Exploring the Implications of Analysing Time-to-Event Outcomes as Binary in Meta-analysis

Systematic reviews and meta-analysis of time-to-event outcomes can be analysed on the hazard ratio (HR) scale but are very often dichotomised and analysed as binary using effect measures such as odds ratios (OR). This thesis investigates the impact of using these different scales by re-analysing meta-analyses from the Cochrane Database of Systematic Reviews (CDSR), using individual participant data (IPD) and a comprehensive simulation study. For the CDSR and IPD, the pooled HR estimates were closer to 1 than the OR estimates in most meta-analyses. Important differences in between-study heterogeneity between the HR and OR analyses were observed. These caused discrepant conclusions between the OR and HR scales in some meta-analyses. Situations under which the clog-log link outperformed the logit link and vice versa were apparent, indicating that the correct method choice does matter. Differences between scales occurred mainly when event probability was high and could occur via differences in between-study heterogeneity or via increased within-study standard error in OR relative to HR analyses. In many simulation scenarios, analysing time-to-event data as binary using the logit link did not substantially affect bias and coverage apart from those where large percentage random censoring and long follow-up time was present. The method though lacks precision particularly for small meta-analyses. Analysing the data as binary using the clog-log link consistently produced more bias, low coverage and low power. If a HR estimate cannot be obtained per trial to perform a meta-analysis of time-to-event data, a meta-analysis using the OR scale (using the logit link) could be conducted but with awareness that this would provide less precise estimates in the analysis. Investigators should avoid performing meta-analyses on the OR scale in the presence of high event probability, large percentage random censoring and therefore longer follow-up times assuming of large event rates of the trials included

Implications of analysing time-to-event outcomes as binary in meta-analysis: empirical evidence from the Cochrane Database of Systematic Reviews

BACKGROUND: Systematic reviews and meta-analysis of time-to-event outcomes are frequently published within the Cochrane Database of Systematic Reviews (CDSR). However, these outcomes are handled differently across meta-analyses. They can be analysed on the hazard ratio (HR) scale or can be dichotomized and analysed as binary outcomes using effect measures such as odds ratios (OR) or risk ratios (RR). We investigated the impact of reanalysing meta-analyses from the CDSR that used these different effect measures. METHODS: We extracted two types of meta-analysis data from the CDSR: either recorded in a binary form only ("binary"), or in binary form together with observed minus expected and variance statistics ("OEV"). We explored how results for time-to-event outcomes originally analysed as "binary" change when analysed using the complementary log-log (clog-log) link on a HR scale. For the data originally analysed as HRs ("OEV"), we compared these results to analysing them as binary on a HR scale using the clog-log link or using a logit link on an OR scale. RESULTS: The pooled HR estimates were closer to 1 than the OR estimates in the majority of meta-analyses. Important differences in between-study heterogeneity between the HR and OR analyses were also observed. These changes led to discrepant conclusions between the OR and HR scales in some meta-analyses. Situations under which the clog-log link performed better than logit link and vice versa were apparent, indicating that the correct choice of the method does matter. Differences between scales arise mainly when event probability is high and may occur via differences in between-study heterogeneity or via increased within-study standard error in the OR relative to the HR analyses. CONCLUSIONS: We identified that dichotomising time-to-event outcomes may be adequate for low event probabilities but not for high event probabilities. In meta-analyses where only binary data are available, the complementary log-log link may be a useful alternative when analysing time-to-event outcomes as binary, however the exact conditions need further exploration. These findings provide guidance on the appropriate methodology that should be used when conducting such meta-analyses

Associations between diagnostic pathways and care experience in colorectal cancer: evidence from patient-reported data.

