Target Trial Emulation and Bias Through Missing Eligibility Data: An Application to a Study of Palivizumab for the Prevention of Hospitalization due to Infant Respiratory Illness

Target trial emulation (TTE) applies the principles of randomised controlled trials to the causal analysis of observational datasets. On challenge that is rarely considered in TTE is the sources of bias that may arise if the variables involved in the definition of eligibility into the trial are missing. We highlight patterns of bias that might arise when estimating the causal effect of a point exposure when restricting the target trial (TT) to individuals with complete eligibility data. Simulations consider realistic scenarios where the variables affecting eligibility modify the causal effect of the exposure and are Missing at Random (MAR) or Missing Not at Random (MNAR). We discuss multiple means to address these patterns of bias, namely, (i) controlling for the collider bias induced by the missing dataon eligibility, and (ii) imputing the missing values of the eligibility variables prior to selection into the TT. Results are compared to when TTE is performed ignoring the impact of missing eligibility. A study of Palivizumab, a monoclonal antibody recommended for the prevention of respiratory hospital admissions due to Respiratory Synctial Virus in high risk infants, is used for illustrations

Birth prevalence of anorectal malformations in England and 5-year survival: a national birth cohort study

OBJECTIVE: To determine the birth prevalence, maternal risk factors and 5-year survival for isolated and complex anorectal malformations. DESIGN: National birth cohort using hospital admission data and death records. SETTING: All National Health Service England hospitals. PATIENTS: Live-born singletons delivered from 2002 through 2018, with evidence in the first year of life of a diagnosis of an anorectal malformation and repair during a hospital admission, or anorectal malformation recorded on the death certificate. Cases were further classified as isolated or complex depending on the presence of additional anomalies. MAIN OUTCOME MEASURES: Birth prevalence of anorectal malformations per 10 000 live births, risk ratios for isolated and complex anorectal malformation by maternal, infant and birth characteristics, and 5-year survival. RESULTS: We identified 3325 infants with anorectal malformations among 9 474 147 live-born singletons; 61.7% (n=2050) of cases were complex. Birth prevalence was 3.5 per 10 000 live births (95% CI 3.4 to 3.6). Complex anorectal malformations were associated with maternal age extremes after accounting for other sociodemographic factors. Compared with maternal ages 25-34 years, the risk of complex anorectal malformations was 31% higher for ≥35 years (95% CI 17 to 48) and 13% higher for ≤24 years (95% CI 0 to 27). Among 2376 anorectal malformation cases (n=1450 complex) born from 2002 through 2014, 5-year survival was lower for complex (86.9%; 95% CI 85.1% to 88.5%) than isolated anorectal malformations (98.2%; 95% CI 97.1% to 98.9%). Preterm infants with complex anorectal malformations had the lowest survival (73.4%; 95% CI 68.1% to 78.0%). CONCLUSIONS: Differences in maternal risk factors for isolated and complex anorectal malformations may reflect different underlying mechanisms for occurrence. Five-year survival is high but lowest for preterm children with complex anorectal malformations

A comparison of child mortality from potentially preventable causes in England and Sweden using birth cohorts from linked administrative datasets

Introduction Child mortality is nearly twice as high in England as in Sweden. A comparison of mortality from potentially preventable causes could inform health system responses. This study focused on respiratory tract infection (RTI)-related deaths, amenable to healthcare interventions, and sudden unexpected deaths in infancy (SUDI), amenable to public health interventions. Objectives and Approach We developed nationally-representative birth cohorts of singleton live births in 2003-2012 using a hospital admissions database in England and the Medical Birth Register in Sweden. Children were followed-up from 31st day of life until their fifth birthday via linkage to hospital admission and mortality records. We compared child mortality using Cox proportional hazards models to estimate hazard ratios (HR) for England versus Sweden for RTI-related mortality at 31-364 days and 1-4 years, and for SUDI mortality at 31-364 days. Models were adjusted for birth characteristics (gestational age, birthweight, sex, congenital anomalies), and socio-economic factors (maternal age and socio-economic status). Results Of 3,928,483 children in England, there were 807 RTI-related deaths at 31-364 days (17% of all deaths in the age range), 691 deaths at 1-4 years (31%), and 1,166 SUDIs (24%) in England. Corresponding figures for 1,012,682 children in Sweden were 136 (18%), 118 (25%) and 189 (24%). Unadjusted HRs for RTI-related deaths in England versus Sweden were 1.50 (95% confidence interval: 1.25-1.80) at 31-364 days. Adjustment for birth characteristics reduced the HR to 1.16 (0.97-1.39), and for socio-economic factors to 1.11 (0.92-1.33). Corresponding figures for RTI-related mortality at 1-4 years were 1.58 (1.30-1.92), 1.32 (1.09-1.61) and 1.30 (1.07-1.59), respectively. Unadjusted HRs for SUDIs reduced from 1.59 (1.36-1.85) to 1.40 (1.20-1.63) after adjusting for birth characteristics, and to 1.19 (1.02-1.39) after adjusting for socio-economic factors. Conclusion/Implications Higher prevalence of adverse birth characteristics (such as prematurity, low birthweight, congenital anomalies) contributed to increased risks of RTI-related and SUDI mortality in England relative to Sweden. Therefore, preventive strategies should focus on maternal health and socio-economic circumstances before and during pregnancy to reduce RTI-related and SUDI mortality in England

