Application and efficiency of sequential tests in matched case-control studies

For large epidemiological observational studies banks of biological samples are sometimes created. To study specific research hypotheses blood, urine or tissue specimens can be obtained from participants to a study and stored for later analysis in a biological bank. Constantly new biochemical, molecular or genetic laboratory techniques are developed. These allow a large number of (new) etiologic hypotheses to be tested on the stored biological material to investigate interesting associations between an exposure and a disease. The amount of stored biological material however is, in general, limited, in particular for the cases (the persons who develop the disease of interest), when the disease is not so common. Furthermore, with most laboratory techniques biological material is destroyed and cannot be used for another test. To combine the large number of interesting hypotheses with the limited number and amount of biological samples statistical methods are needed that can distinguish between more promising and less promising hypotheses at the expense of as little biological material as possible. Sequential statistical methods offer a researcher the possibility to terminate an investigation as soon as sufficient evidence has accumulated to accept the null hypothesis ("no association between exposure and disease") or to reject it in favour of the alternative hypothesis ("an association exists between exposure and disease"). After each new observation or group of observations the accumulated data are tested. Based on the cumulative test result the study is stopped or more information is obtained. A sequential analysis requires, on average, fewer observations to come to a decision ("accept the null hypothesis or reject it") than the corresponding fixed sample size analysis. Sequential methods are thus an efficient way to handle the available data. Matching is used to make cases and controls more comparable by controlling for possible confounding factors. These factors are related to both exposure and disease and may distort the size of the exposure-disease relation. In a case-control study one or more controls can be matched to a case based on the value of the confounding factor. A matched design requires in general less cases and controls than an unmatched design. Matching is thus another way of efficient data handling. The chapters of this thesis describe various sequential tests that can be applied in matched case-control studies. Sequential tests were developed for continuous and dichotomous exposure variables. (Group) sequential analysis was proposed as an alternative for conditional power to stop a study early for 'futility'. Sequential tests for the analysis of gene-environment interactions in matched case-control studies were developed. In the last chapter three approaches to statistical testing theory and their effects on sequential testing were discussed. In general, sequential analysis in matched case-control studies can lead to considerable efficiency gains by saving valuable biological samples, time or money

Feeding frequency and caste differentiation in Bombus terrestris larvae

The frequency with which bumble bee larvae are fed during their development was studied using video-recordings. The behaviour of the workers while feeding worker, male and queen larvae of Bombus terrestris was recorded. At the beginning of development, female larvae of both castes were fed at a similar frequency. However, during their last phase queen larvae were fed much more often than worker larvae. Despite the differences in frequency, both queen and worker larval feeding followed a similar pattern. Male larvae were fed more often than worker larvae, but less often than queen larvae. They also differed from the female larvae in the way their feeding frequency increased during development. This suggests that the process of feeding male larvae occurs in a different way. The time intervals between feedings were very variable for all larvae: from a few seconds up to 3 h. Although there was a general tendency for the intervals to decrease in duration with larval development, the irregularity was always present. The differences in feeding frequency found at the individual level for larvae of the same age and the irregularity of the feeding process can be explained by the variation in the amount of food per feeding. Finally, our data suggest that larvae play an active role in the regulation of the feeding process. This subject is discussed and compared to the situation in honey bees

The effect of online hemodiafiltration on infections: Results from the CONvective TRAnsport STudy

Background: Hemodialysis (HD) patients have a high risk of infections. The uremic milieu has a negative impact on several immune responses. Online hemodiafiltration (HDF) may reduce the risk of infections by ameliorating the uremic milieu through enhanced clearance of middle molecules. Since there are few data on infectious outcomes in HDF, we compared the effects of HDF with low-flux HD on the incidence and type of infections. Patients and Methods: We used data of the 714 HD patients (age 64 ±14, 62% men, 25% Diabetes Mellitus, 7% catheters) participating in the CONvective TRAnsport STudy (CONTRAST), a randomized controlled trial evaluating the effect of HDF as compared to low-flux HD. The events were adjudicated by an independent event committee. The risk of infectious events was compared with Cox regression for repeated events and Cox proportional hazard models. The distributions of types of infection were compared between the groups. Results: Thirty one percent of the patients suffered from one or more infections leading to hospitalization during the study (median follow-up 1.96 years). The risk for infections during the entire follow-up did not differ significantly between treatment arms (HDF 198 and HD 169 infections in 800 and 798 person-years respectively, hazard ratio HDF vs. HD 1.09 (0.88-1.34), P = 0.42. No difference was found in the occurrence of the first infectious event (either fatal, nonfatal or type specific). Of all infections, respiratory infections (25% in HDF, 28% in HD) were most common, followed by skin/musculoskeletal infections (21% in HDF, 13% in HD). Conclusions: HDF as compared to HD did not result in a reduced risk of infections, larger studies are needed to confirm our findings. Trial Registration: ClinicalTrials.gov NCT00205556

