Revealing the results of whole-genome sequencing and whole-exome sequencing in research and clinical investigations: some ethical issues.

The introduction of new sequencing technologies whole-genome sequencing (WGS) and whole-exome sequencing (WES) that are much less finely targeted than previous genetic tests has resulted in ethical debate about what should be done with clinically significant findings that may arise during the sequencing process. In this piece we argue that, in addition to whether the finding has been intentionally sought or arises incidentally, the ethical issues concerning what should be done with WES and WGS findings are also influenced by whether sequencing occurs in a clinical or research setting. We argue that decisions about the disclosure of WGS and WES findings generated in the clinical context are much less ethically contentious than decision making about the feedback of research results. We conclude by calling for greater transparency about the purpose of sample collection, more explicit protocols for transitioning between research and clinical contexts and patients and research participants to be warned of the potential for incidental findings to be generated, their potential significance and the actions that might be taken as a result.

Preconception healthcare and congenital disorders: systematic review of the effectiveness of preconception care programs in the prevention of congenital disorders.

Congenital disorders are a leading cause of global burden of disease; the birth prevalence remains constant at 6%. Initiating preconception care before pregnancy may be an effective strategy to reduce congenital disorders and improve the health of reproductive-age women. Our objectives are: (1) To identify components of preconception interventions, (2) to assess the effectiveness of preconception interventions in reducing the burden of congenital disorders, and (3) to prioritize these interventions. Medline and Science Direct search terms included: preconception, pre-pregnancy, childbearing, reproduction, care, intervention, primary care, healthcare, model, program, prevention, trial, efficacy, effectiveness, congenital disorders OR abnormalities. Inclusion criteria were: (1) English, (2) human subjects, (3) women of childbearing age, (4) 1980-current data, (5) all countries, (6) experimental studies, (7) systematic reviews or meta-analysis, (8) program reports/evaluations. Data was collected and abstracted by two independent reviewers. To prioritize preconception interventions likely to have the largest impact at a population level, a ranked scoring system was created incorporating the following: (1) quality of evidence supporting the intervention, (2) effect size of the intervention, and (3) global burden of the specific congenital disease. Preconception interventions include risk screening, education, motivational counseling, disease optimization and specialist referral. The most effective interventions, based on the strength of evidence, size of impact of intervention, and disease burden are: folic acid fortification/supplementation, diabetic control, smoking and alcohol interventions, HIV management, thrombophillia screening, obesity prevention and epilepsy management. Although multiple conditions require preconception attention, only nine interventions have evidence to support their effect on congenital disorders through a randomised control trial, systematic review or meta-analysis. There is a need for more high-level research in evaluating certain preconception interventions. These findings have significant implications on planning and implementation of preconception care.

Preconception healthcare delivery at a population level: construction of public health models of preconception care.

A key challenge of preconception healthcare is identifying how it can best be delivered at a population level. To review current strategies of preconception healthcare, explore methods of preconception healthcare delivery, and develop public health models which reflect different preconception healthcare pathways. Preconception care strategies, programmes and evaluations were identified through a review of Medline and Embase databases. Search terms included: preconception, pre-pregnancy, intervention, primary care, healthcare, model, delivery, program, prevention, trial, effectiveness, congenital disorders OR abnormalities, evaluation, assessment, impact. Inclusion criteria for review articles were: (1) English, (2) human subjects, (3) women of childbearing age, (4) 1980­current data, (5) all countries, (6) both high risk and universal approaches, (7) guidelines or recommendations, (8) opinion articles, (9) experimental studies. Exclusion criteria were: (1) non-human subjects, (2) non-English, (3) outside of the specified timeframe, (4) articles on male healthcare. The results of the literature review were synthesised into public health models of care: (1) primary care; (2) hospital-based and inter-conception care; (3) specific preconception care clinics; and, (4) community outreach. Fifteen evaluations of preconception care were identified. Community programmes demonstrated a significant impact on substance use, folic acid supplementation, diabetes optimization, and hyperphenylalaninemia. An ideal preconception visits entail risk screening, education, and intervention if indicated. Subsequently, four public health models were developed synthesizing preconception care delivery at a population level. Heterogeneity of risk factors, health systems and strategies of care reflect the lack of consensus about the best way to deliver preconception care. The proposed models aim to reflect differing aspects of preconception healthcare delivery.

Genetics in ophthalmology: equity in service provision?

BACKGROUND: Scientific advances in the understanding of the molecular biology of inherited eye conditions now allow more effective diagnosis and management for patients and families. For translation into clinical practice, it is vital that specialist services are developed with the necessary multi-disciplinary expertise, investigatory resources and organizational arrangements. We investigate the equity of specialist provision in the UK and make recommendations for service development. METHODS: A questionnaire survey was carried out of all providers of specialist genetic services in the UK. Results were analysed by provider, catchment population and Strategic Health Authority population. RESULTS: Nineteen specialist services were identified. Provision of annual out-patient clinics and medical consultant sessions varied widely with many small services lacking full multi-disciplinary teams. There was an 8-fold regional variation in patient activity. Across the UK, we estimated an annual shortfall of 1000 new patient referrals. CONCLUSIONS: There should be a national programme of strategic planning of specialist genetic ophthalmology services. Necessary elements will include service specifications and standards, overall number and configuration of services, models which maximize the efficiency of use of specialist genetics elements and education of specialist and general ophthalmologists in genetics elements of their specialty.

