Search strategy

New search strategies were developed based on scoping searches and strategies reported in the two previous systematic reviews. Fourteen electronic bibliographic databases covering biomedical, science, economic and grey literature were searched. The reference lists of relevant articles and abstracts of conference proceedings were checked. Eighteen health services research-related resources were also consulted via the Internet.

Data extraction and quality assessment

All selected papers were read and critically appraised by a single reviewer, who extracted relevant information from the included studies directly into an evidence table. Any uncertainties were resolved by discussion with another reviewer and/or clinical advisers. The overall strength and quality of evidence included in the review were graded according to the levels of evidence as defined in the previous systematic reviews of neonatal screening for inborn errors of metabolism.

Data synthesis

For the assessment of the clinical and cost-effectiveness evidence, formal meta-analysis techniques were not used because of the concerns over heterogeneity and poor study quality expressed in the previous systematic reviews. Instead, summary results were tabulated with detailed descriptive qualitative analyses.

Evaluation of the relative cost-effectiveness of adopting tandem MS for neonatal screening was undertaken using a probabilistic economic model. Data for the construction of the economic model were derived from previous HTA reports, other published sources and updated information on costs. A probabilistic approach was used to characterise the uncertainty within the model parameters. The model adopted an incremental net benefit approach. A value of information analysis was also undertaken to establish which elements of parameter uncertainty had the largest impact on model results.

Number and quality of clinical effectiveness data

Fifteen studies were identified that evaluated the clinical effectiveness of neonatal screening for inborn errors of metabolism using tandem MS (including two abstracts and one paper that reported the same study but provided additional information or results on tandem MS-based newborn screening from different periods). Seven studies evaluated neonatal screening of amino acids and acylcarnitines using tandem MS. Four used a prospective cohort design with study durations from 2 to 3 years. Three studies did not report the study design. Of these seven studies, three were reported as abstracts and provided limited information. Four studies assessed newborn screening for medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency using tandem MS. Three of these studies used a prospective cohort design with study durations from approximately 2 to 7 years, whereas a study from the UK, of approximately 3 years, used a retrospective cohort design. Two retrospective, analytical studies were also identified.

Assessment of clinical effectiveness

Evidence for neonatal screening of amino acids and acylcarnitines using tandem MS was primarily from observational data of large-scale prospective newborn screening programmes, from several centres outside the UK, namely, Australia, Germany and the USA. In general, newborn screening of dried blood spots for the amino acid and acylcarnitine group of disorders using tandem MS was shown to be rapid, highly sensitive (90-100%) and highly specific (99-100%). However, there was a lack of evidence regarding the false negatives and false positives for individual diagnosable disorders. The variation in the age of sampling and the heterogeneity in the choice of metabolite, as well as in thresholds used to define a positive result, limited direct comparison of the discriminative power of tandem MS between studies.

Evidence from several large-scale prospective newborn screening programmes in Australia, Germany and the USA, and retrospective data from the UK have, in general, illustrated high sensitivities and high specificities of neonatal screening for MCAD deficiency using tandem MS. However, direct comparison about diagnostic performance and outcome of tandem MS between studies was limited owing to use of various analytes and thresholds for detecting disease status and different criteria for the diagnosis of MCAD deficiency.

In most of the large-scale prospective screening studies conducted outside the UK, sampling for selected amino acids and acylcarnitines is usually performed within 72 hours after birth, whereas in the UK, blood samples are usually taken at about 6-14 days of age. The age at which screening is undertaken will affect the sensitivity and specificity of the screening process as concentrations of metabolites change over time, and this time-lapse may be detrimental for conditions that present acutely in infancy. Therefore, the evidence obtained in this review suggests that the collection of newborn blood-spots in the UK slightly earlier than the current 6-14 days may facilitate earlier detection and initiation of effective therapies. However, the earlier collection and reporting of results may influence test performance for other conditions and would underline the need for a good infrastructure for clinical follow-up, management and high-quality clinical services for identified cases and their families.

Evidence from the reviews of inborn errors of metabolism found that the UK screening programme for PKU was well established and there was universal agreement that neonatal screening for PKU was justified. The average UK incidence of PKU (classical and atypical combined) is 11.0 cases per 100,000 live births. Early dietary interventions, including dietary treatment before or during pregnancy, are effective in reducing the severity of developmental delay, and neonatal screening using tandem MS is suitable for the reliable detection of PKU.

Of the many other disorders that can be detected by tandem MS, the best candidate condition for a new screening programme was MCAD deficiency, a disorder of fatty acid metabolism (expected UK birth prevalence/incidence ranges from 4.0 to 9.9 cases per 100,000 live births). The disorder is associated with increased morbidity and mortality. Treatment for MCAD deficiency is relatively simple with dietary management, thus preventing possible early death and neurological disability. After (early) diagnosis, current management makes death rare and improves outcome. Neonatal screening data from tandem MS-based studies show that this method is robust, highly sensitive and specific for MCAD deficiency. Without screening, an unknown number may remain asymptomatic and may never experience any ill effects.

For many other inborn errors of metabolism that can be detected by tandem MS, robust clinical evidence was limited (e.g. natural history of disease, UK incidence, and uncertainties regarding the effectiveness of treatments, and sensitivity and specificity of detection using tandem MS).

Number and quality of cost-effectiveness data

Since the two previous HTA reports, no published studies on the cost-effectiveness of screening for inborn errors of metabolism using tandem MS were identified.

Cost-effectiveness analysis using economic modelling

Cost-effectiveness analysis using economic modelling indicated that substituting the use of tandem MS for existing technologies for the screening of PKU alone could not be justified. Using tandem MS would incur additional costs with no measurable increase in health benefits. However, results from the economic modelling indicate that the addition of screening for MCAD deficiency as part of a neonatal screening programme for PKU using tandem MS would be cost-effective. Using an operational range of 50,000-60,000 specimens per system per year, the mean incremental cost for PKU and MCAD deficiency screening combined using tandem MS from the model was -£23,312 (median -£14,810). This cost saving is associated with a mean incremental gain of 59 life-years for each cohort of 100,000 neonates screened.

Additional economic modelling for other conditions using probabilistic methods was undertaken, but the results are based on limited data; in particular, robust evidence on long-term outcomes, especially systematic differences in outcomes that could be attributed to screening. The evidence therefore does not support including other inherited metabolic diseases within a neonatal screening programme at present.