Christiana A. Naaktgeboren

Value of composite reference standards in diagnostic research

Combining several tests is a common way to improve the final classification of disease status in diagnostic accuracy studies but is often used ambiguously. This article gives advice on proper use and reporting of composite reference standards

Evaluating Diagnostic Accuracy in the Face of Multiple Reference Standards

A universal challenge in studies that quantify the accuracy of diagnostic tests is establishing whether each participant has the disease of interest. Ideally, the same preferred reference standard would be used for all participants; however, for practical or ethical reasons, alternative reference standards that are often less accurate are frequently used instead. The use of different reference standards across participants in a single study is known as differential verification.Differential verification can cause severely biased accuracy estimates of the test or model being studied. Many variations of differential verification exist, but not all introduce the same risk of bias. A risk-of-bias assessment requires detailed information about which participants receive which reference standards and an estimate of the accuracy of the alternative reference standard. This article classifies types of differential verification and explores how they can lead to bias. It also provides guidance on how to report results and assess the risk of bias when differential verification occurs and highlights potential ways to correct for the bias.

Laparoscopy to Predict the Result of Primary Cytoreductive Surgery in Patients With Advanced Ovarian Cancer: A Randomized Controlled Trial

Purpose To investigate whether initial diagnostic laparoscopy can prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced-stage ovarian cancer in whom > 1 cm of residual disease will be left after PCS. Patients and Methods This multicenter, randomized controlled trial was undertaken within eight gynecologic cancer centers in the Netherlands. Patients with suspected advanced-stage ovarian cancer who qualified for PCS were eligible. Participating patients were randomly assigned to either laparoscopy or PCS. Laparoscopy was used to guide selection of primary treatment: either primary surgery or neoadjuvant chemotherapy followed by interval surgery. The primary outcome was futile laparotomy, defined as a PCS with residual disease of > 1 cm. Primary analyses were performed according to the intention-to-treat principle. Results Between May 2011 and February 2015, 201 participants were included, of whom 102 were assigned to diagnostic laparoscopy and 99 to primary surgery. In the laparoscopy group, 63 (62%) of 102 patients underwent PCS versus 93 (94%) of 99 patients in the primary surgery group. Futile laparotomy occurred in 10 (10%) of 102 patients in the laparoscopy group versus 39 (39%) of 99 patients in the primary surgery group (relative risk, 0.25; 95% CI, 0.13 to 0.47; P < .001). In the laparoscopy group, three (3%) of 102 patients underwent both primary and interval surgery compared with 28 (28%) of 99 patients in the primary surgery group ( P < .001). Conclusion Diagnostic laparoscopy reduced the number of futile laparotomies in patients with suspected advanced-stage ovarian cancer. In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to < 1 cm of residual disease seems feasible, to proceed with PCS.

External validation of prognostic models to predict risk of gestational diabetes mellitus in one Dutch cohort: prospective multicentre cohort study

Objective To perform an external validation and direct comparison of published prognostic models for early prediction of the risk of gestational diabetes mellitus, including predictors applicable in the first trimester of pregnancy. Design External validation of all published prognostic models in large scale, prospective, multicentre cohort study. Setting 31 independent midwifery practices and six hospitals in the Netherlands. Participants Women recruited in their first trimester (<14 weeks) of pregnancy between December 2012 and January 2014, at their initial prenatal visit. Women with pre-existing diabetes mellitus of any type were excluded. Main outcome measures Discrimination of the prognostic models was assessed by the C statistic, and calibration assessed by calibration plots. Results 3723 women were included for analysis, of whom 181 (4.9%) developed gestational diabetes mellitus in pregnancy. 12 prognostic models for the disorder could be validated in the cohort. C statistics ranged from 0.67 to 0.78. Calibration plots showed that eight of the 12 models were well calibrated. The four models with the highest C statistics included almost all of the following predictors: maternal age, maternal body mass index, history of gestational diabetes mellitus, ethnicity, and family history of diabetes. Prognostic models had a similar performance in a subgroup of nulliparous women only. Decision curve analysis showed that the use of these four models always had a positive net benefit. Conclusions In this external validation study, most of the published prognostic models for gestational diabetes mellitus show acceptable discrimination and calibration. The four models with the highest discriminative abilities in this study cohort, which also perform well in a subgroup of nulliparous women, are easy models to apply in clinical practice and therefore deserve further evaluation regarding their clinical impact.

