Improving the care of children with GENetic Rare disease: Observational Cohort study (GenROC)-a study protocol.

INTRODUCTION: Around 2000 children are born in the UK per year with a neurodevelopmental genetic syndrome with significantly increased morbidity and mortality. Often little is known about expected growth and phenotypes in these children. Parents have responded by setting up social media groups to generate data themselves. Given the significant clinical evidence gaps, this research will attempt to identify growth patterns, developmental profiles and phenotypes, providing data on long-term medical and educational outcomes. This will guide clinicians when to investigate, monitor or treat symptoms and when to search for additional or alternative diagnoses. METHODS AND ANALYSIS: This is an observational, multicentre cohort study recruiting between March 2023 and February 2026. Children aged 6 months up to 16 years with a pathogenic or likely pathogenic variant in a specified gene will be eligible. Children will be identified through the National Health Service and via self-recruitment. Parents or carers will complete a questionnaire at baseline and again 1 year after recruitment. The named clinician (in most cases a clinical geneticist) will complete a clinical proforma which will provide data from their most recent clinical assessment. Qualitative interviews will be undertaken with a subset of parents partway through the study. Growth and developmental milestone curves will be generated through the DECIPHER website (https://deciphergenomics.org) where 5 or more children have the same genetic syndrome (at least 10 groups expected). ETHICS AND DISSEMINATION: The results will be presented at national and international conferences concerning the care of children with genetic syndromes. Results will also be submitted for peer review and publication.

Implementation of rapid genomic sequencing in safety-net neonatal intensive care units: protocol for the VIrtual GenOme CenteR (VIGOR) proof-of-concept study.

INTRODUCTION: Rapid genomic sequencing (rGS) in critically ill infants with suspected genetic disorders has high diagnostic and clinical utility. However, rGS has primarily been available at large referral centres with the resources and expertise to offer state-of-the-art genomic care. Critically ill infants from racial and ethnic minority and/or low-income populations disproportionately receive care in safety-net and/or community settings lacking access to state-of-the-art genomic care, contributing to unacceptable health equity gaps. VIrtual GenOme CenteR is a 'proof-of-concept' implementation science study of an innovative delivery model for genomic care in safety-net neonatal intensive care units (NICUs). METHODS AND ANALYSIS: We developed a virtual genome centre at a referral centre to remotely support safety-net NICU sites predominantly serving racial and ethnic minority and/or low-income populations and have limited to no access to rGS. Neonatal providers at each site receive basic education about genomic medicine from the study team and identify eligible infants. The study team enrols eligible infants (goal n of 250) and their parents and follows families for 12 months. Enrolled infants receive rGS, the study team creates clinical interpretive reports to guide neonatal providers on interpreting results, and neonatal providers return results to families. Data is collected via (1) medical record abstraction, (2) surveys, interviews and focus groups with neonatal providers and (3) surveys and interviews with families. We aim to examine comprehensive implementation outcomes based on the Proctor Implementation Framework using a mixed methods approach. ETHICS AND DISSEMINATION: This study is approved by the institutional review board of Boston Children's Hospital (IRB-P00040496) and participating sites. Participating families are required to provide electronic written informed consent and neonatal provider consent is implied through the completion of surveys. The results will be disseminated via peer-reviewed publications and data will be made accessible per National Institutes of Health (NIH) policies. TRIAL REGISTRATION NUMBER: NCT05205356/clinicaltrials.gov.

Protocol for a comprehensive prospective cohort study of trio-based whole-genome sequencing for underlying cancer predisposition in paediatric and adolescent patients newly diagnosed with cancer: the PREDICT study.

