Better Safe Than Sorry. A Scoping Review of Monitoring for Negative Effects in Preregistrations of Psychological Interventions.

Although negative effects of psychological interventions are suspected to be common, they are rarely investigated. Experts and international guidelines agree that monitoring for negative effects in clinical studies is needed to make psychological interventions safer and to empower patients before they give their consent to participate. Therefore, monitoring should already be considered during planning and preregistration of a study. The aim of this scoping review was to find out how frequently studies on psychological interventions monitor their negative effects according to preregistrations and to investigate reasons why monitoring is not carried out. Preregistrations of psychological interventions on ClinicalTrials.gov were scrutinized for information on monitoring of negative effects and other study characteristics. In a survey, researchers of studies where no monitoring was reported were asked for reasons for not doing so. Overall, 2231 preregistrations of psychological interventions were found; of these, only 3.4% included explicit information on monitoring for negative effects. In the survey, more researchers reported having conducted monitoring, although the type of monitoring was often inadequate. The type of monitoring varied widely, and specific monitoring measurements were rarely used repeatedly. Monitoring for negative effects was more prevalent in studies investigating treatments versus low-threshold interventions, in studies conducted in Europe versus other continents and in more recent studies. Researchers reported lack of knowledge as the most frequent reason for not monitoring negative effects. Our results imply a lack of monitoring and inconsistent information on negative effects in preregistrations, with inconsistent use of the term monitoring and measurements, and a lack of knowledge among researchers. Improved knowledge and a standardized approach, starting with an adequate preregistration, would be helpful to routinely examine negative effects in psychological interventions to make them safer and better.

Clinically significant differences in self-reported pain scores in children with headaches.

OBJECTIVES: Changes in pain scores that represent clinically significant differences in children with headaches are necessary for study design and interpretation of findings reported in studies. We aimed to determine changes in pain scores associated with a minimum clinically significant difference (MCSD), ideal clinically significant difference (ICSD), and patient-perceived adequate analgesia (PPAA) in this population. METHODS: We performed a secondary analysis of two prospective studies of children with headaches presenting to an emergency department. Two serial assessments were performed in children aged 6-17 and 4-17 years who self-reported their pain intensity using the Verbal Numerical Rating Scale (VNRS) and Faces Pain Scale-Revised (FPS-R), respectively. Children qualitatively described any endorsed change in pain score; those who received an analgesic were asked if they wanted additional analgesics to decrease their pain intensity. We used receiver operating characteristic curve-based methodology to identify changes in pain scores associated with "a little less" (MCSD) and "much less" (ICSD) pain and patients declining additional analgesics because they experienced adequate analgesia after treatment (PPAA). RESULTS: We analyzed 105 children: 63.8% were female and the median (IQR) age was 13 (10-15) years. Ninety-eight children were analyzed for the VNRS and 101 were analyzed for the FPS-R. For the VNRS, raw change and percent reductions in pain scores associated with MCSD, ICSD, and PPAA were 2/10 and 25%, 4/10 and 56%, and 3/10 and 50%, respectively, and for the FPS-R, 2/10 and 25%, 4/10 and 67%, and 4/10 and 60%, respectively. The area under the curve (AUC) associated with a MCSD for both scales ranged from 94% to 98%; the AUC associated with an ICSD or PPAA for both scales ranged from 76% to 83%. CONCLUSIONS: We identified changes in pain score associated with patient-centered outcomes in children with headaches suitable for designing trials and assigning clinical significance to changes in pain scores reported in studies.

An observational study on the adherence to study registrations in German interventional and observational studies from various fields.

Background: The registration of studies, especially in the case of clinical trials, is required by the declaration of Helsinki and the policies of various scientific journals. However, numerous analyses have found considerable discrepancies between published articles and accompanying trial registrations. The aim of this study is to assess such discrepancies for a sample of studies with recruiting locations in Germany. Additionally, the association between the adherence to registrations and possible involvement of Coordinating Centers for Clinical Studies (KKS) as well as Universities of Excellence was tested. Methods: For a sample of 376 interventional or observational study registrations, we found 115 published articles. Subsequently, we searched for discrepancies in the study design, the key inclusion criteria, the interventions, the blinding, and a primary and a secondary outcome. Results: We found discrepancies in 26% of all studies, most frequently in the secondary outcomes, where 16.5% of the secondary outcomes per study that were registered in most detail had discrepancies. When running regression models for adherence discrepancies, the only variable that had a statistically significant association with better adherence was registration on ClinicalTrials.gov. The association of potential involvement of a KKS with adherence ratings was positive, too, but statistically insignificant. Conclusions: In summary, the amount of discrepancies between registrations and published articles remains elevated.

Confidence intervals and sample size planning for optimal cutpoints.

Various methods are available to determine optimal cutpoints for diagnostic measures. Unfortunately, many authors fail to report the precision at which these optimal cutpoints are being estimated and use sample sizes that are not suitable to achieve an adequate precision. The aim of the present study is to evaluate methods to estimate the variance of cutpoint estimations based on published descriptive statistics ('post-hoc') and to discuss sample size planning for estimating cutpoints. We performed a simulation study using widely-used methods to optimize the Youden index (empirical, normal, and transformed normal method) and three methods to determine confidence intervals (the delta method, the parametric bootstrap, and the nonparametric bootstrap). We found that both the delta method and the parametric bootstrap are suitable for post-hoc calculation of confidence intervals, depending on the sample size, the distribution of marker values, and the correctness of model assumptions. On average, the parametric bootstrap in combination with normal-theory-based cutpoint estimation has the best coverage. The delta method performs very well for normally distributed data, except in small samples, and is computationally more efficient. Obviously, not every combination of distributions, cutpoint optimization methods, and optimized metrics can be simulated and a lot of the literature is concerned specifically with cutpoints and confidence intervals for the Youden index. This complicates sample size planning for studies that estimate optimal cutpoints. As a practical tool, we introduce a web-application that allows for running simulations of width and coverage of confidence intervals using the percentile bootstrap with various distributions and cutpoint optimization methods.

