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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. The study prospectively describes the course (timelines, health processes, and preliminary clinical outcomes) for SMA screen-positive newborns from 1 August 2018 to 31 July 2019 in New South Wales and Australian Capital Territory, Australia. In the first year of the program, 103,903 newborns were screened. Ten newborns screened positive for SMA. Genetic confirmation of SMA occurred in 9/10 (90%) of infants. Clinical signs of SMA evolved in 4/9 (44%) within 4 weeks of life, heralded by hypotonia and weakness initially recognized in the neck. Median time to implementing a care plan (including commencement of disease-modifying therapies) was 26.5 days (16–37 days) from birth. NBS is essential for early and equitable identification of patients with SMA. Expedient diagnosis and management are vital, as disease latency appears brief in some cases. NBS shows significant clinical utility to support early parental decision making, improve access to specialist neuromuscular expertise, and facilitate initiation of personalized therapeutic strategies.

In Australia, all newborns born in New South Wales (NSW) and the Australia Capital Territory (ACT) have been offered screening for rare congenital conditions through the NSW Newborn Screening Programme since 1964. Following the development of the Australian Newborn Bloodspot Screening National Policy Framework, screening for congenital adrenal hyperplasia (CAH) was included in May 2018. As part of the assessment for addition of CAH, the national working group recommended a two-tier screening protocol determining 17α-hydroxyprogesterone (17OHP) concentration by immunoassay followed by steroid profile. A total of 202,960 newborns were screened from the 1 May 2018 to the 30 April 2020. A threshold level of 17OHP from first tier immunoassay over 22 nmol/L and/or top 2% of the daily assay was further tested using liquid chromatography tandem mass spectrometry (LC-MS/MS) steroid profiling for 17OHP (MS17OHP), androstenedione (A4) and cortisol. Samples with a ratio of (MS17OHP + A4)/cortisol > 2 and MS17OHP > 200 nmol/L were considered as presumptive positive. These newborns were referred for clinical review with a request for diagnostic testing and a confirmatory repeat dried blood spot (DBS). There were 10 newborns diagnosed with CAH, (9 newborns with salt wasting CAH). So far, no known false negatives have been notified, and the protocol has a sensitivity of 100%, specificity of 99.9% and a positive predictive value of 71.4%. All confirmed cases commenced treatment by day 11, with none reported as having an adrenal crisis by the start of treatment.

Routine screening of newborns by tandem mass spectrometry resulted in the diagnosis of more cases of inborn errors of metabolism than had been diagnosed clinically during earlier periods. In particular, medium-chain acyl-coenzyme A dehydrogenase deficiency (which can be fatal at initial presentation) and other disorders of fatty-acid oxidation were more commonly diagnosed by screening. In many countries, it is a routine component of neonatal care to screen infants for congenital hypothyroidism, phenylketonuria, and a variable number of other disorders. The primary aim is the early detection and treatment of clinically important disorders in order to minimize morbidity and mortality in early childhood. Recently, with the development of electrospray tandem mass spectrometry, it has become possible to use a single test to screen for a wide range of very rare disorders that have not been screened for previously. Formal evidence of the clinical effectiveness of newborn screening is lacking. The only randomized, controlled trials have . . .

Are free carnitine concentrations on newborn screening (NBS) 48–72 h after birth lower in patients who develop type 1 diabetes than in controls? A retrospective case-control study of patients with type 1 diabetes was conducted. NBS results of patients from a Sydney hospital were compared against matched controls from the same hospital (1:5). Multiple imputation was performed for estimating missing data (gestational age) using gender and birthweight. Conditional logistic regression was used to control for confounding and to generate parameter estimates (α = 0.05). The Hommel approach was used for post-hoc analyses. Results are reported as medians and interquartile ranges. A total of 159 patients were eligible (80 females). Antibodies were detectable in 86. Median age at diagnosis was 8 years. Free carnitine concentrations were lower in patients than controls (25.50 µmol/L;18.98–33.61 vs. 27.26; 21.22–34.86 respectively) (p = 0.018). Immunoreactive trypsinogen was higher in this group (20.24 µg/L;16.15–29–52 vs. 18.71; 13.96–26.92) (p = 0.045), which did not persist in the post-hoc analysis. Carnitine levels are lower and immunoreactive trypsinogen might be higher, within 2–3 days of birth and years before development of type 1 diabetes as compared to controls, although the differences were well within reference ranges and provide insight into the pathogenesis into neonatal onset of type 1 diabetes development rather than use as a diagnostic tool. Given trypsinogen’s use for evaluation of new-onset type 1 diabetes, larger studies are warranted.