INTRODUCTION: Identifying an underlying germline cancer predisposition (CP) in a child with cancer has potentially significant implications for both the child and biological relatives. Cohort studies indicate that 10%-15% of paediatric cancer patients carry germline pathogenic or likely pathogenic variants in cancer predisposition genes, but many of these patients do not meet current clinical criteria for genetic testing. This suggests broad tumour agnostic germline testing may benefit paediatric cancer patients. However, the utility and psychosocial impact of this approach remain unknown. We hypothesise that an approach involving trio whole-genome germline sequencing (trio WGS) will identify children and families with an underlying CP in a timely fashion, that the trio design will streamline cancer risk counselling to at-risk relatives if CP was inherited, and that trio testing will not have a negative psychosocial impact on families. METHOD AND ANALYSIS: To test this, we present the Cancer PREDisposition In Childhood by Trio sequencing study (PREDICT). This study will assess the clinical utility of trio WGS to identify CP in unselected patients with cancer 21 years or younger in New South Wales, Australia. PREDICT will perform analysis of biological parents to determine heritability and will examine the psychosocial impact of this trio sequencing approach. PREDICT also includes a broad genomics research programme to identify new candidate genes associated with childhood cancer risk. ETHICS AND DISSEMINATION: By evaluating the feasibility, utility and psychosocial impact of trio WGS to identify CP in paediatric cancer, PREDICT will inform how such comprehensive testing can be incorporated into a standard of care at diagnosis for all childhood cancer patients. TRIAL REGISTRATION NUMBER: NCT04903782.

Burden experienced by informal caregivers of children with sickle cell disease (SCD): a qualitative exploratory study at Tamale Teaching Hospital, Ghana.

OBJECTIVE: This study sought to explore the burden experienced by informal caregivers in caring for their children with sickle cell disease (SCD). DESIGN: A qualitative exploratory design was employed in the study using in-depth interviews. SETTING: The study was conducted at the sickle cell clinic of the Tamale Teaching Hospital, Ghana. PARTICIPANTS: Data were gathered from 15 purposively selected informal caregivers, whose children with SCD received care at the sickle cell clinic of the Tamale Teaching Hospital, using a semistructured in-depth interview guide in May-June 2021. Their responses were audio-taped, transcribed and analysed using the reflexive thematic analysis approach. RESULTS: Five major themes emerged from data analysis. These were: the burden of children's ill-health; financial burden; employment challenges; psychosocial burden and determinants of caregivers' burden. These burdens destabilised the personal lives, financial standing, social relationships, and employment of caregivers in general and that of other immediate family members, thus, impacting family processes and health. CONCLUSIONS: Health professionals must devise strategies for counselling, early diagnosis and effective management of children with SCD across Ghana. The Ministry of Health must subsidise medications and laboratory services for children with SCD to help minimise the financial burden on caregivers. Further, counselling and psychological support services must be established in hospitals to assist caregivers to cope effectively.

Systematic estimates of the global, regional and national under-5 mortality burden attributable to birth defects in 2000-2019: a summary of findings from the 2020 WHO estimates.

OBJECTIVES: To examine the potential for bias in the estimate of under-5 mortality due to birth defects recently produced by the WHO and the Maternal and Child Epidemiology Estimation research group. DESIGN: Systematic analysis. METHODS: We examined the estimated number of under-5 deaths due to birth defects, the birth defect specific under-5 mortality rate, and the per cent of under-5 mortality due to birth defects, by geographic region, national income and under-5 mortality rate for three age groups from 2000 to 2019. RESULTS: The under-5 deaths per 1000 live births from birth defects fell from 3.4 (95% uncertainty interval (UI) 3.1-3.8) in 2000 to 2.9 (UI 2.6-3.3) in 2019. The per cent of all under-5 mortality attributable to birth defects increased from 4.6% (UI 4.1%-5.1%) in 2000 to 7.6% (UI 6.9%-8.6%) in 2019. There is significant variability in mortality due to birth defects by national income level. In 2019, the under-5 mortality rate due to birth defects was less in high-income countries than in low-income and middle-income countries, 1.3 (UI 1.2-1.3) and 3.0 (UI 2.8-3.4) per 1000 live births, respectively. These mortality rates correspond to 27.7% (UI 26.6%-28.8%) of all under-5 mortality in high-income countries being due to birth defects, and 7.4% (UI 6.7%-8.2%) in low-income and middle-income countries. CONCLUSIONS: While the under-5 mortality due to birth defects is declining, the per cent of under-5 mortality attributable to birth defects has increased, with significant variability across regions globally. The estimates in low-income and middle-income countries are likely underestimated due to the nature of the WHO estimates, which are based in part on verbal autopsy studies and should be taken as a minimum estimate. Given these limitations, comprehensive and systematic estimates of the mortality burden due to birth defects are needed to estimate the actual burden.

