Method Of Treatment Allocation Research Articles

Impact of minimal sufficient balance, minimization, and stratified permuted blocks on bias and power in the estimation of treatment effect in sequential clinical trials with a binary endpoint.

Minimization is among the most common methods for controlling baseline covariate imbalance at the randomization phase of clinical trials. Previous studies have found that minimization does not preserve allocation randomness as well as other methods, such as minimal sufficient balance, making it more vulnerable to allocation predictability and selection bias. Additionally, minimization has been shown in simulation studies to inadequately control serious covariate imbalances when modest biased coin probabilities (≤0.65) are used. This current study extends the investigation of randomization methods to the analysis phase, comparing the impact of treatment allocation methods on power and bias in estimating treatment effects on a binary outcome using logistic regression. Power and bias in the estimation of treatment effect was found to be comparable across complete randomization, minimization, and minimal sufficient balance in unadjusted analyses. Further, minimal sufficient balance was found to have the most modest impact on power and the least bias in covariate-adjusted analyses. The minimal sufficient balance method is recommended for use in clinical trials as an alternative to minimization when covariate-adaptive subject randomization takes place.

Statistical properties of minimal sufficient balance and minimization as methods for controlling baseline covariate imbalance at the design stage of sequential clinical trials.

When the number of baseline covariates whose imbalance needs to be controlled in a sequential randomized controlled trial is large, minimization is the most commonly used method for randomizing treatment assignments. The lack of allocation randomness associated with the minimization method has been the source of controversy, and the need to reduce even minor imbalances inherent in the minimization method has been challenged. The minimal sufficient balance (MSB) method is an alternative to the minimization method. It prevents serious imbalance from a large number of covariates while maintaining a high level of allocation randomness. In this study, the two treatment allocation methods are compared with regards to the effectiveness of balancing covariates across treatment arms and allocation randomness in equal allocation clinical trials. The MSB method proves to be equal or superior in both respects. In addition, type I error rate is preserved in analyses for both balancing methods, when using a binary endpoint.

Efficacy and safety of repetitive transcranial magnetic stimulation for generalised anxiety disorder: A meta-analysis

BackgroundPharmacological and conventional non-pharmacological treatments are only moderately effective in treating generalised anxiety disorder (GAD). Recently, repetitive transcranial magnetic stimulation (rTMS) has attracted interest because of its potential therapeutic value.AimTo...

Stroke prevention in atrial fibrillation: re-defining 'real-world data' within the broader data universe.

Real-world data (RWD) has been defined as data generated outside of traditional randomized clinical trials (RCTs). Though RWD has received increasing attention from regulatory authorities and professional societies, dividing evidence into that derived from 'real-world' vs. 'non-real-world' sources provides only one element of a much larger framework for evidence evaluation. Evidence should be evaluated on the source of the data, the method of treatment allocation (whether any intervention being evaluated was assigned or simply observed as used in practice) and the context in which the evidence was generated (overall study design). Under this framework, RWD refers only to data source, and a study incorporates RWD when it primarily uses data collected for non-research purposes, such as insurance claims data or the electronic health record, regardless of study design. Separation of study design, data source, and context enables parallel evaluation of two critical elements: (i) whether a study can support claims of causal inference, which can be assured with a high degree of confidence only in studies where patients are assigned treatments by protocol; and (ii) whether the study population and clinical context mirror clinical practice, a strength of observational studies using data from clinical practice or administrative claims. In this review, we describe the strengths and weaknesses of observational and non-observational studies, and studies involving RWD and non-RWD, through the lens of anticoagulation for atrial fibrillation (AF). Observational studies employing RWD are useful for describing how oral anticoagulants are used in clinical practice, but generally cannot be used to make claims regarding comparative treatment effects. Questions regarding treatment effect generally are best answered through an RCT, and additional pragmatic RCTs are needed to compare different antithrombotic agents for the prevention of thrombotic events in AF.

