Systems validation: application to statistical programs

BACKGROUND: In 2003, the United States Food and Drug Administration (FDA) released a guidance document on the scope of "Part 11" enforcement. In this guidance document, the FDA indicates an expectation of a risk-based approach to determining which systems should undergo validation. Since statistical programs manage and manipulate raw data, their implementation should be critically reviewed to determine whether or not they should undergo validation. However, the concepts of validation are not often discussed in biostatistics curriculum. DISCUSSION: This paper summarizes a "Plan, Do, Say" approach to validation that can be incorporated into statistical training so that biostatisticians can understand and implement validation principles in their research. SUMMARY: Validation is a process that requires dedicated attention. The process of validation can be easily understood in the context of the scientific method

Statistical design considerations for pilot studies transitioning therapies from the bench to the bedside

Pilot studies are often used to transition therapies developed using animal models to a clinical setting. Frequently, the focus of such trials is on estimating the safety in terms of the occurrence of certain adverse events. With relatively small sample sizes, the probability of observing even relatively common events is low; however, inference on the true underlying event rate is still necessary even when no events of interest are observed. The exact upper limit to the event rate is derived and illustrated graphically. In addition, the simple algebraic expression for the confidence bound is seen to be useful in the context of planning studies

Men Are More Likely than Women to Slow in the Marathon

Studies on nonelite distance runners suggest that men are more likely than women to slow their pace in a marathon. Purpose: This study determined the reliability of the sex difference in pacing across many marathons and after adjusting women\u27s performances by 12% to address men\u27s greater maximal oxygen uptake and also incorporating information on racing experience. Methods: Data were acquired from 14 US marathons in 2011 and encompassed 91,929 performances. For 2929 runners, we obtained experience data from a race-aggregating Web site. We operationalized pace maintenance as the percentage change in pace observed in the second half of the marathon relative to the first half. Pace maintenance was analyzed as a continuous variable and as two categorical variables, as follows: maintain the pace, defined as slowing=30%. Results: The mean change in pace was 15.6% and 11.7% for men and women, respectively (P \u3c 0.0001). This sex difference was significant for all 14 marathons. The odds for women were 1.46 (95% confidence interval, 1.41–1.50; P \u3c 0.0001) times higher than men to maintain the pace and 0.36 (95% confidence interval, 0.34–0.38; P \u3c 0.0001) times that of men to exhibit marked slowing. Slower finishing times were associated with greater slowing, especially in men (interaction, P \u3c 0.0001). However, the sex difference in pacing occurred across age and finishing time groups. Making the 12% adjustment to women’s performances lessened the magnitude of the sex difference in pacing but not its occurrence. Although greater experience was associated with less slowing, controlling for the experience variables did not eliminate the sex difference in pacing. Conclusions: The sex difference in pacing is robust. It may reflect sex differences in physiology, decision making, or both

Practical considerations for estimating clinical trial accrual periods: application to a multi-center effectiveness study

Abstract Background Adequate participant recruitment is vital to the conduct of a clinical trial. Projected recruitment rates are often over-estimated, and the time to recruit the target population (accrual period) is often under-estimated. Methods This report illustrates three approaches to estimating the accrual period and applies the methods to a multi-center, randomized, placebo controlled trial undergoing development. Results Incorporating known sources of accrual variation can yield a more justified estimate of the accrual period. Simulation studies can be incorporated into a clinical trial's planning phase to provide estimates for key accrual summaries including the mean and standard deviation of the accrual period. Conclusion The accrual period of a clinical trial should be carefully considered, and the allocation of sufficient time for participant recruitment is a fundamental aspect of planning a clinical trial.</p

Breast vibro-acoustography: initial results show promise

INTRODUCTION: Vibro-acoustography (VA) is a recently developed imaging modality that is sensitive to the dynamic characteristics of tissue. It detects low-frequency harmonic vibrations in tissue that are induced by the radiation force of ultrasound. Here, we have investigated applications of VA for in vivo breast imaging. METHODS: A recently developed combined mammography-VA system for in vivo breast imaging was tested on female volunteers, aged 25 years or older, with suspected breast lesions on their clinical examination. After mammography, a set of VA scans was acquired by the experimental device. In a masked assessment, VA images were evaluated independently by 3 reviewers who identified mass lesions and calcifications. The diagnostic accuracy of this imaging method was determined by comparing the reviewers' responses with clinical data. RESULTS: We collected images from 57 participants: 7 were used for training and 48 for evaluation of diagnostic accuracy (images from 2 participants were excluded because of unexpected imaging artifacts). In total, 16 malignant and 32 benign lesions were examined. Specificity for diagnostic accuracy was 94% or higher for all 3 reviewers, but sensitivity varied (69% to 100%). All reviewers were able to detect 97% of masses, but sensitivity for detection of calcification was lower (≤ 72% for all reviewers). CONCLUSIONS: VA can be used to detect various breast abnormalities, including calcifications and benign and malignant masses, with relatively high specificity. VA technology may lead to a new clinical tool for breast imaging applications