Epidemiology, aetiology, interventions and genomics in children with arthrogryposis multiplex congenita: protocol for a multisite registry.

INTRODUCTION: Arthrogryposis multiplex congenita (AMC) is an umbrella term including hundreds of conditions with the common clinical manifestation of multiple congenital contractures. AMC affects 1 in 3000 live births and is caused by lack of movement in utero. To understand the long-term needs of individuals diagnosed with a rare condition, it is essential to know the prevalence, aetiology and functional outcomes in a large sample. The development and implementation of a multicentre registry is critical to gather this data. This registry aims to improve health through genetic and outcomes research, and ultimately identify new therapeutic targets and diagnostics for treating children with AMC. METHODS AND ANALYSIS: Participants for the AMC registry will be recruited from seven orthopaedic hospitals in North America. Enrollment occurs in two phases; Part 1 focuses on epidemiology, aetiology and interventions. For this part, retrospective and cross-sectional data will be collected using a combination of patient-reported outcomes and clinical measures. Part 2 focuses on core subset of the study team, including a geneticist and bioinformatician, identifying causative genes and linking the phenotype to genotype via whole genome sequencing to identify genetic variants and correlating these findings with pedigree, photographs and clinical information. Descriptive analyses on the sample of 400 participants and logistic regression models to evaluate relationships between outcomes will be conducted. ETHICS AND DISSEMINATION: Ethical approval has been granted from corresponding governing bodies in North America. Dissemination of findings will occur via traditional platforms (conferences, manuscripts) for the scientific community. Other modalities will be employed to ensure that all stakeholders, including youth, families and patient support groups, may be provided with findings derived from the registry. Ensuring the findings are circulated to a maximum amount of interested parties will ensure that the registry can continue to serve as a platform for hypothesis-driven research and further advancement for AMC.

Morbidity and mortality patterns of preterm low birthweight neonates admitted to referral hospitals in the Amhara region of Ethiopia: retrospective follow-up study.

OBJECTIVE: This study aimed to assess the morbidity and mortality patterns of preterm neonates with low birth weight admitted in the Amhara region referral hospitals in Ethiopia. DESIGN: Hospital-based retrospective follow-up study. SETTING: Amhara region referral hospitals, Ethiopia. PARTICIPANTS: A total of 291 preterm neonates low birth weight that were admitted to referral hospitals in the Amhara region between 1 January 2017 and 30 December 2018 were reviewed. Data were entered into Epi-data V.4.4.2.1 and exported to STATA V.14 for analysis, and variables with a p value of <0.05 at 95% confidence level in multivariable logistic regression model analysis were declared as statistically significant associated factors of mortality. PRIMARY OUTCOME: Morbidity and mortality patterns in preterm low birthweight neonates. RESULTS: This study revealed that 37.8% (95% CI 32.4% to 43.5%) of preterm low birthweight neonates died. The most common morbidities found were 219 (75.26%) hypothermia, followed by 201 (69.07%), 145 (49.83%), 39 (13.4%) and 24 (8.25%) with sepsis, respiratory distress, jaundice and congenital anomalies, respectively. Sepsis (AOR: 2.0; 95% CI 1.03 to 3.89), respiratory distress (AOR: 4.6; 95% CI 2.51 to 8.40), hypoglycaemia (AOR 3.91; 95% CI 1.09 to 10.52), APGAR score at fifth minute <7 (AOR 0.39; 95% CI (0.18 to 0.82) and duration of hospital stay below mean (<9.82 days) (AOR 0.17; 95% CI 0.09 to 0.33) were associated with mortality. CONCLUSION: The mortality rate of preterm low birthweight neonates was high, indicating that this is a public health issue. Hypothermia, sepsis, respiratory distress, jaundice and congenital anomalies were the common morbidities. Sepsis, respiratory distress, hypoglycaemia, Apgar score at fifth minute <7 and duration of hospital stay below the mean were independent factors of mortality. However, these need to be further investigated in future research and appropriately addressed using prospective follow-up.

