Economic Evaluation of Newborn Screening for Severe Combined Immunodeficiency.

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.

Modelling the Cost-Effectiveness and Budget Impact of a Newborn Screening Program for Spinal Muscular Atrophy and Severe Combined Immunodeficiency.

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.

Newborn screening for spinal muscular atrophy with disease-modifying therapies: a cost-effectiveness analysis.

OBJECTIVE: To 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. METHODS: Informed 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. RESULTS: By 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. CONCLUSION: NBS 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.

Newborn Screening Samples for Diabetes Research: An Underused Resource.

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.

Newborn screening for congenital hypothyroidism in very-low-birth-weight babies: the need for a second test.

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.

Two-year pilot study of newborn screening for congenital adrenal hyperplasia in New South Wales compared with nationwide case surveillance in Australia.

AIM: To assess the benefits and practicalities of setting up a newborn screening (NBS) program in Australia for congenital adrenal hyperplasia (CAH) through a 2 year pilot screening in ACT/NSW and comparing with case surveillance in other states. METHODS: The pilot newborn screening occurred between 1/10/95 and 30/9/97 in NSW/ACT. Concurrently, case reporting for all new CAH cases occurred through the Australian Paediatric Surveillance Unit (APSU) across Australia. Details of clinical presentation, re-sampling and laboratory performance were assessed. RESULTS: 185,854 newborn infants were screened for CAH in NSW/ACT. Concurrently, 30 cases of CAH were reported to APSU, twelve of which were from NSW/ACT. CAH incidence was 1 in 15 488 (screened population) vs 1 in 18,034 births (unscreened) (difference not significant). Median age of initial notification was day 8 with confirmed diagnosis at 13(5-23) days in the screened population vs 16(7-37) days in the unscreened population (not significant). Of the 5 clinically unsuspected males in the screened population, one had mild salt-wasting by the time of notification, compared with salt-wasting crisis in all 6 males from the unscreened population. 96% of results were reported by day 10. Resampling was requested in 637 (0.4%) and median re-sampling delay was 11(0-28) days with higher resample rates in males (p < 0.0001). The within-laboratory cost per case of clinically unsuspected cases was A$42 717. CONCLUSION: There seems good justification for NBS for CAH based on clear prevention of salt-wasting crises and their potential long-term consequences. Also, prospects exist for enhancing screening performance.

Newborn screening.

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. Two recent advances have greatly changed the pace: modification of tandem mass spectrometry and DNA extraction and analysis from newborn screening dried blood spot. These two technologies make the future possibilities of newborn screening seem almost unlimited. Newborn screening tests are usually carried out on a dried blood spot sample, for which there are special analytical considerations. Dried blood spot calibrators and controls, prepared on the same lot number of filter paper, are needed. Methods have a co-efficient of variation of about 10% due to the increased variability of a dried filter paper sample compared with other biochemical samples. The haematocrit is an additional variable not able to be measured. Also of importance is obtaining a balance between the sensitivity and specificity of each assay. Fixing cut-off points for action needs consideration of what is an acceptable percentage of the population to recall for further testing. Few assays are 100% discriminatory. Programs in Australasia currently screen for at least 30 disorders. Detection of these requires not only the assay of a primary marker but often determination of a ratio of that marker with another, or possibly an alternative assay, for example a DNA mutation. The most important disorders screened for are described briefly: phenylketonuria, primary congenital hypothyroidism, cystic fibrosis, the galactosaemias, medium-chain acyl-CoA dehydrogenase deficiency, glutaryl-CoA dehydrogenase deficiency and congenital adrenal hyperplasia, together with several other disorders detectable by tandem mass spectrometry. Newborn screening deals with rare disorders and benefit cannot be shown easily without very large pilot studies. There have been randomised controlled trials of screening for cystic fibrosis, and now several studies are beginning to establish the benefit of tandem mass spectrometry screening for disorders of fatty acid and amino acid metabolism. Two things will influence the new directions for newborn screening: the development of effective treatments for hitherto untreatable disorders, and advancing technology, enabling new testing strategies to be developed. There are novel treatments on the horizon for many discrete disorders. Susceptibility testing has recently been considered for newborn screening application, but is more controversial. Newborn screening has entered a new and exciting phase, with an explosion of new treatments, new technologies, and, possibly in the future, new preventive strategies.

Healthcare use and costs of medium-chain acyl-CoA dehydrogenase deficiency in Australia: screening versus no screening.

OBJECTIVE: To describe and analyze the use and costs of hospital services for children diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency either with newborn screening or clinical diagnosis in Australia between 1994 and 2002. MCAD deficiency is a potentially lethal disorder of fatty-acid oxidation. STUDY DESIGN: We conducted a retrospective audit of medical records supplemented by a parental survey. RESULTS: A total of 59 children with MCAD deficiency were identified, 24 by using newborn screening. In the first 4 years of life, screening children cost an average of A$1676 (US$1297) per year for inpatient, emergency department, and outpatient visits, compared with A$1796 (US$1390) for children in whom a clinical diagnosis was made. Forty-two percent of the children who underwent screening were admitted to the hospital, compared with 71% of children who did not undergo screening. Children who did not undergo screening used significantly more inpatient services and cost significantly more in emergency services. There were also some significant differences in use on a year-by-year basis. CONCLUSIONS: Children who do not undergo screening may be more likely to be admitted to the hospital and to incur higher emergency department costs than children who underwent screening, and children seem more likely to attend hospital outpatient clinics. Screening does not result in higher costs from a hospital perspective.

Newborn screening--is it really that simple?

The incorporation of tandem mass spectrometry (MSMS) into an existing newborn screening program is an evolving process. Limited worldwide experience has ensured that all stages of reliability testing need to be followed. These include a literature review to establish methodology and analytes/disorders for testing and a pilot screening project including assaying archival samples from subjects with proven target disorders. Algorithms used for analyte concentrations and the relationships of various analytes to one another for resample criteria need to be continually reassessed to maximise screening specificity, sensitivity and positive predictive value. Since 1st of April 1998, the NSW Newborn Screening Program has screened 320, 848 babies using electrospray MSMS for selected amino acids and acyl camitines. Screening for amino acids has led to requests for 415 repeat samples with 94 babies referred for further testing. Of these 73 had a disorder of amino acid metabolism, including 43 with persistent hyperphenylalaninemia (36 of whom had PKU, 2 had a pterin pathway defect, 5 HPAA). Screening for acyl carnitines has led to requests for 245 repeat samples with 63 babies referred for further investigation. Of these 44 had a diagnosed disorder, including 15 with medium chain acyl CoA dehydrogenase deficiency. Five babies with confirmed disorders detectable with MS/MS had negative test results. The cost of screening using MSMS was only $A0.50 more than the method for screening for PKU and homocystinuria alone (ie the bacterial inhibition assays) and has allowed detection of an additional 74 babies at least 48 of whom have a diagnosis for which early treatment seems clearly beneficial. MSMS has shown a sensitivity of 95.9% and specificity of 99.8% in our laboratory with a positive predictive value of 18%.