Bloodspot Screening Programme Research Articles

Genomic sequencing in newborn screening: balancing consent with the right of the asymptomatic at-risk child to be found.

In this paper, we explore key aspects of the complex ethical and legal landscape surrounding consent in the context of incorporating genomic sequencing into existing newborn bloodspot screening programs. In particular, we consider the potential impact of genomic sequencing on the health rights of the child in relation to existing consent practices in newborn screening. We begin with an introduction to newborn screening programs and their population health goals. We then discuss public health ethics as a rationale underpinning newborn screening before turning to consent. We go on to describe seven current research projects on genomic sequencing in newborn screening and then introduce the 'right of the asymptomatic at-risk child to be found' as a useful concept to draw on when considering consent to newborn screening. We draw on this novel right to argue for the adoption of "appropriate consent" when it comes to certain uses of genomics in newborn screening. We contend that, for 'virtual panels' at least, appropriate consent proportionately balances the ongoing universality of newborn screening for important health conditions with an acknowledgement of the complex outcomes that bringing a complicated diagnostic technology into the screening domain will generate.

Direct healthcare costs in the first 2 years of life: A comparison of screened and clinically diagnosed children with cystic fibrosis – The Irish comparative outcomes study of CF (ICOS)

BackgroundIn July 2011, Cystic Fibrosis (CF) was added to the Newborn Bloodspot Screening Programme in Ireland. The Irish Comparative Outcomes Study (ICOS) is a historical cohort study established to compare outcomes between clinically-detected and screen-detected children with CF. Here we present the results of economic analysis comparing direct healthcare costs in the first 2 years of life of children born between mid-2008 and mid-2016, in the pre-CF transmembrane conductance regulator modulator era. MethodsHealthcare resource use information was obtained from Cystic Fibrosis Registry of Ireland (CFRI), medical records and parental questionnaire. Hospital admissions, emergency department visits, outpatient appointments, antibiotics and maintenance medications were included. Costs were estimated using the Health Service Executive Casemix, Irish Medicines Formulary and hospital pharmacy data, adjusted for inflation using Consumer Price Index data from the Central Statistics Office. A Negative Binomial regression was used, with time in the study as an offset. ResultsOverall participation was 93 %. After exclusion of those with meconium ileus, data from 139 patients, with follow-up to 2 years of age, were available. 72 (51.8 %) were from the clinically diagnosed cohort. In the final model (n=105), clinically diagnosed children had 2.62-fold higher costs per annum (p<0.0001), when adjusted for confounders, including homozygous ΔF508 or G511D mutation, socio-demographic factors and time between diagnosis and first CFRI interaction. ConclusionsThere are few studies evaluating economic aspects of newborn screening for CF using routine care data. These results imply that the benefits of newborn screening extend to direct healthcare costs borne by the State.

Australian parental perceptions of genomic newborn screening for non-communicable diseases.

Background: Newborn bloodspot screening (NBS) programs have improved neonatal healthcare since the 1960s. Genomic sequencing now offers potential to generate polygenic risk score (PRS) that could be incorporated into NBS programs, shifting the focus from treatment to prevention of future noncommunicable disease (NCD). However, Australian parents' knowledge and attitudes regarding PRS for NBS is currently unknown. Methods: Parents with at least one Australian-born child under 18years were invited via social media platforms to complete an online questionnaire aimed at examining parents' knowledge of NCDs, PRS, and precision medicine, their opinions on receiving PRS for their child, and considerations of early-intervention strategies to prevent the onset of disease. Results: Of 126 participants, 90.5% had heard the term "non-communicable disease or chronic condition," but only 31.8% and 34.4% were aware of the terms "polygenic risk score" and "precision medicine" respectively. A large proportion of participants said they would consider screening their newborn to receive a PRS for allergies (77.9%), asthma (81.0%), cancer (64.8%), cardiovascular disease (65.7%), mental illness (56.7%), obesity (49.5%), and type 2 diabetes (66.7%). Additionally, participants would primarily consider diet and exercise as interventions for specific NCDs. Discussion: The results from this study will inform future policy for genomic NBS, including expected rate of uptake and interventions that parents would consider employing to prevent the onset of disease.

