Identification of Randomized Trials for Inclusion in Meta-Analyses of Treatments for Childhood Acute Lymphoblastic Leukaemia, and Investigation of Factors Leading to Publication Bias

Purpose: Some randomized trials are reported widely, while others remain unpublished. It is essential to systematic reviewers and meta-analysts that factors leading to publication bias in the form of delayed or non-publication of an eligible study are identified. This thesis is an attempt to do this. Data: The set of randomized trials identified by the Childhood Acute Lymphoblastic Leukaemia (ALL) Collaborative Group was used. This consists of 149 trials comprising 243 randomized comparisons (randomizations), starting prior to 1 January 1988, reported in 257 articles, published prior to 1 January 2000. Each mention of a randomization in an article (irrespective of whether results are given) generates a publication record, of which there are 610. Methods: The main focus is on identifying which trial characteristics lead to a delay in publication of a randomization. Time to the first mention of a randomization in an article (irrespective of whether any results are given) and to the first reporting of its results are both modelled using ordinary linear regression (the independence model). However, when these analyses are extended to include all mentions and all reportings of results respectively, non-independence necessitates the use of techniques for dealing with repeated measures. In such cases the independence model is the starting point, the residuals from which are used to form the covariance matrix, which in turn is used to suggest plausible correlation structures for repeated measures models. Generalised estimating equation (GEE) analysis is used to select an appropriate correlation structure, and a linear mixed effects model serves to confirm this. The conclusions are then discussed in the context of other studies identified. Finally logistic regression is used to identify trial characteristics associated with a randomization remaining unpublished, and Poisson and negative binomial models to identify those affecting frequency of reporting. Results: Evidence was found of ‘pipeline bias’ in the reporting of first results since, although direction of effect was not found to be significant, highly statistically significant results are published faster than others. However this is not so for first mentions. Negative results (i.e. those in favour of the standard/control) arm were submitted for first publication faster than all others, although this did not effect time to publication. In addition, geographic location is an important predictor of whether a randomization is ever mentioned in an article, frequency of mentions and of time to first publication and results from single-centre trials are published more frequently than those with multi-centre participation. Conclusions: Although ‘pipeline bias’ was identified in the analysis of time first reporting of results, it was not present in the analysis of time to first mention, and so not a problem for those wishing only to identify randomized trials for inclusion in meta-analyses. The importance of geographic location suggests that the practice of contacting known trialists is worthwhile in addition to the computerised literature searches and should be continued. </br

Analysis of characteristics of randomized clinical trials in leukemia that are associated with how results are reported

Background Since many trials are small, systematic reviews are essential for obtaining statistically reliable results. However, some trials are better-reported than others. Non-publication or delayed publication could lead to bias in a review. We identify trial characteristics affecting how quickly or widely results of randomized trials are reported, and hence how likely the trial is to be found by reviewers. Methods We analyzed all randomized trials in childhood acute lymphoblastic leukemia that began before 1988 and all articles for these trials published before 2000, as identified by the Childhood Acute Lymphoblastic Leukaemia (ALL) Collaborative Group secretariat. This was the set of 149 trials included in the Second International Collaborative Workshop on Childhood ALL Studies at the end of 1992, comprising 243 randomized comparisons. We used multiple linear regression to analyze time to first mention or to first reporting of results (time to publication), logistic regression for whether a randomization was ever mentioned or reported, and Poisson regression for frequency of mentions or publications. Results Collectively, the articles mentioned 217 randomizations, with results reported for 188. Highly statistically significant results were published faster, each tenfold reduction in the p-value (e.g., going from 0.5 to 0.05 or from 0.05 to 0.005) resulting in publication on average 20 months earlier (95% confidence interval 6-34, p=0.005), non-statistically significant results from trials outside North America and Europe took on average 55 months longer than those without these characteristics (95% CI 22-88, p=0.001), and results from trials in high income countries were more likely to reach publication at some point than were results from other countries (odds ratio 7.8, 95% CI 2.4-25.3, p=0.0006). Randomizations in high income countries were mentioned 73 months earlier than those in middle or low income countries (95% CI 51-94, p&lt;0.0001), were more likely to ever be mentioned (OR 13.1, 95% CI 2.1-80.9, p=0.006), and were mentioned more frequently (incidence ratio 2.5, 95% CI 1.4-4.5, p=0.003), as were North American trials compared with those conducted elsewhere (IR 1.3, 95% CI 1.1-1.6, p=0.01). Conclusions Systematic reviewers should not rely solely on published reports, but should use additional ways of finding trials in order to minimize biases related to results and other trial characteristics. This relates both to published reports of trial results and to mentions of trials in the literature.</p