OBJECTIVE: To examine how different pathways to diagnosis of colorectal cancer may be associated with the experience of subsequent care. DESIGN: Patient survey linked to information on diagnostic route.English patients with colorectal cancer (analysis sample n=6837) who responded to a patient survey soon after their hospital treatment. MAIN OUTCOME MEASURES: Odds Ratios and adjusted proportions of negative evaluation of key aspects of care for colorectal cancer, including the experience of shared decision-making about treatment, specialist nursing and care coordination, by diagnostic route (ie, screening detection, emergency presentation, urgent and elective general practitioner referral). RESULTS: For 14 of 18 questions, there was evidence (p≤0.02) for variation in patient experience by diagnostic route, with 6-31 percentage point differences between routes in adjusted proportions of negative experience. Emergency presenters were more likely to report a negative experience for most questions, including those about adequacy of information about their diagnosis and sufficient explanation before operations. Screen-detected patients were least likely to report negative experiences except for support from primary care. Patients diagnosed through elective primary care referrals were most likely to report worse experience for questions for which overall variation by route was generally small. CONCLUSIONS: Screening-detected patients tend to report the best and emergency presenters the worst experience of subsequent care. Improvement efforts can target care integration for screening-detected patients and provision of information about the diagnosis and treatment of emergency presenters

Diagnostic route is associated with care satisfaction independently of tumour stage: Evidence from linked English Cancer Patient Experience Survey and cancer registration data.

BACKGROUND: Whether diagnostic route (e.g. emergency presentation) is associated with cancer care experience independently of tumour stage is unknown. METHODS: We analysed data on 18 590 patients with breast, prostate, colon, lung, and rectal cancers who responded to the 2014 English Cancer Patient Experience Survey, linked to cancer registration data on diagnostic route and tumour stage at diagnosis. We estimated odds ratios (OR) of reporting a negative experience of overall cancer care by tumour stage and diagnostic route (crude and adjusted for patient characteristic and cancer site variables) and examined their interactions with cancer site. RESULTS: After adjustment, the likelihood of reporting a negative experience was highest for emergency presenters and lowest for screening-detected patients with breast, colon, and rectal cancers (OR versus two-week-wait 1.51, 95% confidence interval [CI] 1.24-1.83; 0.88, 95% CI 0.75-1.03, respectively). Patients with the most advanced stage were more likely to report a negative experience (OR stage IV versus I 1.37, 95% CI 1.15-1.62) with little confounding between stage and route, and no evidence for cancer-stage or cancer-route interactions. CONCLUSIONS: Though the extent of disease is strongly associated with ratings of overall cancer care, diagnostic route (particularly emergency presentation or screening detection) exerts important independent effects.This work is supported by Macmillan Cancer Support grant 5995414 for which GAA and GL are joint principal investigators. GL is supported by a Cancer Research UK Advanced Clinician Scientist Fellowship Award (C18081/A18180)

Sleep duration in preschool age and later behavioral and cognitive outcomes:an individual participant data meta-analysis in five European cohorts