Successful integration of newborn genetic testing into UK routine screening using prospective consent to determine eligibility for clinical trials

ObjectiveINGR1D (INvestigating Genetic Risk for type 1 Diabetes) was a type 1 diabetes (T1D) genetic screening study established to identify participants for a primary prevention trial (POInT, Primary Oral Insulin...

Expanded newborn bloodspot screening: developed country examples and what can be done in Turkey.

Bloodspot screening in newborns is an exemplary public health intervention as it is essential secondary prevention with proven efficacy and benefit for the early diagnosis and prompt treatment of rare diseases. In this mini review, newborn bloodspot screening (NBS) programs of 12 countries were examined in terms of the extent of diseases/disorders screened to form recommendations for Turkey's expanded newborn screening program. Essentially, Turkey and 11 selected countries' official policies/ national programs or strategies in terms of newborn screening and the number of diseases/conditions screened were examined. The current status of spinal muscular atrophy (SMA) screening was also checked through the SMA NBS Alliance. In addition, WHO and EURORDIS guidelines for newborn screening were also reviewed. On the Pubmed database, following the search strategy "((newborn screening[Title/Abstract]) OR (newborn screening program[Title/Abstract])) OR (newborn blood spot screening[Title/Abstract])" in the PubMed database from 1 January 2008 to 1 December 2021. Diseases that will be recommended to be included in the Turkish national newborn bloodspot screening program will be presented by evaluating the updated criteria of Wilson and Jungner by constructing international comparisons. The number of diseases/disorders screened by the inspected 12 countries is eminently variable and ranges from 5 in Turkey to 51 in New York, United States of America (USA). Acknowledging the programs of other countries, it is evident that Turkey must advance its program by evaluating the epidemiological data in Turkey, the health workforce, and infrastructure while relying on the updated screening criteria. The newborn bloodspot screening program should be expanded based on the cost estimates and implemented starting with pilot applications and the diseases/disorders that are deemed appropriate should be included in the national program.

The case for screening in early life for 'non-treatable' disorders: ethics, evidence and proportionality. A report from the Health Council of the Netherlands.

In the Netherlands, the call to add 'non-treatable' disorders to the newborn bloodspot screening programme has found a sympathetic ear with the Government. In 2019, the Health Council of the Netherlands was formally asked for advice on the conditions under which bloodspot screening for such disorders might be offered. Here we present the reasoning and the recommendations of the resulting report, and briefly discuss its reception. The report holds on to the classical view that screening must benefit the child, but argues for a wider account of child benefit than only in terms of substantial health gains. However, screening for 'non-treatable' disorders would still require evidence of a favourable benefits to harm ratio. The report presents a framework for such screening, but concludes that apart perhaps from Duchenne Muscular Dystrophy (DMD), no or only very few 'non-treatable' disorders would at present meet its criteria. Setting up a screening programme that might benefit only a small percentage of families struggling with uncertainty about their child's diagnosis would not seem proportional. Instead, the Government is advised to invest in a better infrastructure for early referral, testing and care. The reaction to the report from proponents of such screening shows that the dividing line in the debate is not about whether screening neonates for 'non-treatable' disorders is acceptable in itself. It is rather whether such screening should be regarded as catering to a parental 'right to know', or as a public health service that should be subject to standards of evidence and proportionality.

Study Design for an Evaluation of Newborn Screening for SCID in the UK.

Severe combined immunodeficiency is a rare inherited disorder, which, if untreated, invariably proves fatal in late infancy or early childhood. With treatment, the prognosis is much improved. Early treatment of the siblings of cases, before they become symptomatic, has shown considerable improvements in outcomes. Based on this and the development of a test that can be used on the whole population of neonates (measurement of T-cell receptor excision circles—TRECs), many countries have added it to their routine newborn bloodspot screening programmes. The UK National Screening Committee (UKNSC) has considered whether SCID should be added to the UK screening programme and concluded that it was likely to be cost effective, but that there were a number of uncertainties that should be resolved before a national roll-out could be recommended. These include some aspects of the test, such as: cost; the use of different assays and cut-off levels to reduce false positive rates, while maintaining sensitivity; the overall benefits of screening for disease outcome in patients with SCID and other identified disorders; the need for a separate pathway for premature babies; the acceptability of the screening programme to parents of babies who have normal and abnormal (both true and false positive) screening results. To achieve this, screening of two thirds of babies born in England over a two-year period has been planned, beginning in September 2021. The outcomes and costs of care of babies identified by the screening will be compared with those of babies identified with SCID in the rest of the UK. The effect of the screening programme on parents will form part of a separate research project.