Towards Patient-Centered Clinical Trial Designs

Rationale, aims and objectives: Evidence shows a trend towards low enrollment in randomized clinical trials (RCTs), which negatively affect validity of conclusions. Low enrollment is associated with different factors, but has recently been attributed to an increasing proportion of patients expressing concerns about randomization. In this paper, we summarize the evidence on reasons for non-enrollment, and we propose preference-based and shared decision-making as alternative methods for allocating patients to treatments in effectiveness and comparative effectiveness trials.Methods: This paper is a narrative review of available literature.Results: Converging findings of quantitative and qualitative studies revealed three interrelated and frequently mentioned reasons for declining enrollment in RCTs: 1) concerns about randomization related to the lack of understanding of equipoise, lack of appreciation of the scientific merits of randomization, and unfavorable perceptions of randomization as not reflecting methods of treatment selection used in practice; 2) preferences for treatments under evaluation, which contribute to unwillingness to be randomized; and 3) desires for involvement in treatment decision-making, which are not respected with randomization.Conclusions: Alternative methods for treatment allocation are needed to make effectiveness and comparative effectiveness trials attractive to patients. Preference-based and shared decision-making are viable methods that respectively represent the informed choice and the collaborative choice styles of treatment selection commonly used in practice. The extent to which these two methods of treatment allocation enhance enrollment should be further investigated.

Effect of the Natural Product Triptolide on Pancreatic Cancer: A Systematic Review of Preclinical Studies.

Objective: Triptolide (TL), a natural product isolated from Tripterygium wilfordii Hook F (TwHF), shows potent anticancer effects in vitro and in vivo. We aimed to summary the biochemical mechanisms through which TL has been shown to induce apoptosis, autophagy and inhibit angiogenesis in pancreatic cancer (PC).Methods: We undertook a systematic review of preclinical evidence. We searched electronic databases. The potential mechanisms and the underlying signaling pathways have been accumulated as well.Results: We screened 116 abstracts for eligibility and included 17 preclinical studies in the analysis. Details of the animals and cell lines were provided in 16 studies (94.1%). Six studies (75.0%) randomly assigned animals to treatment or control groups and only 1 study (12.5%) reported on blinding. The majority of the TL's research field has focused on its pro-apoptotic effects through downregulation of inhibitory pathways and upregulation of apoptotic pathways. The studies have shown that TL is effective both in vitro and in vivo against PC cells.Conclusion: This study provides a systematic summary of TL's anti-pancreatic cancer profile and the underlying mechanisms of with special emphasis on the apoptosis, autophagy, angiogenesis and related molecular pathways. Improved study quality in terms of treatment allocation methods reporting, randomization and blinding will accelerate needed progress toward trials.

Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for the initial treatment of venous thromboembolism.