Recommendations for Planning Pilot Studies in Clinical and Translational Research

Advances in clinical and translation science are facilitated by building on prior knowledge gained through experimentation and observation. In the context of drug development, preclinical studies are followed by a progression of phase I through phase IV clinical trials. At each step, the study design and statistical strategies are framed around research questions that are prerequisites for the next phase. In other types of biomedical research, pilot studies are used for gathering preliminary support for the next research step. However, the phrase "pilot study" is liberally applied to projects with little or no funding, characteristic of studies with poorly developed research proposals, and usually conducted with no detailed thought of the subsequent study. In this article, we present a rigorous definition of a pilot study, offer recommendations for the design, analysis and sample size justification of pilot studies in clinical and translational research, and emphasize the important role that well-designed pilot studies play in the advancement of science and scientific careers

Lung Injury Prevention with Aspirin (LIPS-A): a Protocol for a Multicentre Randomised Clinical Trial in Medical Patients at High Risk of Acute Lung Injury

Introduction: Acute lung injury (ALI) is a devastating condition that places a heavy burden on public health resources. Although the need for effective ALI prevention strategies is increasingly recognised, no effective preventative strategies exist. The Lung Injury Prevention Study with Aspirin (LIPS-A) aims to test whether aspirin (ASA) could prevent and/or mitigate the development of ALI. Methods and analysis LIPS-A is a multicentre, double-blind, randomised clinical trial testing the hypothesis that the early administration of ASA will result in a reduced incidence of ALI in adult patients at high risk. This investigation will enrol 400 study participants from 14 hospitals across the USA. Conditional logistic regression will be used to test the primary hypothesis that early ASA administration will decrease the incidence of ALI. Ethics and dissemination Safety oversight will be under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained from the DSMB prior to enrolling the first study participant. Approval of both the protocol and informed consent documents were also obtained from the institutional review board of each participating institution prior to enrolling study participants at the respective site. In addition to providing important clinical and mechanistic information, this investigation will inform the scientific merit and feasibility of a phase III trial on ASA as an ALI prevention agent. The findings of this investigation, as well as associated ancillary studies, will be disseminated in the form of oral and abstract presentations at major national and international medical specialty meetings. The primary objective and other significant findings will also be presented in manuscript form. All final, published manuscripts resulting from this protocol will be submitted to Pub Med Central in accordance with the National Institute of Health Public Access Policy

Statistical competencies for medical research learners: What is fundamental?

IntroductionIt is increasingly essential for medical researchers to be literate in statistics, but the requisite degree of literacy is not the same for every statistical competency in translational research. Statistical competency can range from 'fundamental' (necessary for all) to 'specialized' (necessary for only some). In this study, we determine the degree to which each competency is fundamental or specialized.MethodsWe surveyed members of 4 professional organizations, targeting doctorally trained biostatisticians and epidemiologists who taught statistics to medical research learners in the past 5 years. Respondents rated 24 educational competencies on a 5-point Likert scale anchored by 'fundamental' and 'specialized.'ResultsThere were 112 responses. Nineteen of 24 competencies were fundamental. The competencies considered most fundamental were assessing sources of bias and variation (95%), recognizing one's own limits with regard to statistics (93%), identifying the strengths, and limitations of study designs (93%). The least endorsed items were meta-analysis (34%) and stopping rules (18%).ConclusionWe have identified the statistical competencies needed by all medical researchers. These competencies should be considered when designing statistical curricula for medical researchers and should inform which topics are taught in graduate programs and evidence-based medicine courses where learners need to read and understand the medical research literature

Measuring the impact of ambulatory red blood cell transfusion on home functional status: study protocol for a pilot randomized controlled trial

SPIRIT 2013: SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) Checklist for clinical trial protocols. (DOCX 65 kb