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Since the introduction of genome sequencing in medicine, the factors involved in deciding how to integrate this technology into population screening programs such as Newborn Screening (NBS) have been widely debated. In Australia, participation in NBS is not mandatory, but over 99.9% of parents elect to uptake this screening. Gauging stakeholder attitudes towards potential changes to NBS is vital in maintaining this high participation rate. The current study aimed to determine the knowledge and attitudes of Australian parents and health professionals to the incorporation of genomic sequencing into NBS programs. Participants were surveyed online in 2016 using surveys adapted from previous studies. The majority of parents (90%) self-reported some knowledge of NBS, with 77% expressing an interest in NBS using the new technology. This was significantly lower than those who would utilise NBS using current technologies (99%). Although, many health professionals (62%) felt that new technologies should currently not be used as an adjunct to NBS, 79% foresaw the use of genomic sequencing in NBS by 2026. However, for genomic sequencing to be considered, practical and technical challenges as well as parent information needs were identified including the need for accurate interpretation of data; pre-and post-test counselling; and appropriate parental consent and opt-out process. Therefore, although some support for implementing genomic sequencing into Australian NBS does exist, there is a need for further investigation into the ethical, social, legal and practical implications of introducing this new technology as a replacement to current NBS methods.

A pilot newborn screening (NBS) program for Duchenne muscular dystrophy (DMD) study proposes to assess the feasibility of the screening procedure, temporal course of the various steps of screening, and the public acceptability of the program. This is particularly vital to ascertain as DMD is considered a ‘non-treatable’ disease and thus does not fit the traditional criteria for newborn screening. However, modern perspectives of NBS for DMD are changing and point to possible net benefits for children and their families undertaking NBS for DMD. The aim of this workshop was to establish pathways for the successful implementation and evaluation of a pilot NBS for DMD program in Australia. Consensus was reached as to the rationale for, potential benefits, risks, barriers and facilitators of screening, alongside the establishment of screening protocols and clinical referral pathways.

ObjectiveTo assess cost-effectiveness of newborn screening (NBS) for spinal muscular atrophy (SMA) and early treatment with nusinersen or onasemnogene abeparvovec (gene therapy), compared with nusinersen without SMA screening.MethodsInformed by an Australian state-wide SMA NBS programme, a decision analytical model nested with Markov models was constructed to evaluate costs and quality-adjusted life-years (QALYs) from a societal perspective with sensitivity analyses.ResultsBy treating one presymptomatic SMA infant with nusinersen or gene therapy, an additional 9.93 QALYs were gained over 60 years compared with late treatment in clinically diagnosed SMA. The societal cost was $9.8 million for early nusinersen treatment, $4.4 million for early gene therapy and $4.8 million for late nusinersen treatment. Compared with late nusinersen treatment, early gene therapy would be dominant, gaining 9.93 QALYs while saving $360 000; whereas early nusinersen treatment would result in a discounted incremental cost-effectiveness ratio (ICER) of $507 000/QALY.At a population level, compared with no screening and late treatment with nusinersen, NBS and early gene therapy resulted in 0.00085 QALY gained over 60 years and saving $24 per infant screened (85 QALYs gained and $2.4 million saving per 100 000 infants screened). More than three quarters of simulated ICERs by probability sensitivity analyses showed NBS and gene therapy would be dominant or less than $50 000/QALY, compared with no screening and late nusinersen treatment.ConclusionNBS coupled with gene therapy improves the quality and length of life for infants with SMA and would be considered value-for-money from an Australian clinical and policy context.

To evaluate the implementation of the first statewide newborn screening (NBS) program for spinal muscular atrophy (SMA) in Australia. Processes that hinder and support clinical development, translation, and sustainability of the first primary genetic screening program in Australia are appraised.

In light of a new therapeutic era for spinal muscular atrophy (SMA), newborn screening has been proposed as a gateway to facilitate expedient diagnosis and access to therapeutics. However, there is paucity of evidence on health outcomes outside the homogenous populations in clinical trials to justify broader implementation of newborn screening for SMA. In this real-world study, we aimed to investigate the effectiveness of newborn screening coupled with access to disease-modifying therapeutics, as an intervention for SMA.

