Development of Strategies to Decrease False Positive Results in Newborn Screening

Abstract

The expansion of national newborn screening (NBS) programmes has provided significant benefits in the diagnosis and early treatment of several rare, heritable conditions, preventing adverse health outcomes for most affected infants. New technological developments have enabled the implementation of testing panel covering over 50 disorders. Consequently, the increment of false positive rate has led to a high number of healthy infants recalled for expensive and often invasive additional testing, opening a debate about the harm-benefit ratio of the expanded newborn screening. The false-positive rate represents a challenge for healthcare providers working in NBS systems. Here, we give an overview on the most commonly used strategies for decreasing the adverse effects due to inconclusive screening results. The focus is on NBS performance improvement through the implementation of analytical methods, the application of new and more informative biomarkers, and by using post-analytical interpretive tools. These strategies, used as part of the NBS process, can to enhance the positive predictive value of the test and reduce the parental anxiety and healthcare costs related to the unnecessary tests and procedures.

Use of Molecular Genetic Analyses in Danish Routine Newborn Screening

“…Most diseases on many newborn screening panels are caused by pathogenic variants in well-known genes and diagnosis using molecular genetic analyses may seem relevant and are feasible to conduct on filter paper blood spot samples [8][9][10]. As alluded to earlier, a main goal for NBS quality development is to decrease the false positive rate and with first-tier NGS, it could theoretically be possible to obtain the same reduction in false positive rates as we observed for second-tier use of molecular genetic analyses [11]. It may also lead to stratification of infants with severe versus benign disease as for isovaleric aciduria [12].…”

“…Investigations may include both expensive and invasive additional testing and a discussion of the benefit-harm ratio is relevant. While some studies cannot show any consequence of this to the families, others have shown an increased number of contacts with the health care system as well as admissions, thus suggesting a vulnerable child syndrome [11,[23][24][25][26][27]. Both concerning the confirmatory investigations in the newborn period and the possible further investigations and admissions later on, the price may be considerable also from an economical point of view.…”

“…Most diseases on many screening panels are genetic; thus, the use of molecular genetic analyses is relevant, and they have been shown to be feasible to conduct on DNA extracted from filter paper blood spot samples [8][9][10]. An important goal for using molecular genetic analyses is to decrease false positive rate [11] and to stratify infants with severe versus benign disease as has been shown for isovaleric aciduria [12]. Another goal could be to increase the adaptability of NBS making it possible to include treatable diseases without a relevant or reliable biochemical biomarker [13].…”

“…Another goal could be to increase the adaptability of NBS making it possible to include treatable diseases without a relevant or reliable biochemical biomarker [13]. Finally, there is a general wish in many countries to increase the number of diseases on newborn screening panels and molecular genetic analyses would be able to fulfil this need because the methods are generally applicable for most inherited diseases [11].…”

Immuno-Hormonal, Genetic and Metabolic Profiling of Newborns as a Basis for the Life-Long OneHealth Medical Record: A Scoping Review

“…The number of disease entities included in the NBS varies from country to country. In some countries, it is not structurally performed, whilst in other countries, up to 40 and even more medical conditions are screened; in fact technological developments enable a testing panel covering over 50 disorders [ 19 ]. Interestingly, NBS is also gaining momentum in countries outside the affluent “western” areas, such as India, particularly for easily diagnosed and treatable conditions such as congenital hypothyroidism [ 20 ].…”