Congenital diaphragmatic hernia subtypes: Comparing birth prevalence, occurrence by maternal age, and mortality in a national birth cohort

BACKGROUND: Population-based administrative data have rarely been used to compare the birth prevalence, risk factors for occurrence, and mortality of congenital diaphragmatic hernia (CDH) subtypes. OBJECTIVES: We used a national birth cohort to identify CDH subtypes and compared their birth prevalence, relationship with maternal age after accounting for sociodemographic factors, and 1-year mortality rates. METHODS: Linked hospital admission and death records were used to identify isolated and complex CDH cases (involving additional anomalies) among singleton livebirths in England between 2002 and 2018. The prevalence of each CDH subtype per 10,000 livebirths was estimated overall and by infant, birth and maternal characteristics. The relationship between maternal age and each subtype relative to no CDH was examined using multivariable log-binomial regression to estimate risk ratios (RRs). One-year mortality rates were examined using Kaplan-Meier curves and the hazard ratio (HR) of complex versus isolated CDH was calculated using Cox regression. RESULTS: Among 9.5 million livebirths, we identified 1285 with isolated CDH and 1150 with complex CDH. The overall prevalence of isolated and complex CDH was 1.4 (95% confidence interval [CI] 1.3, 1.4) and 1.2 (95% CI 1.1, 1.3) per 10,000 livebirths, respectively. Only complex CDH was associated with maternal age. Compared with maternal age 25-34 years, complex CDH risk was elevated for maternal age < 20 years (RR 1.31, 95% CI 1.00, 1.72). Risk was highest for maternal age ≥ 40 years (RR 1.61, 95% CI 1.21, 2.15) although accounting for chromosomal anomalies attenuated the risk (RR 1.39, 95% CI 1.00, 1.92). The 1-year mortality rate for complex CDH (33.1%, 95% CI 30.5, 35.9) was slightly higher than for isolated CDH (29.7%, 95% CI 27.3, 32.3) (HR 1.10, 95% CI 0.96, 1.27). CONCLUSIONS: Mechanisms of occurrence differed between and within CDH subtypes and 1-year mortality of complex CDH was slightly higher than for isolated CDH

What makes administrative data "research-ready"? A systematic review and thematic analysis of published literature.

Introduction: Administrative data are a valuable research resource, but are under-utilised in the UK due to governance, technical and other barriers (e.g., the time and effort taken to gain secure data access). In recent years, there has been considerable government investment in making administrative data "research-ready", but there is no definition of what this term means. A common understanding of what constitutes research-ready administrative data is needed to establish clear principles and frameworks for their development and the realisation of their full research potential. Objective: To define the characteristics of research-ready administrative data based on a systematic review and synthesis of existing literature. Methods: On 29th June 2021, we systematically searched seven electronic databases for (1) peer-reviewed literature (2) related to research-ready administrative data (3) written in the English language. Following supplementary searches and snowball screening, we conducted a thematic analysis of the identified relevant literature. Results: Overall, we screened 2,375 records and identified 38 relevant studies published between 2012 and 2021. Most related to administrative data from the UK and US and particularly to health data. The term research-ready was used inconsistently in the literature and there was some conflation with the concept of data being ready for statistical analysis. From the thematic analysis, we identified five defining characteristics of research-ready administrative data: (a) accessible, (b) broad, (c) curated, (d) documented and (e) enhanced for research purposes. Conclusions: Our proposed characteristics of research-ready administrative data could act as a starting point to help data owners and researchers develop common principles and standards. In the more immediate term, the proposed characteristics are a useful framework for cataloguing existing research-ready administrative databases and relevant resources that can support their development

