BMC Medical Research Methodology - Latest Articles

International Active Surveillance Study of Women Taking Oral Contraceptives (INAS-OC Study)

Juergen Dinger — 2009-11-18T00:00:00Z

Background: A 24-day regimen of contraceptive doses of drospirenone and ethinylestradiol (DRSP/EE 24d) was recently launched. This regimen has properties which may be beneficial for certain user populations (e.g., women suffering from premenstrual dysphoric disorder or acne). However, it is unknown whether this extended regimen has an impact on the cardiovascular risk associated with the use of oral contraceptives (OCs). The INternational Active Surveillance study of women taking Oral Contraceptives (INAS-OC) is designed to investigate the short- and long-term safety of the new regimen in a population which is representative for the typical user of oral contraceptives.Methods / DesignA large, prospective, controlled, non-interventional, long-term cohort study with active surveillance of the study participants has been chosen to ensure reliable and valid results. More than 2,000 gynecologists in the US and 5 European countries (Austria, Germany, Italy, Poland, and Sweden) will recruit more than 80,000 OC users. The two to five year follow-up of these women will result in at least 220,000 documented women-years.The main clinical outcomes of interest for the follow-up are deep venous thrombosis, pulmonary embolism, acute myocardial infarction and cerebrovascular accidents. Secondary objectives are general safety, effectiveness and drug utilization pattern of DRSP/EE 24d, return to fertility after stop of OC use, as well as the baseline risk for users of individual OC formulations.Because of the non-interference character of this study, potential participants (first-time users or switchers) are informed about the study only after the decision regarding prescription of a new OC. There are no specific medical inclusion or exclusion criteria. Study participation is voluntary and a written informed consent is required. After the baseline questionnaire, follow-up questionnaires will be mailed to the participants every 6 months for up to 5 years after baseline. Self-reported serious adverse events will be validated by contacting the relevant physician and by reviewing relevant source documents. At the end of the study an independent blinded adjudication of relevant clinical outcomes will be conducted.Meanwhile, this study has received ethical approval from the Western Institutional Review Board (USA) and the Medical Association in Berlin (Germany).DiscussionThe feasibility of the study is considered to be very high because of its similar design to the EURAS-OC study. All relevant methodological and logistical features of the study were successfully tested in the EURAS study.The chosen design minimizes the impact of referral and misclassification bias, healthy user effect and loss to follow-up. Overall, it is expected that the study design is robust enough to interpret hazard ratios of 1.5 or higher.

Blood spots as an alternative to whole blood collection and the effect of a small monetary incentive to increase participation in genetic association studies

Parveen Bhatti — 2009-11-13T00:00:00Z

Background: Collection of buccal cells from saliva for DNA extraction offers a less invasive and convenient alternative to venipuncture blood collection that may increase participation in genetic epidemiologic studies. However, dried blood spot collection, which is also a convenient method, offers a means of collecting peripheral blood samples from which analytes in addition to DNA can be obtained. Methods: To determine if offering blood spot collection would increase participation in genetic epidemiologic studies, we conducted a study of collecting dried blood spot cards by mail from a sample of female cancer cases (n = 134) and controls (n = 256) who were previously selected for a breast cancer genetics study and declined to provide a venipuncture blood sample. Participants were also randomized to receive either a $2.00 bill or no incentive with the blood spot collection kits. Results: The average time between the venipuncture sample refusal and recruitment for the blood spot collection was 4.4 years. Thirty-seven percent of cases and 28% of controls provided a dried blood spot card. While the incentive was not associated with participation among controls (29% for $2.00 incentive vs. 26% for no incentive, p = 0.6), it was significantly associated with participation among the breast cancer cases (48% vs. 27%, respectively, p = 0.01). There did not appear to be any bias in response since no differences between cases and controls and incentive groups were observed when examining several demographic, work history and radiation exposure variables. Conclusion: This study demonstrates that collection of dried blood spot cards in addition to venipuncture blood samples may be a feasible method to increase participation in genetic case-control studies.