Maternal delays and unfavourable newborn outcomes among skilled deliveries in public hospitals of Hadiya Zone, Southern Ethiopia: a case-control study.

OBJECT: We assessed maternal delays and unfavourable newborn outcomes among skilled deliveries in public hospitals of Hadiya Zone, Southern Ethiopia using 'the three maternal delays' framework. DESIGN: A case-control study was conducted. SETTING: Public hospitals in Hadiya Zone, southern Ethiopia. PARTICIPANTS: Sample of 57 cases and 121 controls participated from 4 September 2019 to 30 October 2019. Consecutive dead newborns at discharge or admitted newborns for more 24 hours after delivery were selected as cases. Two consecutive controls were selected from none cases discharged within 24 hours of skilled delivery. RESULTS: Total of 57 cases and 121 controls participated with 97.3% response rate. Forty-eight (84.2%), 46 (80.7%) and 51 (89.5%) of cases had first, second and third maternal delay, respectively. Eighty-six (71.1%), 18 (14.9%) and 69 (53.7%) of controls had first, second and third maternal delay, respectively. Cases with second maternal delay were 23.9 times more likely to have unfavourable newborn outcome when compared with controls. The first and third delays and wealth index were not significantly associated with newborn outcome in this study. CONCLUSIONS: First, second and third maternal delays were higher in cases than controls. 'Delay in reaching health facility' was determinant for unfavourable newborn outcome in this study. However, 'delay in decision-making to seek care' and 'delay in receiving care' were not significantly associated with new born outcome. Government should work to improve labouring mother transportation.

Mapping the evidence of multidimensional health approaches in treating individuals with Prader-Willi Syndrome: A scoping review protocol.

INTRODUCTION: Prader-Willi Syndrome (PWS) is one of the rare diseases involving genetics and affects various body systems. The disease is known due to the absence of paternal genes on chromosome 15q11-q13. Multisystem complex conditions require interdisciplinary healthcare treatment. However, to the best of our knowledge, there is little evidence of an established successful model of an interdisciplinary approach in managing rare diseases like PWS. METHODS AND ANALYSIS: The scoping review process follows the five-staged Arksey and O'Malley (2005) methodology framework excluding the optional consultation stage (stage 6): the definition of the research questions (step 1); the eligibility criteria and search strategy are defined (stage 2); the study selection process based on the eligibility criteria identified will follow (stage 3); a framework developed for this review will then inform the extraction and charting of data from the included studies (step 4) and results will be aggregated and summarised with criteria relevant for health professionals and policymakers (stage 5). We will search for electronic databases (MEDLINE/PubMed, Scopus, Web of Science), grey literature sources and critical studies' reference lists to determine the appropriate inclusion criteria. Three researchers will review all abstracts and full-text studies for inclusion. ETHICS AND DISSEMINATION: This scoping review methodology does not require ethical approval since it aims to synthesise information from available publications. A scoping review article will be submitted for publication to a scientific journal following this protocol.

Cohort-based association study of germline genetic variants with acute and chronic health complications of childhood cancer and its treatment: Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study protocol.