Low molecular weight heparins (LMWHs) have been shown to be effective and safe in preventing venous thromboembolism (VTE). They may also be effective for the initial treatment of VTE. This is the third update of the Cochrane Review first published in 1999. To evaluate the efficacy and safety of fixed dose subcutaneous low molecular weight heparin compared to adjusted dose unfractionated heparin (intravenous or subcutaneous) for the initial treatment of people with venous thromboembolism (acute deep venous thrombosis or pulmonary embolism). For this update the Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register (15 September 2016). In addition the CIS searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 15 September 2016) and trials' registries. Randomised controlled trials comparing fixed dose subcutaneous LMWH with adjusted dose intravenous or subcutaneous unfractionated heparin (UFH) in people with VTE. Two review authors independently selected trials for inclusion, assessed for quality and extracted data. Six studies were added to this update resulting in a total of 29 included studies (n = 10,390). The quality of the studies was downgraded as there was a risk of bias in some individual studies relating to risk of attrition and reporting bias; in addition several studies did not adequately report on the randomisation methods used nor on how the treatment allocation was concealed.During the initial treatment period, the incidence of recurrent venous thromboembolic events was lower in participants treated with LMWH than in participants treated with UFH (Peto odds ratio (OR) 0.69, 95% confidence intervals (CI) 0.49 to 0.98; 6238 participants; 18 studies; P = 0.04; moderate-quality evidence). After a follow-up of three months, the period in most of the studies for which oral anticoagulant therapy was given, the incidence of recurrent VTE was lower in participants treated with LMWH than in participants with UFH (Peto OR 0.71, 95% CI 0.56 to 0.90; 6661 participants; 16 studies; P = 0.005; moderate-quality evidence). Furthermore, at the end of follow-up, LMWH was associated with a lower rate of recurrent VTE than UFH (Peto OR 0.72, 95% CI 0.59 to 0.88; 9489 participants; 22 studies; P = 0.001; moderate-quality evidence). LMWH was also associated with a reduction in thrombus size compared to UFH (Peto OR 0.71, 95% CI 0.61 to 0.82; 2909 participants; 16 studies; P < 0.00001; low-quality evidence), but there was moderate heterogeneity (I² = 56%). Major haemorrhages occurred less frequently in participants treated with LMWH than in those treated with UFH (Peto OR 0.69, 95% CI 0.50 to 0.95; 8780 participants; 25 studies; P = 0.02; moderate-quality evidence). There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (Peto OR 0.84, 95% CI 0.70 to 1.01; 9663 participants; 24 studies; P = 0.07; moderate-quality evidence). This review presents moderate-quality evidence that fixed dose LMWH reduced the incidence of recurrent thrombotic complications and occurrence of major haemorrhage during initial treatment; and low-quality evidence that fixed dose LMWH reduced thrombus size when compared to UFH for the initial treatment of VTE. There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (moderate-quality evidence). The quality of the evidence was assessed using GRADE criteria and downgraded due to concerns over risk of bias in individual trials together with a lack of reporting on the randomisation and concealment of treatment allocation methods used. The quality of the evidence for reduction of thrombus size was further downgraded because of heterogeneity between studies.

Abstract B50: A church-based diet, physical activity, and stress intervention results in lower waist to hip ratios and reduced chronic inflammation in African-American males

Abstract Introduction: Acute inflammation, the body's response to infection or physical insult, helps to control infection, heal wounds, and promote tissue regeneration. When normal systems of negative feedback fail to turn off inhibitory signaling, persistent chronic inflammation results. Such chronic inflammation has been shown to be associated with cancers of many anatomic sites and other chronic diseases that are both more prevalent and more virulent among African Americans in the Southeastern United States. Also, chronic inflammation has been associated with poor diet, low levels of physical activity, and high levels of psychosocial stress. Using principles of community-based participatory research (CBPR), this randomized controlled trial (RCT) was designed and administered jointly by members of African-American churches and academic researchers. Its goal was to test the effectiveness of a community-based diet, physical activity and stress reduction intervention in reducing inflammation in overweight and obese African-American adults. Methods: The RCT was conducted in greater Columbia, SC from 2010 to 2014. Churches were randomized to receive the intervention either immediately or with a 12-month delay. The latter served as the study's control arm. Church members were the unit of measurement for all health-related outcomes. Three lay health leaders, who constituted the Church Education Team (CET) and facilitated the study, were selected by the pastor of each church. The first intervention phase consisted of 12 weekly group classes led by a trained community health educator and involving hands-on cooking of mainly vegetable-based meals, sharing of healthy recipes, increasing physical activity, and mindfulness-based stress reduction. The second phase included monthly boosters conducted over an additional 9 months, and was meant to reinforce and expand on topics introduced in the more intensive, 12-week phase. Anthropometric measures were taken along with C-reactive protein (CRP), interleukin (IL)-6 and Monocyte Chemoattractant Protein (MCP)-1. A composite inflammatory score was computed by summing the z-scores for CRP, IL-6 and MCP-1. Linear regression models were fit to test intervention effectiveness and to identify predictors of success. Results: Males in the intervention arm had lower mean adjusted CRP values compared to controls (2.6 vs. 3.7mg/L, p=0.05) at 12-week follow-up (immediately after weekly intervention classes). After 1-year follow-up, a difference of similar magnitude, but not statistically significant, was observed (2.6 vs. 3.9, p=0.17). A nearly statistically significant difference in the composite inflammatory biomarker score also was observed between intervention and control arms among males (-0.38 vs. 0.17, p=0.07). Adjustment for ratings of intervention attendance and sustainability revealed a statistically significant difference in waist-to-hip ratio (WHR) between intervention and control group subjects (0.84 vs. 0.86, p=0.03) at 12-week follow-up among all participants. Conclusion: This RCT showed a significant reduction in CRP among males, but not females; and WHR reductions among all participants at 12-week follow-up. Results also included a large dropout and relatively large differences in factors related to retention and participants' investment in the process. Therefore, alternatives to randomization as a method of treatment allocation may be more appropriate from a public health perspective, especially in communities with large cancer-related health disparities. Citation Format: James R. Hebert, Michael D. Wirth, Brook E. Harmon, Nitin Shivappa, Thomas G. Hurley, Lisa C. Davis, Cheryl A. Armstead, Angela E. Murphy. A church-based diet, physical activity, and stress intervention results in lower waist to hip ratios and reduced chronic inflammation in African-American males. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B50.