Congenital hypothyroidism causes intellectual delay unless identified and effectively treated soon after birth. Newborn screening has almost eliminated intellectual disability associated with congenital hypothyroidism. However, clinical uncertainty remains about infants with thyroid-stimulating hormone (TSH) concentrations less than the newborn screening cutoffs. We assessed the association between neonatal TSH concentrations and educational and developmental outcomes.

Although a number of factors have been proposed to explain the increase in food allergy during the last decade, the possibility that vitamin D status may play a pathogenic role has received recent attention.

Purpose:To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries.Methods:A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors.Results:Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events.Conclusion:Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%.Genet Med advance online publication 16 February 2012

To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries.

Purpose: To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort.Methods: Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25–30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance, which is achieved when the median of a disorder range is, and usually markedly outside, either the 99th or the 1st percentile of the normal population. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles of the two populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity taking all available factors into consideration.Results: As of December 1, 2010, 130 sites in 45 countries have uploaded a total of 25,114 percentile data points, 565,232 analyte results of true positive cases with 64 conditions, and 5,341 cutoff values. The average rate of submission of true positive cases between December 1, 2008, and December 1, 2010, was 5.1 cases/day. This cumulative evidence generated 91 high and 23 low cutoff target ranges. The overall proportion of cutoff values within the respective target range was 42% (2,269/5,341).Conclusion: An unprecedented level of cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114 markers to be applied to newborn screening of rare metabolic disorders.

The aim of newborn screening is to detect newborns with serious, treatable disorders so as to facilitate appropriate interventions to avoid or ameliorate adverse outcomes. Mass biochemical testing of newborn babies was pioneered in the 1960s with the introduction of screening for phenylketonuria, a rare inborn error of metabolism, tested by using a dried blood spot sample. The next disorder introduced into screening programs was congenital hypothyroidism and a few more much rarer disorders were gradually included.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the disorder thought most to justify neonatal screening by tandem-mass spectrometry because, without screening, there seems to be substantial morbidity and mortality. Our aim was to assess the overall effectiveness of neonatal screening for MCAD deficiency in Australia.

Iodine deficiency in the postpartum period has the potential to affect neonatal neuropsychointellectual development. We performed a cross-sectional study involving 50 postpartum women and their neonates, measuring maternal urine iodine, breast milk iodine, and neonatal thyroid stimulating hormone (TSH), and examining their interrelationships. Women were studied at a median (range) of 4 (3-9) days postpartum. Moderate to severe iodine deficiency (defined by urine iodine concentration < 50 μg/L) was found in 29 of the 50 subjects (58%). The median ± standard deviation (SD) urine iodine was 46.8 ± 28.5 μg/L and the mean urine iodine expressed in micrograms per gram of creatinine was 86.6 ± 45.6. The median (range) breast milk iodine was 84.0 μg/L (25.0-234.0). Breast milk iodine was significantly correlated with urine iodine in micrograms per gram of creatinine (r= 0.52, p< 0.001) but not with urine iodine measured in micrograms per liter (r= 0.19, p= 0.2). Six percent of neonates had whole-blood TSH values of greater than 5 mIU/L. Neonatal TSH levels were positively correlated with higher breast milk iodine (r= 0.42, p= 0.003). There was no significant correlation between neonatal TSH levels and the mother's urine iodine content. There is a high prevalence of iodine deficiency in these lactating postpartum subjects. Urine iodine as micrograms per gram of creatinine is a good predictor of breast milk iodine content. In our study, higher breast milk iodine was correlated with a higher neonatal TSH. The impact of breast milk iodine content on neonatal TSH levels and neuropsychointellectual development needs further study.

An efficient newborn screening test for detecting cystic fibrosis has been available for over 20 years but is only now coming into widespread use. Blood immunoreactive trypsin is elevated in babies with cystic fibrosis and its measurement in dried blood spots is the primary screening tool. Poor discrimination in the first week requires a re-sampling step. The identification of the cystic fibrosis transmembrane conductance regulator gene and the discovery of a common mutation has allowed a combination of the primary screening test with a DNA test using the same sample. Differing genetic backgrounds have led to the development of population-specific protocols. A false-negative rate of around 5% is usual. Specificity is high. In all protocols involving a DNA test, confirmation of the diagnosis by sweat test is necessary when only one mutation is identified, identification of some carriers therefore being unavoidable. Careful counselling is needed for the families of these carriers.