Health needs assessment for congenital anomalies in middle-income countries: Examining the case for neural tube defects in Brazil.

Recent economic improvement in Brazil has been reflected in better maternal-child health indicators, with decreases in infant and perinatal mortality. However, under-five mortality due to congenital disorders remained unchanged, and congenital disorders have become the second leading cause of infant mortality. In the present study, we used the PHG Foundation Health Needs Assessment (HNA) Toolkit with the objective of first assessing the burden of disease caused by neural tube defects (NTDs) in Brazil and the impact of interventions already put in place to address the burden, and second to evaluate and prioritize further interventions and policies required for its prevention and treatment. The results from these two components of the HNA process are described in this paper. The published literature was reviewed to identify studies of NTDs (prevalence; morbidity; prenatal, perinatal, and postnatal mortality; treatment or prevention). Data on indicators of maternal and child health were obtained directly from the Brazilian Ministry of Health, through the online Live Births Information System (SINASC) and from the Mortality Information System (SIM). Descriptive analyses included reports of the rates of NTD in liveborns, fetal, and infant deaths. Differences between folic acid flour pre-fortification (2001-2004) and post-fortification (2006-2010) periods were expressed as prevalence rate ratios. Around 20 % of fetal deaths were related to congenital disorders with approximately 5 % of those being NTDs. For infant mortality, congenital disorders were notified in approximately 15 % of cases, with NTDs present in 10 % of the malformed children. Although statistically significant, the prevalence rate ratio (PRR) for spina bifida in live births was only 0.937 (95 % confidence interval (CI) 0.884-0.994), a decrease of 6.3 % when comparing the pre and post-fortification periods. The impact of fortification seemed to be more visible in fetal deaths due to anencephaly (PRR = 0.727, 95 % CI 0.681-0.777) and for spina bifida (PRR = 0.700, 95 % CI 0.507-0.967) with associated decreases of 27.3 and 30 %. The lower impact of folic acid fortification in Brazil, compared to other Latin-American countries, can be due to differences in dietary habits, concentration of folic acid in flour, as well as characteristic population ethnic composition. The HNA led to the identification of the needs to be addressed in Brazil, including the improvement of reporting congenital disorders within the nationwide birth certification system, and revision of the policy of flour folic acid fortification.

The use of a Toolkit for health needs assessment on neural tube defects in Argentina.

Health needs assessment (HNA) is a commonly used process for those working in public health. The PHG Foundation has developed a Toolkit to provide users with a stepwise approach for undertaking a HNA on birth defects. We report the findings from using the Toolkit to examine needs in relation to policies and programs, services, and interventions for neural tube defects (NTDs) in Argentina. The trend over the last few decades is one of decline in infant mortality from nutritional and infectious causes, thus further increasing the relative importance of birth defects. The observed prevalence of NTDs is consistent with that reported internationally. Since 2002 folic acid fortification (FAF) has been mandatory by law, and different studies have shown at least a 50 % decrease in the birth prevalence of NTDs after FAF. In Argentina, there is inequity between the public and non-public health sectors. The birth prevalence of NTDs seems lower in the non-public sector, possibly as a result of better nutritional status of women, higher access to folic acid supplementation, and earlier prenatal diagnosis followed by termination of pregnancy (ToP) in non-public hospitals. Although illegal, ToP is believed to be widespread, with better access for people of higher socioeconomic status. Through the process of HNA, we identified several unmet needs regarding registration of cases, public and professional education, legislation, and organization of care pathways. In our experience, the Toolkit brought together people working on the same issue, and it engaged and motivated experts and stakeholders to work together to tackle the problem.

A framework for the prioritization of investment in the provision of genetic tests.

BACKGROUND: The UK Genetic Testing Network (UKGTN) established a process for the evaluation of genetic tests for entry onto the National Health Service (NHS) Directory of Molecular Genetic Testing. The Network requested the development and piloting of a prioritization framework that could be used for the commissioning of genetic tests by the NHS. METHODS: A selected working group developed and piloted a multi-criteria prioritization process using 10 genetic tests evaluated by the UKGTN. RESULTS: The framework was able to rank the 10 genetic tests used in the pilot. The rankings were also consistent with the commissioning recommendations for these genetic tests by the UKGTN. CONCLUSION: A set of criteria for the prioritization of genetic tests has been developed. The results from the pilot suggest that the methodology is valid and robust but requires considerable resources to implement. Further development of the process is needed before the framework could be used to influence commissioning decisions for clinical genetic services in the NHS.