The Contribution of Treatment Allocation Method to Outcomes in Intervention Research.

The purpose of this methodological study was to examine the contribution of treatment allocation method (random vs. preference) on the immediate, intermediate, and ultimate outcomes of a behavioural intervention (MCI) for insomnia. Participants were allocated to the MCI randomly or by preference. Outcomes were assessed before, during, and after completion of the MCI using validated self-report measures. Analysis of covariance was used to compare the post-test outcomes for the 2 groups, controlling for baseline differences. Compared to those randomized, participants in the preference group showed improvement in most immediate outcomes (sleep onset latency, wake after sleep onset, sleep efficiency), both intermediate outcomes (insomnia severity and daytime fatigue), and one ultimate outcome (resolution of insomnia). Using a systematic method for eliciting participants' preferences and involving participants in treatment selection had a beneficial impact on immediate and intermediate outcomes. Additional research should validate the mechanism through which treatment preferences contribute to outcomes.

Attrition in Randomized and Preference Trials of Behavioural Treatments for Insomnia.

Preferences for treatment contribute to attrition. Providing participants with their preferred treatment, as done in a partially randomized clinical or preference trial (PRCT), is a means to mitigate the influence of treatment preferences on attrition. This study examined attrition in an RCT and a PRCT. Persons with insomnia were randomly assigned (n = 150) or allocated (n = 198) to the preferred treatment. The number of dropouts at different time points in the study arms was documented and the influence of participant characteristics and treatment-related factors on attrition was examined. The overall attrition rate was higher in the RCT arm (46%) than in the PRCT arm (33%). In both arms, differences in sociodemographic and clinical characteristics were found between dropouts and completers. The type of treatment significantly predicted attrition (all p ≤ .05). The results provide some evidence of a lower attrition rate in the PRCT arm, supporting the benefit of accounting for preferences as a method of treatment allocation.

Method of Treatment Allocation: Does It Affect Adherence to Behavioural Therapy for Insomnia?

Adherence to treatment is critical in determining the effects of behavioural therapy and may be affected by participants' preference for treatment. The purpose of this study was to determine the extent to which method of allocation to treatment (random vs. preference-based) influences adherence (exposure and enactment) to behavioural therapy. Participants received behavioural therapy for the management of insomnia randomly or by preference. Exposure was assessed as attendance at the treatment sessions, enactment as self-reported application of treatment recommendations. Participants (N = 262) attended a mean of 5.6 treatment sessions, applied the treatment recommendations frequently, and reported high levels of overall compliance. There was no difference between the random and preference groups in terms of exposure to and enactment of treatment. Randomization to the preferred treatment, dissatisfaction with the allocated treatment, and self-report bias could play a role in the findings and should be explored in future research.