Systematic overview finds variation in approaches to investigating and reporting on sources of heterogeneity in systematic reviews of diagnostic studies.

OBJECTIVES To examine how authors explore and report on sources of heterogeneity in systematic reviews of diagnostic accuracy studies. STUDY DESIGN AND SETTING A cohort of systematic reviews of diagnostic tests was systematically identified. Data were extracted on whether an exploration of the sources of heterogeneity was undertaken, how this was done, the number and type of potential sources explored, and how results and conclusions were reported. RESULTS Of the 65 systematic reviews, 12 did not perform a meta-analysis and eight of these gave heterogeneity between studies as a reason. Of the 53 reviews containing a meta-analysis, 40 explored potential sources of heterogeneity in a formal manner and 27 identified at least one source of heterogeneity. The reviews not investigating heterogeneity were smaller than those that did (median [interquartile range {IQR}], 8 [5-15] vs. 14 [11-19] primary studies). Twelve reviews performed a sensitivity analysis, 25 stratified analyses, and 19 metaregression. Many sources of heterogeneity were explored compared with the number of primary studies in a meta-analysis (median ratio, 1:5). Review authors placed importance on the exploration of sources of heterogeneity; 37 mentioned the exploration or the findings thereof in the abstract or conclusion of the main text.results CONCLUSION Methods for investigating sources of heterogeneity varied widely between reviews. Based on our findings of the review, we made suggestions on what to consider and report on when exploring sources of heterogeneity in systematic reviews of diagnostic studies.

Incorporating quality assessments of primary studies in the conclusions of diagnostic accuracy reviews: a cross-sectional study.

BackgroundDrawing conclusions from systematic reviews of test accuracy studies without considering the methodological quality (risk of bias) of included studies may lead to unwarranted optimism about the value of the test(s) under study. We sought to identify to what extent the results of quality assessment of included studies are incorporated in the conclusions of diagnostic accuracy reviews.MethodsWe searched MEDLINE and EMBASE for test accuracy reviews published between May and September 2012. We examined the abstracts and main texts of these reviews to see whether and how the results of quality assessment were linked to the accuracy estimates when drawing conclusions.ResultsWe included 65 reviews of which 53 contained a meta-analysis. Sixty articles (92%) had formally assessed the methodological quality of included studies, most often using the original QUADAS tool (n = 44, 68%). Quality assessment was mentioned in 28 abstracts (43%); with a majority (n = 21) mentioning it in the methods section. In only 5 abstracts (8%) were results of quality assessment incorporated in the conclusions. Thirteen reviews (20%) presented results of quality assessment in the main text only, without further discussion. Forty-seven reviews (72%) discussed results of quality assessment; the most frequent form was as limitations in assessing quality (n = 28). Only 6 reviews (9%) further linked the results of quality assessment to their conclusions, 3 of which did not conduct a meta-analysis due to limitations in the quality of included studies. In the reviews with a meta-analysis, 19 (36%) incorporated quality in the analysis. Eight reported significant effects of quality on the pooled estimates; in none of them these effects were factored in the conclusions.ConclusionWhile almost all recent diagnostic accuracy reviews evaluate the quality of included studies, very few consider results of quality assessment when drawing conclusions. The practice of reporting systematic reviews of test accuracy should improve if readers not only want to be informed about the limitations in the available evidence, but also on the associated implications for the performance of the evaluated tests.

Anticipating missing reference standard data when planning diagnostic accuracy studies

Results obtained using a reference standard may be missing for some participants in diagnostic accuracy studies. This paper looks at methods for dealing with such missing data when designing or conducting a prospective diagnostic accuracy study

Prevalence of intestinal protozoa in communities along the Lake Victoria region of Uganda.

The objective of this study was to assess water-borne parasite point prevalence in communities in close proximity to Lake Victoria in Uganda prior to the implementation of a clean water intervention, and to investigate possible associations of water source and latrine access with protozoan prevalence. Utilizing a rapid antigen test, parasite prevalence for Giardia lamblia and Entamoeba histolytica/dispar was determined from stool samples of individuals living in six Ugandan communities. Stool sample test results were stratified by the independent variables of gender, age, community, water source (improved or lake), and presence of a latrine. The impact of the independent variables on parasite prevalence was investigated with bivariable and multivariable analyses. The prevalence of Giardia (12%) was influenced by age and community of residence. The prevalence of Entamoeba (10%) did not significantly vary by the independent variables. The prevalence of intestinal protozoan parasites is significant in Ugandan communities bordering Lake Victoria. Interventions to continue to improve water sources remain a high priority. Rapid antigen testing is likely to be useful in the monitoring of water-borne parasite prevalence.

Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial

BACKGROUND Respiratory syncytial virus (RSV) infection is associated with subsequent wheeze and asthma. We previously reported on the causal relationship between prevention of RSV infection during infancy and reduced frequency of subsequent wheeze using a double-blind, randomised, placebo-controlled trial (MAKI). We continued follow-up and analysed the effect of RSV prevention during infancy on asthma and lung function at age 6 years. METHODS We studied 429 infants born at 32-35 weeks of gestation between 2008-10 who had randomly received either palivizumab for RSV immunoprophylaxis or placebo during the RSV season of their first year of life. After the first year of follow-up, single, assessor-blind follow-up of children continued until they were aged 6 years. Primary outcomes were parent-reported current asthma and forced expiratory volume in 0·5 s (FEV0·5). The trial is registered in the ISRCTN registry, number ISRCTN73641710. FINDINGS 395 (92%) of 429 participants completed this 6-year follow-up study. Parent-reported current asthma was reported in 28 (14·1%) of 199 children in the RSV prevention group and 47 (24·0%) of 196 children in the placebo group (absolute risk reduction [ARR] 9·9%, 95% CI 2·2 to 17·6). The difference in current asthma, which was a composite endpoint, was due to a difference in infrequent wheeze (one to three episodes in the past year; 12 [6·0%] of 199 vs 26 [13·4%] of 194, ARR 7·4%, 95% CI 1·5 to 13·2). FEV0·5 percentage predicted values were similar between the RSV prevention group (89·1% [SD 10·6]) and placebo group (90·1% [11·1]), with a mean difference of 1·0 (95% CI -1·3 to 3·3). The proportion of children with current physician-diagnosed asthma was similar between the RSV prevention group (19 [10·3%] of 185) and placebo group (18 [9·9%] of 182), with an ARR of -0·4 (95% CI -6·5 to 5·8). INTERPRETATION In otherwise healthy preterm infants, this single-blind, randomised, placebo-controlled trial showed that RSV prevention did not have a major effect on current asthma or lung function at age 6 years. Future research will inform on the effect of RSV prevention on asthma at school age in the general population. FUNDING AbbVie.

Overdiagnosis across medical disciplines : A scoping review

Objective To provide insight into how and in what clinical fields overdiagnosis is studied and give directions for further applied and methodological research. Design Scoping review. Data sources Medline up to August 2017. Study selection All English studies on humans, in which overdiagnosis was discussed as a dominant theme. Data extraction Studies were assessed on clinical field, study aim (ie, methodological or non-methodological), article type (eg, primary study, review), the type and role of diagnostic test(s) studied and the context in which these studies discussed overdiagnosis. Results From 4896 studies, 1851 were included for analysis. Half of all studies on overdiagnosis were performed in the field of oncology (50%). Other prevalent clinical fields included mental disorders, infectious diseases and cardiovascular diseases accounting for 9%, 8% and 6% of studies, respectively. Overdiagnosis was addressed from a methodological perspective in 20% of studies. Primary studies were the most common article type (58%). The type of diagnostic tests most commonly studied were imaging tests (32%), although these were predominantly seen in oncology and cardiovascular disease (84%). Diagnostic tests were studied in a screening setting in 43% of all studies, but as high as 75% of all oncological studies. The context in which studies addressed overdiagnosis related most frequently to its estimation, accounting for 53%. Methodology on overdiagnosis estimation and definition provided a source for extensive discussion. Other contexts of discussion included definition of disease, overdiagnosis communication, trends in increasing disease prevalence, drivers and consequences of overdiagnosis, incidental findings and genomics. Conclusions Overdiagnosis is discussed across virtually all clinical fields and in different contexts. The variability in characteristics between studies and lack of consensus on overdiagnosis definition indicate the need for a uniform typology to improve coherence and comparability of studies on overdiagnosis.