Factors predicting amoxicillin prescribing in primary care among children: a cohort study

Background: Antibiotic prescribing during childhood contributes to antimicrobial resistance, which is a major public health concern. Antibiotics are most commonly prescribed to children for respiratory tract infections (RTI). / Aim: To identify factors associated with amoxicillin prescribing and RTI consultation attendance in primary care in young children. / Design and Setting: Cohort study in Bradford with data from pregnancy to age 24-months collected between 2007-2013, linked to electronic primary care and air pollution data. / Methods: We calculated amoxicillin prescribing rates/1,000 child-years, and fitted mixed-effects logistic regression models, with general practice (GP) surgery as the random effect, to establish risk factors for amoxicillin prescribing and RTI consultation during the first two years. / Results: Among 2,493 children, the amoxicillin prescribing rate was 710/1,000 child-years during the first year (95% CI: 677-744) and 780/1,000 (745-816) during the second year. Odds of amoxicillin prescribing during year one were higher for infants who were male (adjusted OR 1.4 (1.1-1.6)), socio-economically deprived (1.4 (1.0-1.9)), and with a Pakistani ethnic background (1.4 (1.1-1.9)). Odds of amoxicillin prescribing during the second year were higher for infants with a Pakistani ethnic background (1.5 (1.1-2.0)/1.6 (1.2-2.0)) and pre-/early-term infants (1.2 (1.0-1.5)). Additional risk factors included caesarean delivery, congenital anomalies, household overcrowding, birth season, and formal childcare attendance. GP surgery-level variation explained 7-9% of variation in amoxicillin prescribing. / Conclusions: Socio-economic status and ethnic background are strongly associated with amoxicillin prescribing and RTI consultations during childhood. Interventions reducing RTI spread in household and childcare settings may reduce antibiotic prescribing in primary care

Determinants of accident and emergency attendances and emergency admissions in infants: birth cohort study

BACKGROUND: There is limited understanding of the drivers of increasing infant accident and emergency (A&E) attendances and emergency hospital admissions across England. We examine variations in use of emergency hospital services among infants by local areas in England and investigate the extent to which infant and socio-economic factors explain these variations. METHODS: Birth cohort study using linked administrative Hospital Episode Statistics data in England. Singleton live births between 1-April-2012 and 31-March-2019 were followed up for 1 year; from 1-April-2013 (from the discharge date of their birth admission) until their first birthday, death or 31-March-2019. Mixed effects negative binomial models were used to calculate incidence rate ratios for A&E attendances and emergency admissions and mixed effects logistic regression models estimated odds ratio of conversion (the proportion of infants subsequently admitted after attending A&E). Models were adjusted for individual-level factors and included a random effect for local authority (LA). RESULTS: The cohort comprised 3,665,414 births in 150 English LAs. Rates of A&E attendances and emergency admissions were highest amongst: infants born < 32 weeks gestation; with presence of congenital anomaly; and to mothers < 20-years-old. Area-level deprivation was positively associated with A&E attendance rates, but not associated with conversion probability. A&E attendance rates were highest in the North East (916 per 1000 child-years, 95%CI: 911 to 921) and London (876 per 1000, 95%CI: 874 to 879), yet London had the lowest emergency admission rates (232 per 1000, 95%CI: 231 to 234) and conversion probability (25% vs 39% in South West). Adjusting for individual-level factors did not significantly affect variability in A&E attendance and emergency admission rates by local authority. CONCLUSIONS: Drivers of A&E attendances and emergency admissions include individual-level factors such being born premature, with congenital anomaly and from socio-economically disadvantaged young parent families. Support for such vulnerable infants and families should be provided alongside preventative health care in primary and community care settings. The impact of these services requires further investigation. Substantial geographical variations in rates were not explained by individual-level factors. This suggests more detailed understanding of local and underlying service-level factors would provide targets for further research on mechanisms and policy priority

Trends in hospital admissions during transition from paediatric to adult services for young people with learning disabilities or autism: Population-based cohort study