Neonatal blood spot screening

This article describes the neonatal or newborn blood spot screening programme (NBSSP) in the United Kingdom. Babies are screened for nine diseases at 5 days of age by a heel prick test. Although midwifes are the primary health practitioner involved in NBSSP, GPs may be consulted antenatally or postnatally for advice. GPs can aid informed decision making for parents concerned about genetic testing, discuss the implications of positive screening, and provide support for families with confirmed diagnoses. This review of the newborn blood spot test will discuss the programme, its limitations, ethical considerations and the diseases screened.

Expanded Neonatal Bloodspot Screening Programmes: An Evaluation Framework to Discuss New Conditions With Stakeholders.

Neonatal bloodspot screening (NBS) programmes that screen for rare but serious conditions are expanding worldwide. Fast developments for testing and treatment put pressure on implementation processes. In 2015 the Netherlands embarked on an NBS expansion from 17 to 31 conditions. An evaluation framework was developed based on international NBS frameworks to gain insight in test properties, clinical findings, follow-up and implementation. A stakeholder process took place with implications for the planning of the expanded NBS panel. The evaluation framework progressed into a go/no go framework to start national screening, and is currently explored as basis for continuous evaluation of the NBS panel. The framework and stakeholder process may serve as an example for other programmes.

The Cost-Effectiveness of Expanding the UK Newborn Bloodspot Screening Programme to Include Five Additional Inborn Errors of Metabolism.

Glutaric aciduria type 1, homocystinuria, isovaleric acidaemia, long-chain hydroxyacyl CoA dehydrogenase deficiency and maple syrup urine disease are all inborn errors of metabolism that can be detected through newborn bloodspot screening. This evaluation was undertaken in 2013 to provide evidence to the UK National Screening Committee for the cost-effectiveness of including these five conditions in the UK Newborn Bloodspot Screening Programme. A decision-tree model with lifetable estimates of outcomes was built with the model structure and parameterisation informed by a systematic review and expert clinical judgment. A National Health Service/Personal Social Services perspective was used, and lifetime costs and quality-adjusted life years (QALYs) were discounted at 1.5%. Uncertainty in the results was explored using expected value of perfect information analysis methods together with a sensitivity analysis using the screened incidence rate in the UK from 2014 to 2018. The model estimates that screening for all the conditions is more effective and cost saving when compared to not screening for each of the conditions, and the results were robust to the updated incidence rates. The key uncertainties included the sensitivity and specificity of the screening test and the estimated costs and QALYs.

Instability of Acylcarnitines in Stored Dried Blood Spots: The Impact on Retrospective Analysis of Biomarkers for Inborn Errors of Metabolism.

Stored dried blood spots (DBS) can provide valuable samples for the retrospective diagnosis of inborn errors of metabolism, and for validation studies for newborn blood spot screening programs. Acylcarnitine species are subject to degradation upon long-term storage at room temperature, but limited data are available on the stability in original samples and the impact on acylcarnitine ratios. We analysed complete acylcarnitine profiles by flow-injection tandem mass spectrometry in 598 anonymous DBS stored from 2013 to 2017, at +4 °C during the first year and thereafter at room temperature. The concentrations of C2-, C3-, C4-, C5-, C6-, C8-, C10:1-, C10-, C12:1-, C12-, C14:1-, C14-, C16:1-, C16-, C18:2-, C18:1-, C18-, C5OH+C4DC-, C18:1OH-, and C16DC-carnitine decreased significantly, whereas a positive trend was found for free carnitine. Only the C4/C8-, C8/C10-, C14:1/C10- and C14:1/C16-carnitine ratios appeared robust for the metabolite instability. The metabolite instability may provoke the wrong interpretation of test results in the case of retrospective studies and risk the inaccurate estimation of cut-off targets in validation studies when only stored control DBS are used. We recommend including control DBS in diagnostic, retrospective cohort studies, and, for validation studies, we recommend using fresh samples and repeatedly re-evaluating cut-off targets.

