Costs and staffing resource requirements for adaptive clinical trials: quantitative and qualitative results from the Costing Adaptive Trials project

Background Adaptive designs offer great promise in improving the efficiency and patient-benefit of clinical trials. An important barrier to further increased use is a lack of understanding about which additional resources are required to conduct a high-quality adaptive clinical trial, compared to a traditional fixed design. The Costing Adaptive Trials (CAT) project investigated which additional resources may be required to support adaptive trials. Methods We conducted a mock costing exercise amongst seven Clinical Trials Units (CTUs) in the UK. Five scenarios were developed, derived from funded clinical trials, where a non-adaptive version and an adaptive version were described. Each scenario represented a different type of adaptive design. CTU staff were asked to provide the costs and staff time they estimated would be needed to support the trial, categorised into specified areas (e.g. statistics, data management, trial management). This was calculated separately for the non-adaptive and adaptive version of the trial, allowing paired comparisons. Interviews with 10 CTU staff who had completed the costing exercise were conducted by qualitative researchers to explore reasons for similarities and differences. Results Estimated resources associated with conducting an adaptive trial were always (moderately) higher than for the non-adaptive equivalent. The median increase was between 2 and 4% for all scenarios, except for sample size re-estimation which was 26.5% (as the adaptive design could lead to a lengthened study period). The highest increase was for statistical staff, with lower increases for data management and trial management staff. The percentage increase in resources varied across different CTUs. The interviews identified possible explanations for differences, including (1) experience in adaptive trials, (2) the complexity of the non-adaptive and adaptive design, and (3) the extent of non-trial specific core infrastructure funding the CTU had. Conclusions This work sheds light on additional resources required to adequately support a high-quality adaptive trial. The percentage increase in costs for supporting an adaptive trial was generally modest and should not be a barrier to adaptive designs being cost-effective to use in practice. Informed by the results of this research, guidance for investigators and funders will be developed on appropriately resourcing adaptive trials

The MicroRNA-200 Family Is Upregulated in Endometrial Carcinoma

BACKGROUND: MicroRNAs (miRNAs, miRs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. MicroRNAs are dysregulated in cancer and may play essential roles in tumorigenesis. Additionally, miRNAs have been shown to have prognostic and diagnostic value in certain types of cancer. The objective of this study was to identify dysregulated miRNAs in endometrioid endometrial adenocarcinoma (EEC) and the precursor lesion, complex atypical hyperplasia (CAH). METHODOLOGY: We compared the expression profiles of 723 human miRNAs from 14 cases of EEC, 10 cases of CAH, and 10 normal proliferative endometria controls using Agilent Human miRNA arrays following RNA extraction from formalin-fixed paraffin-embedded (FFPE) tissues. The expression of 4 dysregulated miRNAs was validated using real time reverse transcription-PCR. RESULTS: Forty-three miRNAs were dysregulated in EEC and CAH compared to normal controls (p<0.05). The entire miR-200 family (miR-200a/b/c, miR-141, and miR-429) was up-regulated in cases of EEC. CONCLUSIONS: This information contributes to the candidate miRNA expression profile that has been generated for EEC and shows that certain miRNAs are dysregulated in the precursor lesion, CAH. These miRNAs in particular may play important roles in tumorigenesis. Examination of miRNAs that are consistently dysregulated in various studies of EEC, like the miR-200 family, will aid in the understanding of the role that miRNAs play in tumorigenesis in this tumour type

Volunteer Bias in Recruitment, Retention, and Blood Sample Donation in a Randomised Controlled Trial Involving Mothers and Their Children at Six Months and Two Years: A Longitudinal Analysis

BACKGROUND: The vulnerability of clinical trials to volunteer bias is under-reported. Volunteer bias is systematic error due to differences between those who choose to participate in studies and those who do not. METHODS AND RESULTS: This paper extends the applications of the concept of volunteer bias by using data from a trial of probiotic supplementation for childhood atopy in healthy dyads to explore 1) differences between a) trial participants and aggregated data from publicly available databases b) participants and non-participants as the trial progressed 2) impact on trial findings of weighting data according to deprivation (Townsend) fifths in the sample and target populations. 1) a) Recruits (n = 454) were less deprived than the target population, matched for area of residence and delivery dates (n = 6,893) (mean [SD] deprivation scores 0.09[4.21] and 0.79[4.08], t = 3.44, df = 511, p<0.001). b) i) As the trial progressed, representation of the most deprived decreased. These participants and smokers were less likely to be retained at 6 months (n = 430[95%]) (OR 0.29,0.13-0.67 and 0.20,0.09-0.46), and 2 years (n = 380[84%]) (aOR 0.68,0.50-0.93 and 0.55,0.28-1.09), and consent to infant blood sample donation (n = 220[48%]) (aOR 0.72,0.57-0.92 and 0.43,0.22-0.83). ii) Mothers interested in probiotics or research or reporting infants' adverse events or rashes were more likely to attend research clinics and consent to skin-prick testing. Mothers participating to help children were more likely to consent to infant blood sample donation. 2) In one trial outcome, atopic eczema, the intervention had a positive effect only in the over-represented, least deprived group. Here, data weighting attenuated risk reduction from 6.9%(0.9-13.1%) to 4.6%(-1.4-+10.5%), and OR from 0.40(0.18-0.91) to 0.56(0.26-1.21). Other findings were unchanged. CONCLUSIONS: Potential for volunteer bias intensified during the trial, due to non-participation of the most deprived and smokers. However, these were not the only predictors of non-participation. Data weighting quantified volunteer bias and modified one important trial outcome. TRIAL REGISTRATION: This randomised, double blind, parallel group, placebo controlled trial is registered with the International Standard Randomised Controlled Trials Register, Number (ISRCTN) 26287422. Registered title: Probiotics in the prevention of atopy in infants and children