Neurology

Contains reports on six research projects.Public Health Service (B-3055, B-3090)United States Air Force (AF33(616)-7282, AF49(638)-1130)United States Navy, Office of Naval Research (Nonr-609(39))United States Army Chemical Corps (DA-18-108-405-Cml-942)National Science Foundation (Grant G-16526

The Number of Patients and Events Required to Limit the Risk of Overestimation of Intervention Effects in Meta-Analysis—A Simulation Study

BACKGROUND: Meta-analyses including a limited number of patients and events are prone to yield overestimated intervention effect estimates. While many assume bias is the cause of overestimation, theoretical considerations suggest that random error may be an equal or more frequent cause. The independent impact of random error on meta-analyzed intervention effects has not previously been explored. It has been suggested that surpassing the optimal information size (i.e., the required meta-analysis sample size) provides sufficient protection against overestimation due to random error, but this claim has not yet been validated. METHODS: We simulated a comprehensive array of meta-analysis scenarios where no intervention effect existed (i.e., relative risk reduction (RRR) = 0%) or where a small but possibly unimportant effect existed (RRR = 10%). We constructed different scenarios by varying the control group risk, the degree of heterogeneity, and the distribution of trial sample sizes. For each scenario, we calculated the probability of observing overestimates of RRR>20% and RRR>30% for each cumulative 500 patients and 50 events. We calculated the cumulative number of patients and events required to reduce the probability of overestimation of intervention effect to 10%, 5%, and 1%. We calculated the optimal information size for each of the simulated scenarios and explored whether meta-analyses that surpassed their optimal information size had sufficient protection against overestimation of intervention effects due to random error. RESULTS: The risk of overestimation of intervention effects was usually high when the number of patients and events was small and this risk decreased exponentially over time as the number of patients and events increased. The number of patients and events required to limit the risk of overestimation depended considerably on the underlying simulation settings. Surpassing the optimal information size generally provided sufficient protection against overestimation. CONCLUSIONS: Random errors are a frequent cause of overestimation of intervention effects in meta-analyses. Surpassing the optimal information size will provide sufficient protection against overestimation

A randomised clinical trial on cardiotocography plus fetal blood sampling versus cardiotocography plus ST-analysis of the fetal electrocardiogram (STAN®) for intrapartum monitoring

<p>Abstract</p> <p>Background</p> <p>Cardiotocography (CTG) is worldwide the method for fetal surveillance during labour. However, CTG alone shows many false positive test results and without fetal blood sampling (FBS), it results in an increase in operative deliveries without improvement of fetal outcome. FBS requires additional expertise, is invasive and has often to be repeated during labour. Two clinical trials have shown that a combination of CTG and ST-analysis of the fetal electrocardiogram (ECG) reduces the rates of metabolic acidosis and instrumental delivery. However, in both trials FBS was still performed in the ST-analysis arm, and it is therefore still unknown if the observed results were indeed due to the ST-analysis or to the use of FBS in combination with ST-analysis.</p> <p>Methods/Design</p> <p>We aim to evaluate the effectiveness of non-invasive monitoring (CTG + ST-analysis) as compared to normal care (CTG + FBS), in a multicentre randomised clinical trial setting. Secondary aims are: 1) to judge whether ST-analysis of fetal electrocardiogram can significantly decrease frequency of performance of FBS or even replace it; 2) perform a cost analysis to establish the economic impact of the two treatment options.</p> <p>Women in labour with a gestational age ≥ 36 weeks and an indication for CTG-monitoring can be included in the trial.</p> <p>Eligible women will be randomised for fetal surveillance with CTG and, if necessary, FBS or CTG combined with ST-analysis of the fetal ECG.</p> <p>The primary outcome of the study is the incidence of serious metabolic acidosis (defined as pH < 7.05 and Bd_ecf> 12 mmol/L in the umbilical cord artery). Secondary outcome measures are: instrumental delivery, neonatal outcome (Apgar score, admission to a neonatal ward), incidence of performance of FBS in both arms and cost-effectiveness of both monitoring strategies across hospitals.</p> <p>The analysis will follow the intention to treat principle. The incidence of metabolic acidosis will be compared across both groups. Assuming a reduction of metabolic acidosis from 3.5% to 2.1 %, using a two-sided test with an alpha of 0.05 and a power of 0.80, in favour of CTG plus ST-analysis, about 5100 women have to be randomised. Furthermore, the cost-effectiveness of CTG and ST-analysis as compared to CTG and FBS will be studied.</p> <p>Discussion</p> <p>This study will provide data about the use of intrapartum ST-analysis with a strict protocol for performance of FBS to limit its incidence. We aim to clarify to what extent intrapartum ST-analysis can be used without the performance of FBS and in which cases FBS is still needed.</p> <p>Trial Registration Number</p> <p>ISRCTN95732366</p