Data de publicació electrònica: 07-02-2023Short sleep duration has been linked to adverse behavioral and cognitive outcomes in schoolchildren, but few studies examined this relation in preschoolers. We aimed to investigate the association between parent-reported sleep duration at 3.5 years and behavioral and cognitive outcomes at 5 years in European children. We used harmonized data from five cohorts of the European Union Child Cohort Network: ALSPAC, SWS (UK); EDEN, ELFE (France); INMA (Spain). Associations were estimated through DataSHIELD using adjusted generalized linear regression models fitted separately for each cohort and pooled with random-effects meta-analysis. Behavior was measured with the Strengths and Difficulties Questionnaire. Language and non-verbal intelligence were assessed by the Wechsler Preschool and Primary Scale of Intelligence or the McCarthy Scales of Children's Abilities. Behavioral and cognitive analyses included 11,920 and 2981 children, respectively (34.0%/13.4% of the original sample). In meta-analysis, longer mean sleep duration per day at 3.5 years was associated with lower mean internalizing and externalizing behavior percentile scores at 5 years (adjusted mean difference: - 1.27, 95% CI [- 2.22, - 0.32] / - 2.39, 95% CI [- 3.04, - 1.75]). Sleep duration and language or non-verbal intelligence showed trends of inverse associations, however, with imprecise estimates (adjusted mean difference: - 0.28, 95% CI [- 0.83, 0.27] / - 0.42, 95% CI [- 0.99, 0.15]). This individual participant data meta-analysis suggests that longer sleep duration in preschool age may be important for children's later behavior and highlight the need for larger samples for robust analyses of cognitive outcomes. Findings could be influenced by confounding or reverse causality and require replication.Open Access funding enabled and organized by Projekt DEAL. This research (LifeCycle Project ID: ECCNLC201914) was funded by the European Union’s Horizon 2020 research and innovation programme under Grant Agreement N: 733206, LifeCycle project. Kathrin Guerlich was granted a LifeCycle Fellowship (Grant Agreement N: 733206, LifeCycle project). Berthold Koletzko is the Else Kröner Seniorprofessor of Paediatrics at LMU – University of Munich, financially supported by Else Kröner-Fresenius-Foundation, LMU Medical Faculty and LMU University Hospital. Deborah A Lawlor and Ahmed Elhakeem work in a Unit that receives support from the University of Bristol and UK Medical Research Council (MC_UU_00011/6). Deborah A Lawlor is a British Heart Foundation Chair (CH/F/20/90003) and a National Institute of Health Research Senior Investigator (NF-0616–10102). Mònica Guxens is funded by a Miguel Servet II fellowship (CPII18/00018) awarded by the Spanish Institute of Health Carlos III. Jordi Julvez holds Miguel Servet-II contract (CPII19/00015) awarded by the Instituto de Salud Carlos III (Co-funded by European Social Fund "Investing in your future"). Tim Cadman was funded a Marie Sklodowska-Curie Individual Fellowship. Funding details for each cohort are provided in Online Resource 1. No funder had any influence on the study design, data collection, statistical analyses or interpretation of findings. The views expressed in this paper are those of the authors and not necessarily of any funders

Associations of Maternal Educational Level, Proximity to Green Space During Pregnancy, and Gestational Diabetes With Body Mass Index From Infancy to Early Adulthood:A Proof-of-Concept Federated Analysis in 18 Birth Cohorts

International sharing of cohort data for research is important and challenging. We explored the feasibility of multicohort federated analyses by examining associations between 3 pregnancy exposures (maternal education, exposure to green vegetation, and gestational diabetes) and offspring body mass index (BMI) from infancy to age 17 years. We used data from 18 cohorts (n = 206,180 mother-child pairs) from the EU Child Cohort Network and derived BMI at ages 0-1, 2-3, 4-7, 8-13, and 14-17 years. Associations were estimated using linear regression via 1-stage individual participant data meta-analysis using DataSHIELD. Associations between lower maternal education and higher child BMI emerged from age 4 and increased with age (difference in BMI z score comparing low with high education, at age 2-3 years = 0.03 (95% confidence interval (CI): 0.00, 0.05), at 4-7 years = 0.16 (95% CI: 0.14, 0.17), and at 8-13 years = 0.24 (95% CI: 0.22, 0.26)). Gestational diabetes was positively associated with BMI from age 8 years (BMI z score difference = 0.18, 95% CI: 0.12, 0.25) but not at younger ages; however, associations attenuated towards the null when restricted to cohorts that measured gestational diabetes via universal screening. Exposure to green vegetation was weakly associated with higher BMI up to age 1 year but not at older ages. Opportunities of cross-cohort federated analyses are discussed.</p

The LifeCycle Project-EU Child Cohort Network : a federated analysis infrastructure and harmonized data of more than 250,000 children and parents

Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life.Peer reviewe

Do comorbidities influence help-seeking for cancer alarm symptoms? A population-based survey in England