Practical guidance for running late-phase platform protocols for clinical trials: lessons from experienced UK clinical trials units

Background Late-phase platform protocols (including basket, umbrella, multi-arm multi-stage (MAMS), and master protocols) are generally agreed to be more efficient than traditional two-arm clinical trial designs but are not extensively used. We have gathered the experience of running a number of successful platform protocols together to present some operational recommendations. Methods Representatives of six UK clinical trials units with experience in running late-phase platform protocols attended a 1-day meeting structured to discuss various practical aspects of running these trials. We report and give guidance on operational aspects which are either harder to implement compared to a traditional late-phase trial or are specific to platform protocols. Results We present a list of practical recommendations for trialists intending to design and conduct late-phase platform protocols. Our recommendations cover the entire life cycle of a platform trial: from protocol development, obtaining funding, and trial set-up, to a wide range of operational and regulatory aspects such as staffing, oversight, data handling, and data management, to the reporting of results, with a particular focus on communication with trial participants and stakeholders as well as public and patient involvement. Discussion Platform protocols enable many questions to be answered efficiently to the benefit of patients. Our practical lessons from running platform trials will support trial teams in learning how to run these trials more effectively and efficiently

Suicide in Sri Lanka 1975-2012:age, period and cohort analysis of police and hospital data

BACKGROUND: Sri Lanka has experienced major changes in its suicide rates since the 1970s, and in 1995 it had one of the highest rates in the world. Subsequent reductions in Sri Lanka’s suicide rates have been attributed to the introduction of restrictions on the availability of highly toxic pesticides. We investigate these changes in suicide rates in relation to age, gender, method specific trends and birth-cohort and period effects, with the aim of informing preventative strategies. METHODS: Secular trends of suicide in relation to age, sex, method, birth-cohort and period effects were investigated graphically using police data (1975–2012). Poisoning case-fatality was investigated using national hospital admission data (2004–2010). RESULTS: There were marked changes to the age-, gender- and method-specific incidence of suicide over the study period. Year on year declines in rates began in 17–25 year olds in the early 1980s. Reduction in older age groups followed and falls in all age groups occurred after all class I (the most toxic) pesticides were banned. Distinct changes in the age/gender pattern of suicide are observed: in the 1980s suicide rates were highest in 21–35 year old men; by the 2000s, this pattern had reversed with a stepwise increase in male rates with increasing age. Throughout the study period female rates were highest in 17–25 year olds. There has been a rise in suicide by hanging, though this rise is relatively small in relation to the marked decline in self-poisoning deaths. The patterns of suicides are more consistent with a period rather than birth-cohort effect. CONCLUSIONS: The epidemiology of suicide in Sri Lanka has changed noticeably in the last 30 years. The introduction of pesticide regulations in Sri Lanka coincides with a reduction in suicide rates, with evidence of limited method substitution. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2458-14-839) contains supplementary material, which is available to authorized users

Insights into deposition of Lower Cretaceous black shales from meager accumulation of organic matter in Albian sediments from ODP site 763, Exmouth Plateau, Northwest Australia

The amount and type of organic matter present in an exceptionally complete upper Aptian to lower Cenomanian sequence of sediments from ODP site 763 on the Exmouth Plateau has been determined. Organic carbon concentrations average 0.2%. Organic matter is marine in origin, and its production and preservation was low over the ca. 20-million-year interval recorded by this sequence. Because this section was tectonically isolated from mainland Australia in the early Aptian, it better represents global oceanic conditions than the many basin-edge locations in which Albian-age black shales have been found. Formation of the basin-edge black shales evidently resulted from rapid, turbiditic burial of organic matter rather than from enhanced oceanic production or from basin-wide anoxia during the Albian.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47134/1/367_2005_Article_BF02202605.pd

Scio Ergo Sum: Knowledge of the Self in a Nonhuman Primate

The pressures of developing and maintaining intricate social relationships may have led to the evolution of enhanced cognitive abilities in many social nonhuman species, particularly primates. Knowledge of the dominance ranks and social relationships of other individuals, for example, is important in evaluating one’s position in the prevailing affiliative and dominance networks within a primate society and could be acquired through direct or perceived experience. Our analysis of allogrooming supplants among wild bonnet macaques had revealed that individual females successfully evaluate social relationships among other group females and possess egotistical knowledge of their own positions, relative to those of others, in the social hierarchy. These individuals, therefore, appeared to have abstracted and mentally represented their own personal attributes as well as those of other members of the group. Bonnet macaques also seem to recognise that other individuals have beliefs that may be different from their own, manipulate another individual’s actions and beliefs in a variety of social situations, and selectively reveal or withhold information from others—capabilities displayed by certain individuals that became evident in the course of our earlier studies on tactical deception in the species. In conclusion, the ability to develop belief systems and form mental representations, generated by direct personal experience, suggests a rather early evolutionary origin for fairly sophisticated cognitive capabilities, characterised by an objectified self with limited regulatory control over more subjective levels of self-awareness, in cercopithecine primates, pre-dating those of the great apes. We, therefore, argue, in this review, that bonnet macaques might represent an intermediate stage in the evolution of self-awareness, a process which began with the subjective awareness that characterises most, if not all, higher animal species and culminates in the most sophisticated form of symbolic self-awareness, apparently the hallmark of the human species alone