Parasite threshold associated with clinical malaria in areas of different transmission intensities in north eastern Tanzania

Bruno Mmbando — 2009-11-12T00:00:00Z

Background: In Sub-Sahara Africa, malaria due to Plasmodium falciparum is the main cause of ill health. Evaluation of malaria interventions, such as drugs and vaccines depends on clinical definition of the disease, which is still a challenge due to lack of distinct malaria specific clinical features. Parasite threshold is used in definition of clinical malaria in evaluation of interventions. This however, is likely to be influenced by other factors such as transmission intensity as well as individual level of immunity against malaria. Methods: This paper describes step function and dose response model with threshold parameter as a tool for estimation of parasite threshold for onset of malaria fever in highlands (low transmission) and lowlands (high transmission intensity) strata. These models were fitted using logistic regression stratified by strata and age groups (0-1, 2-3, 4-5, 6-9, and 10-19 years). Dose response model was further extended to fit all age groups combined in each stratum. Sub-sampling bootstrap was used to compute confidence intervals. Cross-sectional and passive case detection data from Korogwe district, north eastern Tanzania were used. Results: Dose response model was better in the estimation of parasite thresholds. Parasite thresholds (scale = log parasite/μL) were high in lowlands than in highlands. In the lowlands, children in age group 4-5 years had the highest parasite threshold (8.73) while individuals aged 10-19 years had the lowest (6.81). In the highlands, children aged 0-1 years had the highest threshold (7.12) and those aged 10-19 years had the lowest (4.62). Regression analysis with all ages combined showed similar pattern of thresholds in both strata, whereby, in the lowlands the threshold was highest in age group 2-5 years and lowest in older individuals, while in the highlands was highest in age group 0-1 and decreased with increased age. The sensitivity of parasite threshold by age group ranged from 64%-74% in the lowlands and 67%-97% in the highlands; while specificity ranged between 67%-90% in the lowlands and 37%-73% in the highlands. Conclusion: Dose response model with threshold parameter can be used to estimate parasite threshold associated with malaria fever onset. Parasite threshold were lower in older individuals and in low malaria transmission area.

Computer-aided assessment of diagnostic images for epidemiological research

Alison Abraham — 2009-11-11T00:00:00Z

Background: Diagnostic images are often assessed for clinical outcomes using subjective methods, which are limited by the skill of the reviewer. Computer-aided diagnosis (CAD) algorithms that assist reviewers in their decisions concerning outcomes have been developed to increase sensitivity and specificity in the clinical setting. However, these systems have not been well utilized in research settings to improve the measurement of clinical endpoints. Reductions in bias through their use could have important implications for etiologic research. Methods: Using the example of cortical cataract detection, we developed an algorithm for assisting a reviewer in evaluating digital images for the presence and severity of lesions. Available image processing and statistical methods that were easily implementable were used as the basis for the CAD algorithm. The performance of the system was compared to the subjective assessment of five reviewers using 60 simulated images. Cortical cataract severity scores from 0 to 16 were assigned to the images by the reviewers and the CAD system, with each image assessed twice to obtain a measure of variability. Image characteristics that affected reviewer bias were also assessed by systematically varying the appearance of the simulated images. Results: The algorithm yielded severity scores with smaller bias on images where cataract severity was mild to moderate (approximately ≤ 6/16 ths ). On high severity images, the bias of the CAD system exceeded that of the reviewers. The variability of the CAD system was zero on repeated images but ranged from 0.48 to 1.22 for the reviewers. The direction and magnitude of the bias exhibited by the reviewers was a function of the number of cataract opacities, the shape and the contrast of the lesions in the simulated images. Conclusion: CAD systems are feasible to implement with available software and can be valuable when medical images contain exposure or outcome information for etiologic research. Our results indicate that such systems have the potential to decrease bias and discriminate very small changes in disease severity. Simulated images are a tool that can be used to assess performance of a CAD system when a gold standard is not available.

Multivariate random effects meta-analysis of diagnostic tests with multiple thresholds

Taye Hamza — 2009-11-10T00:00:00Z

Background: Bivariate random effects meta-analysis of diagnostic tests is becoming a well established approach when studies present one two-by-two table or one pair of sensitivity and specificity. When studies present multiple thresholds for test positivity, usually meta-analysts reduce the data to a two-by-two table or take one threshold value at a time and apply the well developed meta-analytic approaches. However, this approach does not fully exploit the data. Methods: In this paper we generalize the bivariate random effects approach to the situation where test results are presented with k thresholds for test positivity, resulting in a 2 by (k+1) table per study. The model can be fitted with standard likelihood procedures in statistical packages such as SAS (Proc NLMIXED). We follow a multivariate random effects approach; i.e., we assume that each study estimates a study specific ROC curve that can be viewed as randomly sampled from the population of all ROC curves of such studies. In contrast to the bivariate case, where nothing can be said about the shape of study specific ROC curves without additional untestable assumptions, the multivariate model can be used to describe study specific ROC curves. The models are easily extended with study level covariates. Results: The method is illustrated using published meta-analysis data. The SAS NLMIXED syntax is given in the appendix. Conclusions: We conclude that the multivariate random effects meta-analysis approach is an appropriate and convenient framework to meta-analyse studies with multiple threshold without losing any information by dichotomizing the test results.