Background Very-low-birth-weight babies (VLBW) with hypothyroidism may show a delayed postnatal rise in thyroid stimulating hormone (TSH), mainly due to immaturity of the hypothalamic-pituitary-thyroid axis. Transient hypothyroidism is prevalent in VLBW babies and some affected babies are considered to need treatment. There is disagreement about whether a second screening test is needed in VLBW babies to detect all cases that need treatment. Methods We included in the study all babies with a birth weight ≤ 1,500 g born in New South Wales and the Australian Capital Territory between January 2006 and December 2008. Newborn screening samples for TSH measurement were taken in the first days of life and again at 1 month. During week 1, a blood-spot TSH level of ≥20 mIU/L was considered positive, and at 1 month a positive level was ≥7 mIU/L, and triggered full investigation. Results In the cohort of 301,000 babies, 2,313 VLBW babies survived for testing, and 2,117 repeat screening samples were received. Forty-three babies had transient hypothyroidism, with thyroid function normalising before 2 months of age, usually without treatment. Eighteen babies required treatment beyond 2 months of age (1:128 of surviving babies), 16 having had normal TSH results on initial testing, and 12 having levels below 6 mIU/L. Conclusion Significant hypothyroidism, transient or permanent, but persisting beyond 2 months of age is common in VLBW babies. There is a delayed rise in TSH in some, and secondary screening at 1 month of age detects babies deemed by local paediatric endocrinologists as needing treatment.

There have been few reports of cases missed by expanded newborn screening. Tandem mass spectrometry was introduced in New South Wales, Australia in 1998 to screen for selected disorders of amino acid, organic acid and fatty acid metabolism. Of 1,500,000 babies screened by 2012, 1:2700 were diagnosed with a target disorder. Fifteen affected babies were missed by testing, and presented clinically or in family studies. In three cases (cobalamin C defect, very-long-chain acyl-CoA dehydrogenase deficiency and glutaric aciduria type 1), this led to modification of analyte cut-off values or protocols during the first 3 years. Two patients with intermittent MSUD, two with β-ketothiolase deficiency, two with citrin deficiency, two siblings with arginosuccinic aciduria, two siblings with homocystinuria, and one with cobalamin C defect had analyte values and ratios below the action limits which could not have been detected without unacceptable false-positive rates. A laboratory interpretation error led to missing one case of cobalamin C defect. Reference ranges, regularly reviewed, were not altered. For citrin deficiency, while relevant metabolites are detectable by tandem mass spectrometry, our cut-off values do not specifically screen for that disorder. Most of the missed cases are doing well and with no acute presentations although eight of 15 are likely to have been somewhat adversely affected by a late diagnosis. Analyte ratio and cut-off value optimisations are important, but for some disorders occasional missed cases may have to be tolerated to maintain an acceptable specificity, and avoid harm from screening.

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. We identified MCAD-deficient patients from a total population of 2 495 000 Australian neonates (810 000 screened) born between April 1, 1994, and March 31, 2004. Those from a cohort of 1 995 000 (460 000 screened) were followed up for at least 4 years, and we recorded number of deaths and severe episodes, medical and neuropsychological outcome, and hospital admissions within the screened and unscreened groups. In cohorts aged at least 4 years there were 35 MCAD-deficient patients in those not screened (2·28 per 100 000 total population) and 24 in the screened population (5·2 per 100 000). We estimated that patients with this disorder in the unscreened cohort remained undiagnosed. Before 4 years of age, three screened patients had an episode of severe decompensation (including one neonatal death) versus 23 unscreened patients (including five deaths). At the most conservative estimate, relative risk of an adverse event was 0·44 (95% CI 0·13–1·45). In the larger cohort the relative risk (screened vs unscreened) of an adverse event by age 2 years was 0·26 (95% CI 0·07–0·97), also a conservative estimate. 38 of 52 living patients had neuropsychological testing, with no suggestions of significant differences in general cognitive outcome between the groups. Screening is effective in patients with MCAD deficiency since early diagnosis reduces deaths and severe adverse events in children up to the age of 4 years.