Background We examined associations between different chronic morbidities and help-seeking for possible cancer symptoms. Methods Postal survey of individuals aged>50 years in England. Participants could report prior morbidities in respect of 12 pre-defined conditions. Among patients experiencing possible cancer symptoms we examined associations between specific morbidities and self-reported help-seeking (i.e. contacted versus not contacted a GP) for each alarm symptom using regression analyses. Results Among 2042 respondents (42% response rate), 936 (46%) recently experienced one of 14 possible cancer symptoms considered in our analysis. Of them, 80% reported one or more morbidities, most frequently hypertension/hypercholesterolemia (40%), osteomuscular (36%) and heart diseases (21%). After adjustment for socio-demographic characteristics, patients with hypertension/hypercholesterolemia were more likely to report help-seeking for possible cancer symptoms, such as unexplained cough (OR=2.0; 95%CI 1.1-3.5), pain (OR=2.2; 95%CI 1.0-4.5) and abdominal bloating (OR=2.3; 95%CI 1.1-4.8). Urinary morbidity was associated with increased help-seeking for abdominal bloating (OR=5.4; 95%CI 1.2-23.7) or rectal bleeding (OR=5.8; 95%CI 1.4-23.8). In contrast, heart problems reduced help-seeking for change in bowel habits (OR=0.4; 95%CI 0.2-1.0). Conclusions Comorbidities are common and may facilitate help-seeking for possible cancer symptoms, but associations vary for specific symptom-comorbidity pairs. The findings can contribute to the design of future cancer symptom awareness campaigns

Association of assisted reproductive technology with offspring growth and adiposity from infancy to early adulthood

Importance: people conceived using assisted reproductive technology (ART) make up an increasing proportion of the world's population.Objective: to investigate the association of ART conception with offspring growth and adiposity from infancy to early adulthood in a large multicohort study.Design, setting, and participants: this cohort study used a prespecified coordinated analysis across 26 European, Asia-Pacific, and North American population-based cohort studies that included people born between 1984 and 2018, with mean ages at assessment of growth and adiposity outcomes from 0.6 months to 27.4 years. Data were analyzed between November 2019 and February 2022.Exposures: conception by ART (mostly in vitro fertilization, intracytoplasmic sperm injection, and embryo transfer) vs natural conception (NC; without any medically assisted reproduction).Main outcomes and measures: the main outcomes were length / height, weight, and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Each cohort was analyzed separately with adjustment for maternal BMI, age, smoking, education, parity, and ethnicity and offspring sex and age. Results were combined in random effects meta-analysis for 13 age groups.Results: up to 158 066 offspring (4329 conceived by ART) were included in each age-group meta-analysis, with between 47.6% to 60.6% females in each cohort. Compared with offspring who were NC, offspring conceived via ART were shorter, lighter, and thinner from infancy to early adolescence, with differences largest at the youngest ages and attenuating with older child age. For example, adjusted mean differences in offspring weight were -0.27 (95% CI, -0.39 to -0.16) SD units at age younger than 3 months, -0.16 (95% CI, -0.22 to -0.09) SD units at age 17 to 23 months, -0.07 (95% CI, -0.10 to -0.04) SD units at age 6 to 9 years, and -0.02 (95% CI, -0.15 to 0.12) SD units at age 14 to 17 years. Smaller offspring size was limited to individuals conceived by fresh but not frozen embryo transfer compared with those who were NC (eg, difference in weight at age 4 to 5 years was -0.14 [95% CI, -0.20 to -0.07] SD units for fresh embryo transfer vs NC and 0.00 [95% CI, -0.15 to 0.15] SD units for frozen embryo transfer vs NC). More marked differences were seen for body fat measurements, and there was imprecise evidence that offspring conceived by ART developed greater adiposity by early adulthood (eg, ART vs NC difference in fat mass index at age older than 17 years: 0.23 [95% CI, -0.04 to 0.50] SD units).Conclusions and relevance: these findings suggest that people conceiving or conceived by ART can be reassured that differences in early growth and adiposity are small and no longer evident by late adolescence.</p