Collecting household water usage data: telephone questionnaire or diary?

Joanne O'Toole — 2009-11-09T00:00:00Z

Background: Quantitative Microbial Risk Assessment (QMRA), a modelling approach, is used to assess health risks. Inputs into the QMRA process include data that characterise the intensity, frequency and duration of exposure to risk(s). Data gaps for water exposure assessment include the duration and frequency of urban non-potable (non-drinking) water use. The primary objective of this study was to compare household water usage results obtained using two data collection tools, a computer assisted telephone interview (CATI) and a 7-day water activity diary, in order to assess the effect of different methodological survey approaches on derived exposure estimates. Costs and logistical aspects of each data collection tool were also examined. Methods: A total of 232 households in an Australian dual reticulation scheme (where households are supplied with two grades of water through separate pipe networks) were surveyed about their water usage using both a CATI and a 7-day diary. Householders were questioned about their use of recycled water for toilet flushing, garden watering and other outdoor activities. Householders were also questioned about their water use in the laundry. Agreement between reported CATI and diary water usage responses was assessed. Results: Results of this study showed that the level of agreement between CATI and diary responses was greater for more frequent water-related activities except toilet flushing and for those activities where standard durations or settings were employed. In addition, this study showed that the unit cost of diary administration was greater than for the CATI, excluding consideration of the initial selection and recruitment steps. Conclusion: This study showed that it is possible to successfully 'remotely' coordinate diary completion providing that adequate instructions are given and that diary recording forms are well designed. In addition, good diary return rates can be achieved using a monetary incentive and the diary format allows for collective recording, rather than an individual's estimation, of household water usage. Accordingly, there is merit in further exploring the use of diaries for collection of water usage information either in combination with a mail out for recruitment, or potentially in the future with Internet-based recruitment (as household Internet uptake increases).

Clinical trial participant characteristics and saliva and DNA metrics

Denise Nishita — 2009-10-29T00:00:00Z

Background: Clinical trial and epidemiological studies need high quality biospecimens from a representative sample of participants to investigate genetic influences on treatment response and disease. Obtaining blood biospecimens presents logistical and financial challenges. As a result, saliva biospecimen collection is becoming more frequent because of the ease of collection and lower cost. This article describes an assessment of saliva biospecimen samples collected through the mail, trial participant demographic and behavioral characteristics, and their association with saliva and DNA quantity and quality. Methods: Saliva biospecimens were collected using the Oragene® DNA Self-Collection Kits from participants in a National Cancer Institute funded smoking cessation trial. Saliva biospecimens from 565 individuals were visually inspected for clarity prior to and after DNA extraction. DNA samples were then quantified by UV absorbance, PicoGreen®, and qPCR. Genotyping was performed on 11 SNPs using TaqMan® SNP assays and two VNTR assays. Univariate, correlation, and analysis of variance analyses were conducted to observe the relationship between saliva sample and participant characteristics. Results: The biospecimen kit return rate was 58.5% among those invited to participate (n = 967) and 47.1% among all possible COMPASS participants (n = 1202). Significant gender differences were observed with males providing larger saliva volume (4.7 vs. 4.5 ml, p = 0.019), samples that were more likely to be judged as cloudy (39.5% vs. 24.9%, p < 0.001), and samples with greater DNA yield as measured by UV (190.0 vs. 138.5, p = 0.002), but reduced % human DNA content (73.2 vs. 77.6 p = 0.005) than females. Other participant characteristics (age, self-identified ethnicity, baseline cigarettes per day) were associated with saliva clarity. Saliva volume and saliva and DNA clarity were positively correlated with total DNA yield by all three quantification measurements (all r > 0.21, P < 0.001), but negatively correlated with % human DNA content (saliva volume r = -0.148 and all P < 0.010). Genotyping completion rate was not influenced by saliva or DNA clarity. Conclusion: Findings from this study show that demographic and behavioral characteristics of smoking cessation trial participants have significant associations with saliva and DNA metrics, but not with the performance of TaqMan® SNP or VNTR genotyping assays.Trial registrationCOMPASS; registered as NCT00301145 at clinicaltrials.gov.

Evaluating the informatics for integrating biology and the bedside system for clinical research.