Application of generalized estimating equations and linear mixed effects models to analysis of correlated data in the field of publication bias in the reporting of randomized clinical trials

The research focused on identifying trial characteristics leading to delayed publication of randomized comparisons, and hence publication bias. Time to first mention in an article (irrespective of whether results are given) and to first reporting of results were modelled using ordinary linear regression (independence model). These analyses were extended to include all mentions and all reportings of results where non-independence necessitated using repeated measures techniques. The residuals from the independence model were used to construct a covariance matrix, thereby suggesting plausible correlation structures for repeated measures models. Results from two methods; generalized estimating equations (GEE) and linear mixed effects modelling, are compared. Problems caused by missing data and their solution are also discussed. This paper concentrates on methodology and the use of repeated measures techniques for incorporating appropriate correlation structures, rather than interpretation of findings, which is published separately. Application of the methods is described, as is the importance of the correct use of repeated measures analyses when an independence model is inappropriate; an independence model may approximate well to the final model, but should only be used to suggest useful correlation structures. Repeated measures methods are easily implemented, providing practical ways of dealing with correlated data

A descriptive study of randomised trials of treatments for childhood acute lymphoblastic leukaemia: Randomised trials in childhood leukaemia

This report presents a historical and descriptive account of randomised trials in childhood leukaemia since the earliest such studies in the 1960s. It focuses on trials that began before 1988 making use of the register of trials developed for a systematic review of treatments for acute lymphoblastic leukaemia in children. The number of randomised trials starting each year has increased from one or two in the 1960s to an annual average of five or six in the 1980s. However trials remained relatively small, with more than half of all randomisations accruing less than 200 patients, and only five having more than 1000. Most trials were published more than once.This is the accepted version of the following article: [BURRETT, J. A. & CLARKE, M. J. 2002. A descriptive study of randomized trials of treatments for childhood acute lymphoblastic leukaemia British Journal of Haematology 118, 986-990.], which has been published in final form at [http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2002.03730.x

Alcohol consumption and mortality: the Khon Kaen Cohort Study, Thailand.

BACKGROUND: The prevalence of alcohol consumption among Thais is high, around 30%. We quantified the relationship between alcohol drinking and mortality in a rural population in the most populous region of Thailand. METHODS: The data were from the Khon Kaen Cohort Study. About 24 000 Thai adults were enrolled between 1990 and 2001, and follow-up for vital status continued until March 16, 2012. Mortality data were obtained from the Bureau of Policy and Strategy, Ministry of the Interior, Thailand. A Cox proportional hazards model was used to analyze the association between alcohol drinking and death, controlling for age, education level, and smoking, and floating absolute risk was used to estimate the 95% confidence intervals of hazard ratios. RESULTS: In total, 18 457 participants (5829 men and 12 628 women) were recruited, of whom 3155 died (1375 men and 1780 women) during a median follow-up period of 13.6 years. Although alcohol drinking was common (64% of men and 25% of women), the amounts consumed were very low (average, 4.3 g/day in men and 0.8 g/day in women). As compared with never drinkers, mortality risk was lower among current drinkers and higher among ex-drinkers. Current drinking was not associated with mortality from cancer or diseases of the circulatory system, although ex-drinkers appeared to have a higher risk of death from the latter. CONCLUSIONS: The leading causes of mortality were not associated with current alcohol drinking at the low consumption levels observed in this population

