Multifactorial Rare Diseases: Can Uncertainty Analysis Bring Added Value to the Search for Risk Factors and Etiopathogenesis?

Uncertainty analysis is the process of identifying limitations in knowledge and evaluating their implications for scientific conclusions. Uncertainty analysis is a stable component of risk assessment and is increasingly used in decision making on complex health issues. Uncertainties should be identified in a structured way and prioritized according to their likely impact on the outcome of scientific conclusions. Uncertainty is inherent to the rare diseases (RD) area, where research and healthcare have to cope with knowledge gaps due to the rarity of the conditions; yet a systematic approach toward uncertainties is not usually undertaken. The uncertainty issue is particularly relevant to multifactorial RD, whose etiopathogenesis involves environmental factors and genetic predisposition. Three case studies are presented: the newly recognized acute multisystem inflammatory syndrome in children and adolescents associated with SARS-CoV-2 infection; the assessment of risk factors for neural tube defects; and the genotype-phenotype correlation in familial Mediterranean fever. Each case study proposes the initial identification of the main epistemic and sampling uncertainties and their impacts. Uncertainty analysis in RD may present aspects similar to those encountered when conducting risk assessment in data-poor scenarios; therefore, approaches such as expert knowledge elicitation may be considered. The RD community has a main strength in managing uncertainty, as it proactively develops stakeholder involvement, data sharing and open science. The open science approaches can be profitably integrated by structured uncertainty analysis, especially when dealing with multifactorial RD involving environmental and genetic risk factors.

Caring for patients with rare diseases during the COVID-19 pandemic.

Rare diseases frequently attack and weaken the immune system, increasing the patient's vulnerability to develop severe conditions after viral infections, such as COVID-19. Many patients with rare diseases also suffer from mental retardation and disability. These rare disease phenotypes do not emerge in older people who are susceptible to COVID-19 infection, but present at a very young age or at birth. These factors must be taken in consideration when caring for this vulnerable patient population during a pandemic, such as COVID-19. Patients with a rare disease have to take their regular medication continuously to control their condition and frequently, the medications, directly or indirectly, affect their immune system. It is important for this patient population, if infected with COVID-19 or another severe form of infection, to adjust the treatment protocol by specialists, in consultation with their own medical team. Special awareness and educational programs, understandable for mentally retarded patients, must be developed to educate them about social distancing, curfew, sanitization, and sensitization to the disease and quarantine. The COVID-19 pandemic highlighted the importance to reconsider the care required by patients with a rare disease during a pandemic or disaster, a program that should be adopted by the World Health Organization and governmental institutions for consideration.