Registration quality and availability of publications for clinical trials in Germany and the influence of structural factors.

INTRODUCTION: Analyses of clinical trial registries (CTRs) offer insights into methodological problems of published research studies, e.g., non-publication and outcome-switching. Here, we use CTRs as a tool to evaluate clinical studies conducted in Germany and test how their registration quality is associated with time and structural factors: Coordinating Centers for Clinical Trials (KKS) and Universities of Excellence. METHODS: We searched ClinicalTrials.gov, the DRKS, and the ICTRP for clinical trials recruiting participants in Germany. As a measure for the methodological quality, we assessed the proportion of trials that were pre-registered. In addition, the registration quality and availability of publications relating to the trials were manually assessed for a sample (n = 639). Also, the influence of the structural factors was tested using regression models. RESULTS: We identified 35,912 trials that were conducted in Germany. 59% of trials were pre-registered. Surprisingly, Universities of Excellence had lower pre-registration rates. The influence of KKS was unclear and also difficult to test. Interventional trials were more likely to be pre-registered. Registration quality improved over time and was higher in interventional trials. As of early 2021, 49% of trials that started until the end of 2015 have published scientific articles. 187 of 502 studies on ClinicalTrials.gov for which we found published articles did not reference any in the registry entry. DISCUSSION: The structural predictors did not show consistent relationships with the various outcome variables. However, the finding that the study type and time were related to better registration quality suggests that regulatory regimes may have an impact. Limitations of this non-pre-registered study were that no modifications to registry entries were tracked and the coarse measure of KKS involvement.

Not sad enough for a depression trial? A systematic review of depression measures and cut points in clinical trial registrations.

INTRODUCTION: Patient reported outcomes are central to the evaluation of behavioral, drug, or somatic interventions focusing depression. Continuous measures are mostly interpreted with cut points that serve as inclusion criteria and define remission. The present review provides an overview of measures (BDI; BDI-II; CESD; HADS; HAMD-17; MADRS; PHQ-9; QIDS) and cut points in clinical trials on depression and tests for systematic differences concerning varying types of interventions. METHODS: We analyzed 2632 trials registered via clinicaltrials.gov registered between 2000/01/01 - 2019/12/31 that used one or more pre-specified measures of depression of which 1600 reported cut points for either inclusion of participants or the definition of clinical remission. RESULTS: The included studies more often used clinician-administered scales than self-report questionnaires as criterion for the inclusion of study participants and for the definition of clinical remission. Clinician administered scales are dominating in drug trials, while self-report questionnaires are primarily used in behavioral trials. This trend accelerated during the last 20 years. Compared to studies on behavioral therapies, studies with drug or other interventions used higher cut points to include patients. Comparisons between the interventions revealed highly significant differences in the used cut points of MADRS, HAMD-17 and PHQ-9. CONCLUSIONS: Choice of measure and cut points is an important aspect of trial design and should be homogenized in order to make trials of different types of interventions more readily comparable. Similarly, systematic differences between treatment types in how patients are included and how remission is defined also hamper the comparisons between different treatment modalities.

Screening for health-related quality of life in children and adolescents: Optimal cut points for the KIDSCREEN-10 for epidemiological studies.

INTRODUCTION: Generic measures of health-related quality of life are important in pediatrics. Here, we try to establish optimal cut points for the self-report and parental-report versions of the KIDSCREEN-10. METHOD: We re-analyzed data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) study. In total, data from 2566 children, 2136 younger adolescents, and 2740 older adolescents were used. The KIDSCREEN-10 was contrasted to three different anchors: the strength and difficulties questionnaire, self-rated general health, and chronic diseases. A kernel-based method and bootstrapping were used to determine the optimal cut points and their variability. RESULTS: We found large differences in HRQoL between children with vs. without mental health problems but there is only medium-to-small differences in HRQoL between children with vs. without chronic diseases and children with self-rated good vs. poor physical health. Acceptable levels of classification accuracy were found in relation to mental health problems for all versions (AUCs between 0.77 and 0.79), but only for the parental-report version in relation to general health and for no version in relation to chronic diseases. Cut points identified as optimal differed systematically between parental-report versions (cut point = 41.13) and self-report for younger (cut point = 42.52) and older adolescents (cut point = 40.29). CONCLUSION: The results aid the interpretation of KIDSCREEN-10 in epidemiological studies. Specifically, we suggest a cut point of 41 should be used to interpret the parental-report version of the KIDSCREEN and 40 and 42, respectively, for young and older adolescents.

Membrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression.

The serine/threonine kinase LKB1 regulates various cellular processes such as cell proliferation, energy homeostasis and cell polarity and is frequently downregulated in various tumours. Many downstream pathways controlled by LKB1 have been described but little is known about the upstream regulatory mechanisms. Here we show that targeting of the kinase to the membrane by a direct binding of LKB1 to phosphatidic acid is essential to fully activate its kinase activity. Consequently, LKB1 mutants that are deficient for membrane binding fail to activate the downstream target AMPK to control mTOR signalling. Furthermore, the in vivo function of LKB1 during development of Drosophila depends on its capacity to associate with membranes. Strikingly, we find LKB1 to be downregulated in malignant melanoma, which exhibit aberrant activation of Akt and overexpress phosphatidic acid generating Phospholipase D. These results provide evidence for a fundamental mechanism of LKB1 activation and its implication in vivo and during carcinogenesis.