Impact of COVID-19 mitigation measures on the incidence of preterm birth: a national quasi-experimental study

BackgroundPreterm birth is the leading cause of child mortality globally, with many survivors experiencing long-term adverse consequences. Preliminary evidence suggests that numbers of preterm births greatly reduced following implementation of policy measures aimed at mitigating the effects of the COVID-19 pandemic. We aimed to study the impact of the COVID-19 mitigation measures implemented in the Netherlands in a stepwise fashion on March 9, March 15, and March 23, 2020, on the incidence of preterm birth.MethodsWe used a national quasi-experimental difference-in-regression-discontinuity approach. We used data from the neonatal dried blood spot screening programme (2010–20) cross-validated against national perinatal registry data. Stratified analyses were done according to gestational age subgroups, and sensitivity analyses were done to assess robustness of the findings. We explored potential effect modification by neighbourhood socioeconomic status, sex, and small-for-gestational-age status.FindingsData on 1 599 547 singleton neonates were available, including 56 720 births that occurred after implementation of COVID-19 mitigation measures on March 9, 2020. Consistent reductions in the incidence of preterm birth were seen across various time windows surrounding March 9 (± 2 months [n=531 823] odds ratio [OR] 0·77, 95% CI 0·66–0·91, p=0·0026; ± 3 months [n=796 531] OR 0·85, 0·73–0·98, p=0·028; ± 4 months [n=1 066 872] OR 0·84, 0·73–0·97, p=0·023). Decreases in incidence observed following the March 15 measures were of smaller magnitude, but not statistically significant. No changes were observed after March 23. Reductions in the incidence of preterm births after March 9 were consistent across gestational age strata and robust in sensitivity analyses. They appeared confined to neighbourhoods of high socioeconomic status, but effect modification was not statistically significant.InterpretationIn this national quasi-experimental study, initial implementation of COVID-19 mitigation measures was associated with a substantial reduction in the incidence of preterm births in the following months, in agreement with preliminary observations elsewhere. Integration of comparable data from across the globe is needed to further substantiate these findings and start exploring underlying mechanisms.FundingNone.

Qualitative exploration of health professionals’ experiences of communicating positive newborn bloodspot screening results for nine conditions in England

ObjectiveTo explore health professionals’ experiences of communicating positive newborn bloodspot screening (NBS) results, highlight differences, share good practice and make recommendations for future research.DesignQualitative exploratory design was employed using semi-structured...

Blood spot screening programme for newborns

The blood spot screening programme for newborns allows potentially harmful diseases to be identified at a very early stage prior to any significant damage being done. This article offers an overview of the blood spot screening programmes offered by the NHS in all four countries of the UK. Blood spot screening does not provide a diagnosis, it identifies those at risk of being affected. Babies who have positive results will undergo further diagnostic tests in order to exclude or confirm the diagnosis.

P054 Parents' experience of receiving a diagnosis of cystic fibrosis through the UK Newborn Blood Spot Screening programme

P054 Parents' experience of receiving a diagnosis of cystic fibrosis through the UK Newborn Blood Spot Screening programme

What is in a Name? Parent, Professional and Policy-Maker Conceptions of Consent-Related Language in the Context of Newborn Screening.

Newborn bloodspot screening programs are some of the longest running population screening programs internationally. Debate continues regarding the need for parents to give consent to having their child screened. Little attention has been paid to how meanings of consent-related terminology vary among stakeholders and the implications of this for practice. We undertook semi-structured interviews with parents (n = 32), healthcare professionals (n = 19) and policy decision makers (n = 17) in two Canadian provinces. Conceptions of consent-related terms revolved around seven factors within two broad domains, decision-making and information attainment. Decision-making comprised: parent decision authority; voluntariness; parent engagement with decision-making; and the process of enacting choice. Information ascertainment comprised: professional responsibilities (including disclosure of information and time to review); parent responsibilities; and the need for discussion and understanding prior to a decision. Our findings indicate that consent-related terms are variously understood, with substantive implications for practice. We suggest that consent procedures should be explained descriptively, regardless of approach, so there are clear indications of what is expected of parents and healthcare professionals. Support systems are required both to meet the educational needs of parents and families and to support healthcare professionals in delivering information in a manner in keeping with parent needs.