INTRODUCTION: Childhood cancer and its treatment may lead to various health complications. Related impairment in quality of life, excess in deaths and accumulated healthcare costs are relevant. Genetic variations are suggested to contribute to the wide inter-individual variability of complications but have been used only rarely to risk-stratify treatment and follow-up care. This study aims to identify germline genetic variants associated with acute and late complications of childhood cancer. METHODS AND ANALYSIS: The Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. Eligible are patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Paediatric Biobank for Research in Haematology and Oncology, Geneva, host of the national Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS).GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study. Clinical outcome data consists of organ function testing, health conditions diagnosed by physicians, second primary neoplasms and self-reported information from participants. Germline genetic samples and sequencing data are collected in BISKIDS. We will perform association analyses using primarily whole-exome or whole-genome sequencing to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models. DISCUSSION: GECCOS will improve knowledge of germline genetic variants associated with childhood cancer-associated health conditions and help to further individualise cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects. ETHICS AND DISSEMINATION: The Geneva Cantonal Commission for Research Ethics has approved the GECCOS study.Research findings will be disseminated through national and international conferences, publications in peer-reviewed journals and in lay language online. TRIAL REGISTRATION NUMBER: NCT04702321.

Association of the incidence of atopic dermatitis until 3 years old with birth month and with sunshine duration and humidity in the first 6 months of life: Japan Environment and Children's Study.

OBJECTIVE: To compare the incidence of atopic dermatitis in children aged from 6 months to 3 years across birth seasons and climate conditions. DESIGN: Cohort study. SETTING: Fifteen regional centres across Japan. PARTICIPANTS: A total of 100 304 children born from 2011 to 2014. EXPOSURE: Birth month, and mean sunshine duration (short/long) and humidity (high/low) in the first 6 months of life. PRIMARY OUTCOME MEASURE: Incidence of atopic dermatitis. RESULTS: The highest incidence of atopic dermatitis was in children born in the months of October to December. The lowest incidence of atopic dermatitis was in the months of April to June and in periods with a long duration of sunshine and high humidity. Low humidity was significantly associated with a higher incidence of atopic dermatitis. However, this significant difference disappeared when the birth season and parental history of allergic disease were considered in multivariate analysis. CONCLUSIONS: In Japan, being born in the late autumn to early winter months is associated with a risk of developing atopic dermatitis until the age of 3 years. Sunshine duration and humidity from birth to 6 months of age are not associated with the incidence of atopic dermatitis.

Caring and living with Prader-Willi syndrome in Italy: integrating children, adults and parents' experiences through a multicentre narrative medicine research.

OBJECTIVES: Prader-Willi syndrome (PWS) significantly impacts health-related quality of life; however, its relational and existential aspects remain unknown in Italian clinical and social debate. The project aimed to investigate the impact of PWS on illness experience through narrative medicine (NM) to understand the daily life, needs and resources of patients with PWS and their caregivers, and to furnish insights for clinical practice. DESIGN AND SETTING: The project involved 10 medical centres of the Italian Network for Rare Diseases and PWS family associations and targeted underage and adult patients with PWS and their caregivers. Written interviews, composed by a sociodemographic survey and a narrative, were collected through the project's website. Three dedicated illness plots employed evocative and open words to facilitate individual expression and to encourage reflection. Narratives were analysed through NVivo software. Researchers discussed the results with the project's steering committee. PARTICIPANTS: Twenty-one children and adolescents and 34 adults with PWS joined the project, as well as 138 caregivers. A PWS diagnosis or the caregiving of a patient with PWS older than 5 years represented the eligibility criteria, as well as the willingness to share their illness experience by writing and the ability to communicate in Italian. RESULTS: The analysis of narratives led to understanding the PWS social and relational issues concerning diagnosis and current management, PWS daily experiences and social contexts, PWS implications in the working sphere and participants' future perspectives. Narratives demonstrated that PWS management affects relationships and work-life balance and that social stigma remains present. CONCLUSION: The project represented the first effort to investigate the impact of PWS on illness experience in Italy through NM while considering the perspectives of patients with PWS and their caregivers. The findings indicated that a multiprofessional approach is fundamental to ensure adequate treatment and provided elements for its improvement.