability to provide another essential public health service: linking to or providing care.