Educational inequalities and premature mortality: the Cuba Prospective Study

Background Although socioeconomic status is a major determinant of premature mortality in many populations, the impact of social inequalities on premature mortality in Cuba, a country with universal education and health care, remains unclear. We aimed to assess the association between educational level and premature adult mortality in Cuba. Methods The Cuba Prospective Study (a cohort study) enrolled 146 556 adults aged 30 years and older from the general population in five provinces from Jan 1, 1996, to Nov 24, 2002. Participants were followed up until Jan 1, 2017, for cause-specific mortality. Deaths were identified through linkage to the Cuban Public Health Ministry's national mortality records. Cox regression models yielded rate ratios (RRs) for the effect of educational level (a commonly used measure for social status) on mortality at ages 35–74 years, with assessment for the mediating effects of smoking, alcohol consumption, and BMI. Findings A total of 127 273 participants aged 35–74 years were included in the analyses. There was a strong inverse association between educational level and premature mortality. Compared with a university education, men who did not complete primary education had an approximately 60% higher risk of premature mortality (RR 1·55, 95% CI 1·40–1·72), while the risk was approximately doubled in women (1·96, 1·81–2·13). Overall, 28% of premature deaths could be attributed to lower education levels. Excess mortality in women was primarily due to vascular disease, while vascular disease and cancer were equally important in men. 31% of the association with education in men and 18% in women could be explained by common modifiable risk factors, with smoking having the largest effect. Interpretation This study highlights the value of understanding the determinants of health inequalities in different populations. Although many major determinants lie outside the health system in Cuba, this study has identified the diseases and risk factors that require targeted public health interventions, particularly smoking. Funding UK Medical Research Council, British Heart Foundation, Cancer Research UK, CDC Foundation (with support from Amgen)

Alcohol consumption and cause-specific mortality in Cuba: prospective study of 120 623 adults

Background: the associations of cause-specific mortality with alcohol consumption have been studied mainly in higher-income countries. We relate alcohol consumption to mortality in Cuba.Methods: in 1996-2002, 146 556 adults were recruited into a prospective study from the general population in five areas of Cuba. Participants were interviewed, measured and followed up by electronic linkage to national death registries until January 1, 2017. After excluding all with missing data or chronic disease at recruitment, Cox regression (adjusted for age, sex, province, education, and smoking) was used to relate mortality rate ratios (RRs) at ages 35–79 years to alcohol consumption. RRs were corrected for long-term variability in alcohol consumption using repeat measures among 20 593 participants resurveyed in 2006-08.Findings: after exclusions, there were 120 623 participants aged 35-79 years (mean age 52 [SD 12]; 67 694 [56%] women). At recruitment, 22 670 (43%) men and 9490 (14%) women were current alcohol drinkers, with 15 433 (29%) men and 3054 (5%) women drinking at least weekly; most alcohol consumption was from rum. All-cause mortality was positively and continuously associated with weekly alcohol consumption: each additional 35cl bottle of rum per week (110g of pure alcohol) was associated with ∼10% higher risk of all-cause mortality (RR 1.08 [95%CI 1.05-1.11]). The major causes of excess mortality in weekly drinkers were cancer, vascular disease, and external causes. Non-drinkers had ∼10% higher risk (RR 1.11 [1.09-1.14]) of all-cause mortality than those in the lowest category of weekly alcohol consumption (&lt;1 bottle/week), but this association was almost completely attenuated on exclusion of early follow-up.Interpretation: in this large prospective study in Cuba, weekly alcohol consumption was continuously related to premature mortality. Reverse causality is likely to account for much of the apparent excess risk among non-drinkers. The findings support limits to alcohol consumption that are lower than present recommendations in Cuba.Funding: Medical Research Council, British Heart Foundation, Cancer Research UK, CDC Foundation (with support from Amgen

Burden of hypertension and associated risks for cardiovascular mortality in Cuba: a prospective cohort study