Time to be BRAVE: is educating surgeons the key to unlocking the potential of randomised clinical trials in surgery? A qualitative study.

BackgroundWell-designed randomised clinical trials (RCTs) provide the best evidence to inform decision-making and should be the default option for evaluating surgical procedures. Such trials can be challenging, and surgeons’ preferences may influence whether trials are initiated and successfully conducted and their results accepted. Preferences are particularly problematic when surgeons’ views play a key role in procedure selection and patient eligibility. The bases of such preferences have rarely been explored. Our aim in this qualitative study was to investigate surgeons’ preferences regarding the feasibility of surgical RCTs and their understanding of study design issues using breast reconstruction surgery as a case study.MethodsSemistructured qualitative interviews were undertaken with a purposive sample of 35 professionals practicing at 15 centres across the United Kingdom. Interviews were transcribed verbatim and analysed thematically using constant comparative techniques. Sampling, data collection and analysis were conducted concurrently and iteratively until data saturation was achieved.ResultsSurgeons often struggle with the concept of equipoise. We found that if surgeons did not feel ‘in equipoise’, they did not accept randomisation as a method of treatment allocation. The underlying reasons for limited equipoise were limited appreciation of the methodological weaknesses of data derived from nonrandomised studies and little understanding of pragmatic trial design. Their belief in the value of RCTs for generating high-quality data to change or inform practice was not widely held.ConclusionThere is a need to help surgeons understand evidence, equipoise and bias. Current National Institute of Health Research/Medical Research Council investment into education and infrastructure for RCTs, combined with strong leadership, may begin to address these issues or more specific interventions may be required.

Internal versus external tocodynamometry during induced or augmented labour

Uterine contractions can be registered by external tocodynamometry (ET) or, after rupture of the membranes, by internal tocodynamometry (IT). Monitoring of the frequency of contractions is important especially when intravenous oxytocin is used as excessive uterine activity (hyperstimulation or tachysystole) can cause fetal distress. During induction of labour as well as during augmentation with intravenous oxytocin, some clinicians choose to monitor frequency and strength of contractions with IT rather than with ET as an intrauterine pressure catheter measures intrauterine activity more accurately than an extra-abdominal tocodynamometry device. However, insertion of an intrauterine catheter has higher costs and also potential risks for mother and child. To assess the effectiveness of IT compared with using ET when intravenous oxytocin is used for induction or augmentation of labour. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2013) and PubMed (1966 to 6 April 2013). We included all published randomised controlled trials with data from women in whom IT was compared with ET in induced or augmented labour with oxytocin. We excluded trials that employed quasi-randomised methods of treatment allocation. We found no unpublished or ongoing studies on this subject. Two review authors independently assessed trial eligibility and risk of bias, and independently extracted data. Data were checked for accuracy. Where necessary, we contacted study authors for additional information. Three studies involving a total of 1945 women were included. Overall, risk of bias across the three trials was mixed. No serious complications were reported in the trials and no neonatal or maternal deaths occurred. The neonatal outcome was not statistically different between groups: Apgar score less than seven at five minutes (RR 1.78, 95% CI 0.83 to 3.83; three studies, n = 1945); umbilical artery pH less than 7.15 (RR 1.31, 95% CI 0.95 to 1.79; one study, n = 1456); umbilical artery pH less than 7.16 (RR 1.23, 95% CI 0.39 to 3.92; one study, n = 239); admission to the neonatal intensive care unit (RR 0.34, 95% CI 0.07 to 1.67; two studies, n = 489); and more than 48 hours hospitalisation (RR 0.92, 95% CI 0.71 to 1.20; one study, n = 1456). The pooled risk for instrumental delivery (including caesarean section, ventouse and forceps extraction) was not statistically significantly different (RR 1.05, 95% CI 0.91 to 1.21; three studies, n = 1945). Hyperstimulation was reported in two studies (n = 489), but there was no statistically significant difference between groups (RR 1.21, 95% CI 0.78 to 1.88). This review found no differences between the two types of monitoring (internal or external tocodynamometry) for any of the maternal or neonatal outcomes. Given that this review is based on three studies (N = 1945 women) of moderate quality, there is insufficient evidence to recommend the use of one form of tocodynamometry over another for women where intravenous oxytocin was administered for induction or augmentation of labour.