Economic impact of screening for X-linked Adrenoleukodystrophy within a newborn blood spot screening programme

BackgroundA decision tree model was built to estimate the economic impact of introducing screening for X-linked adrenoleukodystrophy (X-ALD) into an existing tandem mass spectrometry based newborn screening programme. The model was based upon the UK National Health Service (NHS) Newborn Blood Spot Screening Programme and a public service perspective was used with a lifetime horizon. The model structure and parameterisation were based upon literature reviews and expert clinical judgment. Outcomes included health, social care and education costs and quality adjusted life years (QALYs). The model assessed screening of boys only and evaluated the impact of improved outcomes from hematopoietic stem cell transplantation in patients with cerebral childhood X-ALD (CCALD). Threshold analyses were used to examine the potential impact of utility decrements for non-CCALD patients identified by screening.ResultsIt is estimated that screening 780,000 newborns annually will identify 18 (95%CI 12, 27) boys with X-ALD, of whom 10 (95% CI 6, 15) will develop CCALD. It is estimated that screening may detect 7 (95% CI 3, 12) children with other peroxisomal disorders who may also have arisen symptomatically. If results for girls are returned an additional 17 (95% CI 12, 25) cases of X-ALD will be identified. The programme is estimated to cost an additional £402,000 (95% CI £399–407,000) with savings in lifetime health, social care and education costs leading to an overall discounted cost saving of £3.04 (95% CI £5.69, £1.19) million per year. Patients with CCALD are estimated to gain 8.5 discounted QALYs each giving an overall programme benefit of 82 (95% CI 43, 139) QALYs.ConclusionIncluding screening of boys for X-ALD into an existing tandem mass spectrometry based newborn screening programme is projected to reduce lifetime costs and improve outcomes for those with CCALD. The potential disbenefit to those identified with non-CCALD conditions would need to be substantial in order to outweigh the benefit to those with CCALD. Further evidence is required on the potential QALY impact of early diagnosis both for non-CCALD X-ALD and other peroxisomal disorders. The favourable economic results are driven by estimated reductions in the social care and education costs.

Provision of information about newborn screening antenatally: a sequential exploratory mixed-methods project.

Participation in the UK Newborn Bloodspot Screening Programme (NBSP) requires parental consent but concerns exist about whether or not this happens in practice and the best methods and timing to obtain consent at reasonable cost. To collate all possible modes of prescreening communication and consent for newborn (neonatal) screening (NBS); examine midwives', screening professionals' and users' views about the feasibility, efficiency and impact on understanding of each; measure midwives' and parents' preferences for information provision; and identify key drivers of cost-effectiveness for alternative modes of information provision. Six study designs were used: (1) realist review - to generate alternative communication and consent models; (2) qualitative interviews with parents and health professionals - to examine the implications of current practice for understanding and views on alternative models; (3) survey and observation of midwives - to establish current costs; (4) stated preference surveys with midwives, parents and potential future parents - to establish preferences for information provision; (5) economic analysis - to identify cost-effectiveness drivers of alternative models; and (6) stakeholder validation focus groups and interviews - to examine the acceptability, views and broader impact of alternative communication and consent models. Providers and users of NBS in England. Study 2: 45 parents and 37 health professionals; study 3: 22 midwives and eight observations; study 4: 705 adults aged 18-45 years and 134 midwives; and study 6: 12 health-care professionals and five parents. The realist review identified low parental knowledge and evidence of coercive consent practices. Interview, focus group and stated preference data suggested a preference for full information, with some valuing this more than choice. Health professionals preferred informed choice models but parents and health professionals queried whether or not current consent was fully informed. Barriers to using leaflets effectively were highlighted. All studies indicated that a 'personalised' approach to NBS communication, allowing parents to select the mode and level of information suited to their learning needs, could have added value. A personalised approach should rely on midwife communication and should occur in the third trimester. Overall awareness was identified as requiring improvement. Starting NBS communication by alerting parents that they have a choice to make and telling them that samples could be stored are both likely to enhance engagement. The methods of information provision and maternal anxiety causing additional visits to health-care professionals were the drivers of relative cost-effectiveness. Lack of data to populate an economic analysis, confirmed by value of information analysis, indicated a need for further research. There are some limitations with regard to the range of participants used in studies 2 and 3 and so caution should be exercised when interpreting some of the results. This project highlighted the importance of focusing on information receipt and identified key communication barriers. Health professionals strongly preferred informed consent, which parents endorsed if they were made aware of sample storage. Uniform models of information provision were perceived as ineffective. A choice of information provision was supported by health professionals and parents, which both enhances cost-effectiveness and improves engagement, understanding and the validity of consent. Remaining uncertainties suggest that more research is needed before new communication modes are introduced into practice. Future research should measure the impact of the suggested practice changes (informing in third trimester, information toolkits, changed role of midwife). Current Controlled Trials ISRCTN70227207. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 55. See the NIHR Journals Library website for further project information.