Effect of increased convective clearance by on-line hemodiafiltration on all cause and cardiovascular mortality in chronic hemodialysis patients – the Dutch CONvective TRAnsport STudy (CONTRAST): rationale and design of a randomised controlled trial [ISRCTN38365125]

BACKGROUND: The high incidence of cardiovascular disease in patients with end stage renal disease (ESRD) is related to the accumulation of uremic toxins in the middle and large-middle molecular weight range. As online hemodiafiltration (HDF) removes these molecules more effectively than standard hemodialysis (HD), it has been suggested that online HDF improves survival and cardiovascular outcome. Thus far, no conclusive data of HDF on target organ damage and cardiovascular morbidity and mortality are available. Therefore, the CONvective TRAnsport STudy (CONTRAST) has been initiated. METHODS: CONTRAST is a Dutch multi-center randomised controlled trial. In this trial, approximately 800 chronic hemodialysis patients will be randomised between online HDF and low-flux HD, and followed for three years. The primary endpoint is all cause mortality. The main secondary outcome variables are fatal and non-fatal cardiovascular events. CONCLUSION: The study is designed to provide conclusive evidence whether online HDF leads to a lower mortality and less cardiovascular events as compared to standard HD

Quantifying, displaying and accounting for heterogeneity in the meta-analysis of RCTs using standard and generalised Q statistics

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background Clinical researchers have often preferred to use a fixed effects model for the primary interpretation of a meta-analysis. Heterogeneity is usually assessed via the well known Q and I2 statistics, along with the random effects estimate they imply. In recent years, alternative methods for quantifying heterogeneity have been proposed, that are based on a 'generalised' Q statistic. Methods We review 18 IPD meta-analyses of RCTs into treatments for cancer, in order to quantify the amount of heterogeneity present and also to discuss practical methods for explaining heterogeneity. Results Differing results were obtained when the standard Q and I2 statistics were used to test for the presence of heterogeneity. The two meta-analyses with the largest amount of heterogeneity were investigated further, and on inspection the straightforward application of a random effects model was not deemed appropriate. Compared to the standard Q statistic, the generalised Q statistic provided a more accurate platform for estimating the amount of heterogeneity in the 18 meta-analyses. Conclusions Explaining heterogeneity via the pre-specification of trial subgroups, graphical diagnostic tools and sensitivity analyses produced a more desirable outcome than an automatic application of the random effects model. Generalised Q statistic methods for quantifying and adjusting for heterogeneity should be incorporated as standard into statistical software. Software is provided to help achieve this aim.Published versio

Non-invasive cardiac assessment in high risk patients (The GROUND study): rationale, objectives and design of a multi-center randomized controlled clinical trial

Background: Peripheral arterial disease (PAD) is a common disease associated with a considerably increased risk of future cardiovascular events and most of these patients will die from coronary artery disease (CAD). Screening for silent CAD has become an option with recent non-invasive developments in CT (computed tomography)-angiography and MR (magnetic resonance) stress testing. Screening in combination with more aggressive treatment may improve prognosis. Therefore we propose to study whether a cardiac imaging algorithm, using non-invasive imaging techniques followed by treatment will reduce the risk of cardiovascular disease in PAD patients free from cardiac symptoms. Design: The GROUND study is designed as a prospective, multi-center, randomized clinical trial. Patients with peripheral arterial disease, but without symptomatic cardiac disease will be asked to participate. All patients receive a proper risk factor management before randomization. Half of the recruited patients will enter the 'control group' and only undergo CT calcium scoring. The other half of the recruited patients (index group) will undergo the non invasive cardiac imaging algorithm followed by evidence-based treatment. First, patients are submitted to CT calcium scoring and CT angiography. Patients with a left main (or equivalent) coronary artery stenosis of > 50% on CT will be referred to a cardiologist without further imaging. All other patients in this group will undergo dobutamine stress magnetic resonance (DSMR) testing. Patients with a DSMR positive for ischemia will also be referred to a cardiologist. These patients are candidates for conventional coronary angiography and cardiac interventions (coronary artery bypass grafting (CABG) or percutaneous cardiac interventions (PCI)), if indicated. All participants of the trial will enter a 5 year follow up period for the occurrence of cardiovascular events. Sequential interim analysis will take place. Based on sample size calculations about 1200 patients are needed to detect a 24% reduction in primary outcome. Implications: The GROUND study will provide insight into the question whether non-invasive cardiac imaging reduces the risk of cardiovascular events in patients with peripheral arterial disease, but without symptoms of coronary artery disease. Trial registration: Clinicaltrials.gov NCT0018911