Morning versus evening induction of labour for improving outcomes

Induction of labour is a common intervention in obstetric practice. Traditionally, in most hospitals induction of labour with medication starts early in the morning, with the start of the working day for the day shift. In human and animal studies spontaneous onset of labour is proven to have a circadian rhythm with a preference for start of labour in the evening. Moreover, when spontaneous labour starts in the evening, the total duration of labour and delivery shortens and fewer obstetric interventions are needed. Based on these observations one might assume that starting induction of labour in the evening, in harmony with the circadian rhythm of natural birth, is more beneficial for both mother and child. To assess whether induction of labour starting in the evening, coinciding with the endogenous circadian rhythm, improves the outcome of labour compared with induction of labour starting in the early morning, organised to coincide with office hours. We contacted the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group's Trials Register (28 February 2012). In addition, we searched MEDLINE (1966 to 16 February 2012) and EMBASE (1980 to 16 February 2012). We included all published and unpublished randomised controlled trials. We excluded trials that employed quasi-random methods of treatment allocation. Two review authors independently assessed trials for inclusion and risk of bias. Two review authors independently extracted data. Data were checked for accuracy. Where necessary, we contacted study authors for additional information. The search resulted in 2693 articles that we screened on title and abstract for eligibility.Thirteen studies were selected for full text assessment. We included three randomised trials involving 1150 women. Two trials compared the administration of prostaglandins in the morning versus the evening in women with an unfavourable cervix, and one trial compared induction of labour in the morning versus the evening in women with a favourable cervix and/or ruptured membranes with intravenous oxytocin. Because of the different mechanism, we have reported results for these two comparisons separately.In the two trials comparing prostaglandins in the morning versus the evening there were few clinically significant differences between study groups for maternal or neonatal outcomes. One study reported a statistically significant preference by women to start induction of labour with prostaglandins in the morning.In the trial examining induction of labour with intravenous oxytocin, the number of neonatal admissions was statistically significantly increased in the group of women that started induction in the morning. This finding was unexpected, and while the trial authors offered some possible explanations for this, it is important that any future trials examine neonatal outcomes. Taking into account women's preferences that favoured administration of prostaglandins in the morning, we conclude that caregivers should preferably consider administering prostaglandins in the morning.There is no strong evidence that induction of labour with intravenous oxytocin in the evening is more or less effective than induction in the morning. Consideration may be given to start induction of labour with oxytocin in the evening when indicated.

Authors’ reply to: single-incision laparoscopic surgery (SILS) vs. conventional multiport cholecystectomy: systematic review and meta-analysis