The Cost-Effectiveness Of Screening For Severe Combined Immunodeficiency (SCID) In The UK NHS Newborn Bloodspot Screening Programme

To assess the cost-effectiveness of including screening for severe combined immunodeficiency (SCID) in the NHS newborn bloodspot screening programme. A decision tree model with life-table estimates of outcomes was built. Model structure and parameterisation were informed by systematic review and expert clinical judgment. A public service perspective was used and lifetime costs and quality adjusted life years (QALYs) were discounted at 3.5%. Standard treatment following screening was hematopoietic stem cell transplantation with additional treatment options for adenosine deaminase deficiency SCID. The model estimated the number of non-SCID cases identified incidentally. Probabilistic sensitivity analyses was undertaken. An exploratory disbenefit analysis was conducted for false positives and those diagnosed with non-SCID T-cell lymphopenia (TCL) who would have presented as healthy at birth. Screening for SCID was estimated to result in 310 (72-811) presumptive positive cases per year including 260 (25-760) false positives cases, 7 (1-21) preterm cases, 26 (9-50) non-SCID TCL cases and 17 (14-22) SCID cases. Screening would increase overall QALYs and costs and result in an incremental cost-effectiveness ratio (ICER) of £17,642. The increase in QALYs was driven by improved survival in the screened cohort with mortality reducing from 8 (5.3-12) deaths to 1.7 (0.6-4.1). Results were sensitive to a number of parameters including the cost of the screening test, the incidence of SCID and quality of life estimates. The disbenefit analysis estimated that to push the cost-effectiveness over the £20,000 threshold the 6.5 (1.5-16) healthy at birth cases would need to experience a disbenefit of 2 QALYs and the false positive cases a disbenefit of over 12 quality adjusted days. Screening for SCID is potentially cost-effective at £20,000 per QALY, key uncertainties relate to the impact of false positives and the identification of children with non-SCID TCL.

Eliciting Preferences for Information Provision in Newborn Bloodspot Screening Programs.

The national newborn bloodspot screening programs (NBSPs) are continually expanding to screen for more conditions. To quantify parents' preferences for information and the way in which this is provided in example NBSPs. A hybrid choice experiment, combining a conjoint analysis and a discrete choice experiment, was designed. A sample of current and future parents between the ages of 18 and 45 years was identified via an Internet panel. Respondents completed one of two survey versions (9 conditions and 20 conditions) comprising a validated measure of attitudes toward involvement in decision making, 6 CA questions (11 information attributes), 10 DCE questions (4 attributes: 3 process and the ability to make an informed decision), and demographic questions. Of the 702 respondents who completed the survey, 58% were women, 48% were between 25 and 34 years old, and 48% were current parents. All types of information were identified to statistically significantly improve parents' ability to make a decision. Participants preferred taking an "active" role in decision making. Respondents to the 9-condition survey preferred information before 20 weeks (willingness to pay [WTP] £11.88; CI £5.56 to £19.53) and the 20-condition group after 20 weeks (WTP £15.91; CI £10.64 to £21.63). All respondents disliked receiving information 3 days after birth, with the 20-condition group also being averse to receiving it on day 5 (WTP -£11.20; CI -£18.40 to 5.72). Respondents in both groups preferred to receive their information in an individual discussion. This study suggests that parents' preferences for receiving NBS information differ from how this information is given in current UK practice.