Summary Background Transition from paediatric to adult health care may disrupt continuity of care, and result in unmet health needs. We describe changes in planned and unplanned hospital admission rates before, during and after transition for young people with learning disability (LD), or autism spectrum disorders (ASD) indicated in hospital records, who are likely to have more complex health needs. Methods We developed two mutually exclusive cohorts of young people with LD, and with ASD without LD, born between 1990 and 2001 in England using national hospital admission data. We determined the annual rate of change in planned and unplanned hospital admission rates before (age 10–15 years), during (16–18 years) and after (19–24 years) transition to adult care using multilevel negative binomial regression models, accounting for area-level deprivation, sex, birth year and presence of comorbidities. Findings The cohorts included 51,291 young people with LD, and 46,270 autistic young people. Admission rates at ages 10–24 years old were higher for young people with LD (54 planned and 25 unplanned admissions per 100 person-years) than for autistic young people (17/100 and 16/100, respectively). For young people with LD, planned admission rates were highest and constant before transition (rate ratio [RR]: 0.99, 95% confidence interval [CI] 0.98–0.99), declined by 14% per year of age during (RR: 0.86, 95% CI: 0.85–0.88), and remained constant after transition (RR: 0.99, 95% CI: 0.99–1.00), mainly due to fewer admissions for non-surgical care, including respite care. Unplanned admission rates increased by 3% per year of age before (RR: 1.03, 95% CI: 1.02–1.03), remained constant during (RR: 1.01, 95% CI: 1.00–1.03) and increased by 3% per year after transition (RR: 1.03, 95% CI: 1.02–1.04). For autistic young people, planned admission rates increased before (RR: 1.06, 95% CI: 1.05–1.06), decreased during (RR: 0.95, 95% CI: 0.93–0.97), and increased after transition (RR: 1.05, 95%: 1.04–1.07). Unplanned admission rates increased most rapidly before (RR: 1.16, 95% CI: 1.15–1.17), remained constant during (RR: 1.01, 95% CI: 0.99–1.03), and increased moderately after transition (RR: 1.03, 95% CI: 1.02–1.04). Interpretation Decreases in planned admission rates during transition were paralleled by small but consistent increases in unplanned admission rates with age for young people with LD and autistic young people. Decreases in non-surgical planned care during transition could reflect disruptions to continuity of planned/respite care or a shift towards provision of healthcare in primary care and community settings and non-hospital arrangements for respite care. Funding National Institute for Health Research Policy Research Programme

Factors predicting amoxicillin prescribing in primary care among children: a cohort study

Background: Antibiotic prescribing during childhood contributes to antimicrobial resistance, which is a major public health concern. Antibiotics are most commonly prescribed to children for respiratory tract infections (RTI). Aim: To identify factors associated with amoxicillin prescribing and RTI consultation attendance in primary care in young children. Design and Setting: Cohort study in Bradford with data from pregnancy to age 24-months collected between 2007-2013, linked to electronic primary care and air pollution data. Methods: We calculated amoxicillin prescribing rates/1,000 child-years, and fitted mixed-effects logistic regression models, with general practice (GP) surgery as the random effect, to establish risk factors for amoxicillin prescribing and RTI consultation during the first two years. Results: Among 2,493 children, the amoxicillin prescribing rate was 710/1,000 child-years during the first year (95% CI: 677-744) and 780/1,000 (745-816) during the second year. Odds of amoxicillin prescribing during year one were higher for infants who were male (adjusted OR 1.4 (1.1-1.6)), socio-economically deprived (1.4 (1.0-1.9)), and with a Pakistani ethnic background (1.4 (1.1-1.9)). Odds of amoxicillin prescribing during the second year were higher for infants with a Pakistani ethnic background (1.5 (1.1-2.0)/1.6 (1.2-2.0)) and pre-/early-term infants (1.2 (1.0-1.5)). Additional risk factors included caesarean delivery, congenital anomalies, household overcrowding, birth season, and formal childcare attendance. GP surgery-level variation explained 7-9% of variation in amoxicillin prescribing. Conclusions: Socio-economic status and ethnic background are strongly associated with amoxicillin prescribing and RTI consultations during childhood. Interventions reducing RTI spread in household and childcare settings may reduce antibiotic prescribing in primary care.</jats:p