We thank Garg et al. [1] for their interest in our publication [2]. The meta-analysis was aimed at comparing clinical outcome following single-incision (SILS) vs. multiport laparoscopic cholecystectomy. We demonstrated that SILS cholecystectomy was a safe procedure with a similar clinical outcome to standard multiport laparoscopic cholecystectomy. In their letter Garg et al. [1] raise four points of interest that we wish to deal with in turn. First, we agree that improved cosmesis is one of the major benefits of single-incision surgery. However, with the advent of any new surgical technique, patient safety must be the primary concern before the focus can turn to more subjective outcomes such as cosmesis or pain. This meta-analysis clearly demonstrated that SILS cholecystectomy is a safe procedure for uncomplicated gallstone disease in the hands of experienced laparoscopic surgeons. There was insufficient comparable data to allow the analysis of cosmesis as a primary outcome measure. As part of the discussion in our article we described three studies that reported improved patient wound satisfaction scores (different scoring systems were used making meta-analysis impossible). We also alluded to the need for future highpowered randomized studies to examine patient wound satisfaction associated with these different techniques. Second, the authors suggested that postoperative pain may reflect a function of wound tension. This may be a contributing factor, yet not one of the papers that they cited made any correlation of wound tension with the subjective nature of pain. This makes their conclusions difficult to follow. More importantly, the extent of dissection, the site of the incision, wound infection rates, and the method of closure will also affect the pain response. Therefore, to imply that wound tension is solely responsible is a gross oversimplification. One of the major benefits of laparoscopic cholecystectomy has been the significant reduction in postoperative pain when compared to standard open cholecystectomy. In several institutions across the world, laparoscopic cholecystectomy is performed as a day-case procedure, which directly reflects the benefits in postoperative pain seen with this technique. Thus, as the authors suggest, it may be challenging to demonstrate a significant improvement in pain associated with SILS cholecystectomy as multiport laparoscopic cholecystectomy has already dramatically improved pain associated with open surgery. However, this meta-analysis does demonstrate equivalent short-term pain scores for both techniques. Third, Garg et al. [1] raised concerns regarding the methodology employed in trial selection. In particular, they highlighted the inclusion of the Asakuma et al. [3] study. A method of quasirandomization was used by Asakuma et al. [3], with ‘‘allocation to SILS or conventional multiport cholecystectomy based solely on the day of the week.’’ As Garg et al. [1] mentioned in their correspondence, ‘‘there was no attempt to randomize patients blindly, and patient requests for a particular procedure were honored.’’ While we agree with their statement that this method of treatment allocation is not randomization in its purest sense, Asakuma et al. [3] attempted to randomize patients to each treatment. However, we are happy to acknowledge that differences in opinion may exist regarding the inclusion and exclusion of trials based on the methodology of randomization employed. Fourth, Garg et al. [1] suggested that an error occurred in the Table 5 in reporting the incidence of bile leak in the Lee et al. [4] paper. In their paper Lee et al. [4] described S. Markar (&) J. Kinross Academic Surgical Unit, St. Mary’s Hospital, 10th Floor, Praed Street, London W2 1NY, UK e-mail: sheraz_markar@hotmail.com

Two-Way Minimization: A Novel Treatment Allocation Method for Small Trials

Randomization is a hallmark of clinical trials. If a trial entails very few subjects and has many prognostic factors (or many factor levels) to be balanced, minimization is a more efficient method to achieve balance than a simple randomization. We propose a novel minimization method, the ‘two-way minimization’. The method separately calculates the ‘imbalance in the total numbers of subjects’ and the ‘imbalance in the distributions of prognostic factors’. And then to allocate a subject, it chooses—by probability—to minimize either one of these two aspects of imbalances. As such, it is a method that is both treatment-adaptive and covariate-adaptive. We perform Monte-Carlo simulations to examine its statistical properties. The two-way minimization (with proper regression adjustment of the force-balanced prognostic factors) has the correct type I error rates. It also produces point estimates that are unbiased and variance estimates that are accurate. When there are important prognostic factors to be balanced in the study, the method achieves the highest power and the smallest variance among randomization methods that are resistant to selection bias. The allocation can be done in real time and the subsequent data analysis is straightforward. The two-way minimization is recommended to balance prognostic factors in small trials.

Studies with group treatments required special power calculations, allocation methods, and statistical analyses