Summary: Background: In Cuba, hypertension control in primary care has been prioritised as a cost-effective means of addressing premature death from cardiovascular disease. However, there is little evidence from large-scale studies on the prevalence and management of hypertension in Cuba, and no direct evidence of the expected benefit of such efforts on cardiovascular mortality. Methods: In a prospective cohort study, adults in the general population identified via local family medical practices were interviewed between Jan 1, 1996, and Nov 24, 2002, in five areas of Cuba, and a subset of participants were resurveyed between July 14, 2006, and Oct 19, 2008, in one area. During household visits, blood pressure was measured and information obtained on diagnosis and treatment of hypertension. We calculated the prevalence of hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or receiving treatment for hypertension) and the proportion of people with hypertension in whom it was diagnosed, treated, and controlled (systolic blood pressure <140 mm Hg, diastolic blood pressure <90 mm Hg). Deaths were identified through linkage by national identification numbers to the Cuban Public Health Ministry records, to Dec 31, 2016. We used Cox regression analysis to compare cardiovascular mortality between participants with versus without uncontrolled hypertension. Rate ratios (RRs) were used to estimate the fraction of cardiovascular deaths attributable to hypertension. Findings: 146 556 participants were interviewed in the baseline survey in 1996–2002 and 24 345 were interviewed in the resurvey in 2006–08. After exclusion for incomplete data and age outside the range of interest, 136 111 respondents aged 35–79 years (mean age 54 [SD 12] years; 75 947 [56%] women, 60 164 [44%] men) were eligible for inclusion in the analyses. 34% of participants had hypertension. Among these, 67% had a diagnosis of hypertension. 76% of participants with diagnosed hypertension were receiving treatment and blood pressure was controlled in 36% of those people. During 1·7 million person-years of follow-up there were 5707 cardiovascular deaths. In the age groups 35–59, 60–69, and 70–79 years, uncontrolled hypertension at baseline was associated with RRs of 2·15 (95% CI 1·88–2·46), 1·86 (1·69–2·05), and 1·41 (1·32–1·52), respectively, and accounted for around 20% of premature cardiovascular deaths. Interpretation: In this Cuban population, a third of people had hypertension. Although levels of hypertension diagnosis and treatment were commensurate with those in some high-income countries, the proportion of participants whose blood pressure was controlled was low. As well as reducing hypertension prevalence, improvement in blood pressure control among people with diagnosed hypertension is required to prevent premature cardiovascular deaths in Cuba. Funding: Medical Research Council, British Heart Foundation, Cancer Research UK

Body-mass index, blood pressure, diabetes and cardiovascular mortality in Cuba: prospective study of 146,556 participants

Background: cardiovascular disease accounts for about one-third of all premature deaths (ie, age &lt; 70) in Cuba. Yet, the relevance of major risk factors, including systolic blood pressure (SBP), diabetes, and body-mass index (BMI), to cardiovascular mortality in this population remains unclear.Methods: in 1996–2002, 146,556 adults were recruited from the general population in five areas of Cuba. Participants were interviewed, measured (height, weight and blood pressure) and followed up by electronic linkage to national death registries until Jan 1, 2017; in 2006–08, 24,345 participants were resurveyed. After excluding all with missing data, cardiovascular disease at recruitment, and those who died in the first 5 years, Cox regression (adjusted for age, sex, education, smoking, alcohol and, where appropriate, BMI) was used to relate cardiovascular mortality rate ratios (RRs) at ages 35–79 years to SBP, diabetes and BMI; RR were corrected for regression dilution to give associations with long-term average (ie, ‘usual’) levels of SBP and BMI.Results: after exclusions, there were 125,939 participants (mean age 53 [SD12]; 55% women). Mean SBP was 124 mmHg (SD15), 5% had diabetes, and mean BMI was 24.2 kg/m2 (SD3.6); mean SBP and diabetes prevalence at recruitment were both strongly related to BMI. During follow-up, there were 4112 cardiovascular deaths (2032 ischaemic heart disease, 832 stroke, and 1248 other). Cardiovascular mortality was positively associated with SBP (&gt;=120 mmHg), diabetes, and BMI (&gt;=22.5 kg/m2): 20 mmHg higher usual SBP about doubled cardiovascular mortality (RR 2.02, 95%CI 1.88–2.18]), as did diabetes (2.15, 1.95–2.37), and 10 kg/m2 higher usual BMI (1.92, 1.64–2.25). RR were similar in men and in women. The association with BMI and cardiovascular mortality was almost completely attenuated following adjustment for the mediating effect of SBP. Elevated SBP (&gt;=120 mmHg), diabetes and raised BMI (&gt;=22.5 kg/m2) accounted for 27%, 14%, and 16% of cardiovascular deaths, respectively.Conclusions: this large prospective study provides direct evidence for the effects of these major risk factors on cardiovascular mortality in Cuba. Despite comparatively low levels of these risk factors by international standards, the strength of their association with cardiovascular death means they nevertheless exert a substantial impact on premature mortality in Cuba