How longitudinal observational studies can guide screening strategy for rare diseases

Abstract

Newborn screening (NBS) is an important secondary prevention program, aiming to shift the paradigm of medicine to the pre-clinical stage of a disease. Starting more than 50 years ago, technical advances, such as tandem mass spectrometry (MS/MS), paved the way to a continuous extension of NBS programs. However, formal evidence of the long-term clinical benefits in large cohorts and cost-effectiveness of extended NBS programs is still scarce. Although published studies confirmed important benefits of NBS programs, it also unraveled a significant number of limitations. These include an incompletely understood natural history and phenotypic diversity of some screened diseases, unreliable early and precise prediction of individual disease severity, uncertainty about case definition, risk stratification, and indication to treat, resulting in a diagnostic and treatment dilemma in individuals with ambiguous screening and confirmatory test results. Interoperable patient registries are multi-purpose tools that could help to close the current knowledge gaps and to inform further optimization of NBS strategy. Standing at the edge of introducing high throughput genetic technologies to NBS programs with the opportunity to massively extend NBS programs and with the risk of aggravating current limitations of NBS programs, it seems overdue to include mandatory long-term follow-up of NBS cohorts into the list of screening principles and to build an international collaborative framework that enables data collection and exchange in a protected environment, integrating the perspectives of patients, families, and the society.

Genomic newborn screening: Are we entering a new era of screening?

“…A thoughtful approach builds on interdisciplinary scientific knowledge, theory of science, context‐sensitive ethics approaches, 61,62 and evidence‐based medicine 63 . It is aware of the gray zones and uncertainties in science and medicine 4,7,64 and the “devil squares of screening and diagnosis” as described above.…”

“…A thoughtful approach builds on interdisciplinary scientific knowledge, theory of science, context-sensitive ethics approaches, 61,62 and evidence-based medicine. 63 It is aware of the gray zones and uncertainties in science and medicine 4,7,64 and the "devil squares of screening and diagnosis" as described above. It fosters real informed consent and shared decision making via highly skilled communications skills and the application of evidence-based decision aids (for newborn genomic screening 65 ) that should include important information as the big data-informed consent checklist, 23,62,66 as outlined in Table 8 and as included in the recommendations of Genomics England.…”

Clinical outcomes and survival of individuals with methylmalonic acidemia, propionic acidemia, classic homocystinuria, and remethylation disorders identified through newborn screening

“…Although agreeing on the same set of NBS criteria, national NBS panels vary widely (3). Since it might be difficult to meet all NBS criteria for rare diseases that are considered candidates for extended NBS panels, pilot studies demonstrating the feasibility, diagnostic process quality, and patient benefit are an important tool to evaluate these candidate diseases through collection of structured data and careful evaluation (4). Since 2016, the NBS center at the University Hospital Heidelberg has been coordinating a pilot panel utilizing a combined second-tier algorithm for identification of individuals with different types of methylmalonic acidemia (MMA), propionic acidemia (PA; MIM #606054), cystathionine-β-synthase (CBS; EC no.…”

Improving Recognition of Treatable Rare Neuromuscular Disorders in Primary Care: A Pilot Feasibility Study

“…To foster a prompt diagnosis of NMDs, three methods have been considered: newborn screening (NBS), pediatric population screening, and screening of a population at risk. NBS programs have the potential to identify individuals with rare treatable conditions at an early stage and to shorten the time to starting disease-changing therapies, thus improving health, development, and life expectancy [ 15 ]. They are considered an important measure of secondary disease prevention and one of the greatest advances of modern public health with significant individual, socio-economic, and societal benefits [ 16 ].…”