ObjectiveIn some trials, the intervention is delivered to individuals in groups, for example, groups that exercise together. The group structure of such trials has to be taken into consideration in the analysis and has an impact on the power of the trial. Our aim was to provide optimal methods for the design and analysis of such trials. Study Design and SettingWe described various treatment allocation methods and presented a new allocation algorithm: optimal batchwise minimization (OBM). We carried out a simulation study to evaluate the performance of unrestricted randomization, stratification, permuted block randomization, deterministic minimization, and OBM. Furthermore, we described appropriate analysis methods and derived a formula to calculate the study size. ResultsStratification, deterministic minimization, and OBM had considerably less risk of imbalance than unrestricted randomization and permuted block randomization. Furthermore, OBM led to unpredictable treatment allocation. The sample size calculation and the analysis of the study must be based on a multilevel model that takes the group structure of the trial into account. ConclusionTrials evaluating interventions that are carried out in subsequent groups require adapted treatment allocation, power calculation, and analysis methods. From the perspective of obtaining overall balance, we conclude that minimization is the method of choice. When the number of prognostic factors is low, stratification is an excellent alternative. OBM leads to better balance within the batches, but it is more complicated. It is probably most worthwhile in trials with many prognostic factors. From the perspective of predictability, a treatment allocation method, such as OBM, that allocates several subjects at the same time, is superior to other methods because it leads to the lowest possible predictability.

Generalized method for adaptive randomization in clinical trials

A flexible, generalized method of treatment allocation is proposed. The method uses a set of controlling parameters that enables the generic algorithm to produce a family of possible outcomes ranging from simple randomization to deterministic allocation. The method controls balance at stratum level, stratification level and overall without detriment to the predictability of the method. The paper lists the desirable characteristics of allocation methods and shows that the proposed method fulfils the majority and is easy to use in the clinical context, once the coding has been established. An explanation of the method for 2, 3 and 4 treatment group allocations is given. Simulations demonstrate the flexibility of the method.

Characteristics of clinical trials assessing antimicrobial treatment of bovine respiratory disease, 1970-2005

To evaluate reporting of key study design features and study outcomes in trials of antimicrobial treatment of bovine respiratory disease (BRD) in North American feedlots. Systematic review. 29 manuscripts (41 studies) reporting antimicrobial treatment of BRD in North American feedlot cattle. A search of the electronic citation databases AGRICOLA, Commonwealth Agricultural Bureau, and PubMed was conducted to identify relevant manuscripts published between 1970 and 2005. Key study design features were extracted by 2 reviewers. 12 of 29 (41%) manuscripts did not disclose a funding source, and 21 (72%) had an author clearly identified as an employee of a pharmaceutical company. At the study level, 36 of 41 (88%) studies reported a random method of treatment allocation, 9 (22%) described the method of allocation sequence generation, 20 (49%) reported that study investigators were blinded to treatment, and 3 (7%) included a study size justification. No studies described the null hypothesis to be tested. Thirty-seven (90%) studies reported at least 3 outcomes; the largest number of outcomes reported was 14. It was not possible to conduct the statistical analysis as originally planned because it was not possible to discern the primary outcome for the majority of studies. Many studies did not report key study design features that would assist critical evaluation by readers. It was not clear whether the studies failed to use the design features or failed to report them. Several nondesign features, such as reporting of the null hypothesis, a primary outcome, and sample size rationale, represent relatively new standards for reporting; however, reporting these features would substantially clarify the study objective.

Studywise minimization: A treatment allocation method that improves balance among treatment groups and makes allocation unpredictable

Objectives In randomized controlled trials with many potential prognostic factors, serious imbalance among treatment groups regarding these factors can occur. Minimization methods can improve balance but increase the possibility of selection bias. We described and evaluated the performance of a new method of treatment allocation, called studywise minimization, that can avoid imbalance by chance and reduce selection bias. Study Design and Setting The studywise minimization algorithm consists of three steps: (1) calculate the imbalance for all possible allocations, (2) list all allocations with minimum imbalance, and (3) randomly select one of the allocations with minimum imbalance. We carried out a simulation study to compare the performance of studywise minimization with three other allocation methods: randomization, biased-coin minimization, and deterministic minimization. Performance was measured, calculating maximal and average imbalance as a percentage of the group size. Results Independent of trial size and number of prognostic factors, the risk of serious imbalance was the highest in randomization and absent in studywise minimization. The largest differences among the allocation methods regarding the risk of imbalance were found in small trials. Conclusion Studywise minimization is particularly useful in small trials, where it eliminates the risk of serious imbalances without generating the occurrence of selection bias.