Spinal muscular atrophy (SMA) and severe combined immunodeficiency (SCID) are rare, inherited genetic disorders with severe mortality and morbidity. The benefits of early diagnosis and initiation of treatment are now increasingly recognized, with the most benefits in patients treated prior to symptom onset. The aim of the economic evaluation was to investigate the costs and outcomes associated with the introduction of universal newborn screening (NBS) for SCID and SMA, by generating measures of cost-effectiveness and budget impact. A stepwise approach to the cost-effectiveness analyses by decision analytical models nested with Markov simulations for SMA and SCID were conducted from the government perspective. Over a 60-year time horizon, screening every newborn in the population and treating diagnosed SCID by early hematopoietic stem cell transplantation and SMA by gene therapy, would result in 95 QALYs gained per 100,000 newborns, and result in cost savings of USD 8.6 million. Sensitivity analysis indicates 97% of simulated results are considered cost-effective against commonly used willingness-to-pay thresholds. The introduction of combined NBS for SCID and SMA is good value for money from the long-term clinical and economic perspectives, representing a cost saving to governments in the long-term, as well as improving and saving lives.

Evidence on the cost-effectiveness of newborn screening (NBS) for severe combined immunodeficiency (SCID) in the Australian policy context is lacking. In this study, a pilot population-based screening program in Australia was used to model the cost-effectiveness of NBS for SCID from the government perspective. Markov cohort simulations were nested within a decision analytic model to compare the costs and quality-adjusted life-years (QALYs) over a time horizon of 5 and 60 years for two strategies: (1) NBS for SCID and treat with early hematopoietic stem cell transplantation (HSCT); (2) no NBS for SCID and treat with late HSCT. Incremental costs were compared to incremental QALYs to calculate the incremental cost-effectiveness ratios (ICER). Sensitivity analyses were performed to assess the model uncertainty and identify key parameters impacting on the ICER. In the long-term over 60 years, universal NBS for SCID would gain 10 QALYs at a cost of US$0.3 million, resulting in an ICER of US$ 33,600/QALY. Probabilistic sensitivity analysis showed that more than half of the simulated ICERs were considered cost-effective against the common willingness-to-pay threshold of A $50,000/QALY (US$ 35,000/QALY). In the Australian context, screening for SCID should be introduced into the current NBS program from both clinical and economic perspectives.

Inborn errors of metabolism and diabetes share common derangements in analytes of metabolic networks that are tested for in newborn screening, usually performed 48–72 h after birth. There is limited research examining the metabolic imprint of diabetes on newborn screening results. This paper aims to demonstrate the links between diabetes, biochemical genetics and newborn screening in investigating disease pathophysiology in diabetes, provide possible reasons for the lack of research in diabetes in newborn screening and offer recommendations on potential research areas. We performed a systematic search of the available literature from 1 April 1998 to 31 December 2018 involving newborn screening and diabetes using OVID, MEDLINE, Cochrane and the PROSPERO register, utilizing a modified extraction tool adapted from Cochrane. Eight studies were included after screening 1312 records. Five studies reanalyzed dried blood spots (DBS) on filter paper cards, and three studies utilized pre-existing results. The results of these studies and how they relate to cord blood studies, the use of cord blood versus newborn screening dried blood spots as a sample and considerations on newborn screening and diabetes research is further discussed. The timing of sampling of newborn screening allows insight into neonatal physiology in a catabolic state with minimal maternal and placental influence. This, combined with the wide coverage of newborn screening worldwide, may aid in our understanding of the origins of diabetes.