Vikrant Deshmukh — 2009-10-28T00:00:00Z

Background: Selecting patient cohorts is a critical, iterative, and often time-consuming aspect of studies involving human subjects; informatics tools for helping streamline the process have been identified as important infrastructure components for enabling clinical and translational research. We describe the evaluation of a free and open source cohort selection tool from the Informatics for Integrating Biology and the Bedside (i2b2) group: the i2b2 hive. Methods: Our evaluation included the usability and functionality of the i2b2 hive using several real world examples of research data requests received electronically at the University of Utah Health Sciences Center between 2006 - 2008. The hive server component and the visual query tool application were evaluated for their suitability as a cohort selection tool on the basis of the types of data elements requested, as well as the effort required to fulfill each research data request using the i2b2 hive alone. Results: We found the i2b2 hive to be suitable for obtaining estimates of cohort sizes and generating research cohorts based on simple inclusion/exclusion criteria, which consisted of about 44% of the clinical research data requests sampled at our institution. Data requests that relied on post-coordinated clinical concepts, aggregate values of clinical findings, or temporal conditions in their inclusion/exclusion criteria could not be fulfilled using the i2b2 hive alone, and required one or more intermediate data steps in the form of pre- or post-processing, modifications to the hive metadata, etc. Conclusion: The i2b2 hive was found to be a useful cohort-selection tool for fulfilling common types of requests for research data, and especially in the estimation of initial cohort sizes. For another institution that might want to use the i2b2 hive for clinical research, we recommend that the institution would need to have structured, coded clinical data and metadata available that can be transformed to fit the logical data models of the i2b2 hive, strategies for extracting relevant clinical data from source systems, and the ability to perform substantial pre- and post-processing of these data.

Comparing recruitment strategies in a study of acupuncture for chronic back pain

Karen Sherman — 2009-10-27T00:00:00Z

Background: Meeting recruitment goals is challenging for many clinical trials conducted in primary care populations. Little is known about how the use of different recruitment strategies affects the types of individuals choosing to participate or the conclusions of the study. Methods: A secondary analysis was performed using data from participants recruited to a clinical trial evaluating acupuncture for chronic back pain among primary care patients in a large integrated health care organization. We used two recruitment methods: mailed letters of invitation and an advertisement in the health plan's magazine. For these two recruitment methods, we compared recruitment success (% randomized, treatment completers, drop outs and losses to follow-up), participant characteristics, and primary clinical outcomes. A linear regression model was used to test for interaction between treatment group and recruitment method. Results: Participants recruited via mailed letters closely resembled those responding to the advertisement in terms of demographic characteristics, most aspects of their back pain history and current episode and beliefs and expectations about acupuncture. No interaction between method of recruitment and treatment group was seen, suggesting that study outcomes were not affected by recruitment strategy. Conclusion: In this trial, the two recruitment strategies yielded similar estimates of treatment effectiveness. However, because this finding may not apply to other recruitment strategies or trial circumstances, trials employing multiple recruitment strategies should evaluate the effect of recruitment strategy on outcome.Trial registrationClinical Trials.gov NCT00065585.

A multidisciplinary systematic literature review on frailty: Overview of the methodology used by the Canadian Initiative on Frailty and Aging

Sathya Karunananthan — 2009-10-12T00:00:00Z

Background: Over the past two decades, there has been a substantial growth in the body of literature on frailty in older persons. However, there is no consensus on its definition or the criteria used to identify frailty. In response to this lack of consensus, the Canadian Initiative on Frailty and Aging carried out a set of systematic reviews of the literature in ten areas of frailty research: biological basis; social basis; prevalence; risk factors; impact; identification; prevention and management; environment and technology; health services; health and social policy. This paper describes the methodology that was developed for the systematic reviews. Methods: A Central Coordination Group (CCG) was responsible for developing the methodology. This involved the development of search strategies and keywords, article selection processes, quality assessment tools, and guidelines for the synthesis of results. Each review was conducted by two experts in the content area, with the assistance of methodologists and statisticians from the CCG. Results: Conducting a series of systematic literature reviews involving a range of disciplines on a concept that does not have a universally accepted definition posed several conceptual and methodological challenges. The most important conceptual challenge was determining what would qualify as literature on frailty. The methodological challenges arose from our goal of structuring a consistent methodology for reviewing literature from diverse fields of research. At the outset, certain methodological guidelines were deemed essential to ensure the validity of all the reviews. Nevertheless, it was equally important to permit flexibility in the application of the proposed methodology to capture the essence of frailty research within the given fields. Conclusion: The results of these reviews allowed us to establish the status of current knowledge on frailty and promote collaboration between disciplines. Conducting systematic literature reviews in health science that involve multiple disciplines is a mechanism to facilitate interdisciplinary collaboration and a more integrated understanding of health. This initiative highlighted the need for further methodological development in the performance of multidisciplinary systematic reviews.