Regression without regrets -initial data analysis is a prerequisite for multivariable regression.

Statistical regression models are used for predicting outcomes based on the values of some predictor variables or for describing the association of an outcome with predictors. With a data set at hand, a regression model can be easily fit with standard software packages. This bears the risk that data analysts may rush to perform sophisticated analyses without sufficient knowledge of basic properties, associations in and errors of their data, leading to wrong interpretation and presentation of the modeling results that lacks clarity. Ignorance about special features of the data such as redundancies or particular distributions may even invalidate the chosen analysis strategy. Initial data analysis (IDA) is prerequisite to regression analyses as it provides knowledge about the data needed to confirm the appropriateness of or to refine a chosen model building strategy, to interpret the modeling results correctly, and to guide the presentation of modeling results. In order to facilitate reproducibility, IDA needs to be preplanned, an IDA plan should be included in the general statistical analysis plan of a research project, and results should be well documented. Biased statistical inference of the final regression model can be minimized if IDA abstains from evaluating associations of outcome and predictors, a key principle of IDA. We give advice on which aspects to consider in an IDA plan for data screening in the context of regression modeling to supplement the statistical analysis plan. We illustrate this IDA plan for data screening in an example of a typical diagnostic modeling project and give recommendations for data visualizations.

Gender-specific factors influencing the glenoid version and reference values for it.

BACKGROUND: Glenoid version is an important factor in the evaluation of shoulder stability and shoulder pathologies. However, there are neither established reference values nor known factors that influence the glenoid version, even though valid reference values are needed for diagnostic and orthopaedic surgery like corrective osteotomy and total or reverse shoulder arthroplasty (TSA/RSA). The aim of our population-based study was to identify factors influencing the glenoid version and to establish reference values from a large-scale population cohort. RESULTS: Our study explored the glenoid versions in a large sample representing the general adult population. We investigated 3004 participants in the population-based Study of Health in Pomerania (SHIP). Glenoid version was measured for both shoulders via magnetic resonance imaging (MRI). Associations with the glenoid version were calculated for sex, age, body height, body weight and BMI. The reference values for glenoid version in the central European population range between -9° and 7.5°, while multiple factors are associated with the glenoid version. CONCLUSION: To achieve a reliable interpretation prior to orthopaedic surgery, sex- and age-adjusted reference values are proposed.

Towards an Interoperability Landscape for a National Research Data Infrastructure for Personal Health Data.

The German initiative "National Research Data Infrastructure for Personal Health Data" (NFDI4Health) focuses on research data management in health research. It aims to foster and develop harmonized informatics standards for public health, epidemiological studies, and clinical trials, facilitating access to relevant data and metadata standards. This publication lists syntactic and semantic data standards of potential use for NFDI4Health and beyond, based on interdisciplinary meetings and workshops, mappings of study questionnaires and the NFDI4Health metadata schema, and literature search. Included are 7 syntactic, 32 semantic and 9 combined syntactic and semantic standards. In addition, 101 ISO Standards from ISO/TC 215 Health Informatics and ISO/TC 276 Biotechnology could be identified as being potentially relevant. The work emphasizes the utilization of standards for epidemiological and health research data ensuring interoperability as well as the compatibility to NFDI4Health, its use cases, and to (inter-)national efforts within these sectors. The goal is to foster collaborative and inter-sectoral work in health research and initiate a debate around the potential of using common standards.

Promoting pedestrian safety in Bangladesh: Identifying factors for drivers' yielding behavior at designated crossings using behavior change theories.

OBJECTIVE: In Bangladesh, drivers' failure to yield to pedestrians at designated crossings poses a significant safety risk and discourages their use of such crossings. The use of behavior change theories could be more appropriate in such complex situations where the interdependent behaviors of drivers and pedestrians interact. While many studies have identified factors that affect drivers' yielding behavior in the literature, fewer efforts have been made to apply behavior change theories in exploring and validating these factors, and to reach a consensus among competing road users. This study is among the first to utilize behavior change theories in Bangladesh to identify pedestrians' safety factors that could promote drivers' yielding behavior, upon which a consensus between drivers and pedestrians could be established. METHODS: A self-reported attitudinal survey was administered to 202 drivers on two highways in Bangladesh with a questionnaire using the capability, opportunity, motivation, and behavior (COM-B) model for the comprehensive coverage of behavior change theories. The focus group interviews were also conducted with 40 pedestrians and 19 drivers who have experience with four crossing sites on the selected highways. The collected data were analyzed using a regression model to identify significant factors influencing the drivers' yielding behavior. These factors were then justified using a deductive thematic coding framework based on behavior change theories. RESULTS: The regression model explained the variance in drivers' yielding by 45.1% with eight factors. The model found seven positive significant contributory factors in the drivers' yielding that could promote pedestrian safety. Of them, the motivation factors were avoiding random crossing by pedestrians, vulnerable groups, assertiveness, and facial fear expressions; and the opportunity factors were traffic signs or advanced yield lines, crossing in groups at specific times, and enforcement. CONCLUSIONS: The study's findings have practical implications for policymakers, highway designers, and other stakeholders involved in promoting pedestrian safety by acknowledging their stake in making any decision that might impact them. Highway designers can use the thematic coding framework to recommend any contributory factors involved, where competing drivers' unwillingness to yield is the primary threat to pedestrians' safety.

How socio-political change is associated with the number of individually reported negative life events: a population-based study using the German reunification 1989/1990 as an example.

BACKGROUND: Socio-political change often leads to disruptions in employment and social networks, which can exacerbate health issues and increase mortality rates. These consequences are likely observed as an increase in negative life events (NLEs), serving as indicators of the broader social and health impacts. Using the German reunification in 1989/1990 as an example, this study investigates changes in reported numbers of NLEs and differences regarding sociodemographic characteristics. METHODS: We used data from the population-based Study of Health in Pomerania (SHIP-START-0, SHIP-Life-Events and Gene-Environment Interaction in Depression; N=1932). Numbers of NLEs in different categories (work/financial, social/interpersonal, illness (own) and illness/death (others)) were measured retrospectively in 5-year intervals (1980-2004) using a semistructured interview. Pre-reunification and post-reunification changes were modelled using piecewise mixed-effects Poisson regressions with the 1990-1994 interval (reunification) as change point. Interactions with age, sex and education were examined. RESULTS: The number of most NLE categories, except social/interpersonal NLEs, increased at reunification. Whereas work/financial NLEs slightly decreased post-reunification, illness-related NLEs continued to increase. Higher numbers of social/interpersonal NLEs were found with younger age. More illness-related NLEs were reported with older age, lower education (illness (own)) and by women (illness/death (others)). However, the majority reported no NLEs at reunification (68.2%-80.7%, varying by category). CONCLUSION: Our findings suggest that although some individuals experience a marked increase in NLEs due to socio-political changes, many remain unaffected, emphasising the need for a differentiated understanding of these effects. This increase in NLEs may partly account for ongoing health and well-being disparities among countries with differing transformation histories.

Bringing Communities Together: Mapping the Investigation-Study-Assay-Model (ISA) to Fast Healthcare Interoperability Resources (FHIR).

Adhering to FAIR principles (findability, accessibility, interoperability, reusability) ensures sustainability and reliable exchange of data and metadata. Research communities need common infrastructures and information models to collect, store, manage and work with data and metadata. The German initiative NFDI4Health created a metadata schema and an infrastructure integrating existing platforms based on different information models and standards. To ensure system compatibility and enhance data integration possibilities, we mapped the Investigation-Study-Assay (ISA) model to Fast Healthcare Interoperability Resources (FHIR). We present the mapping in FHIR logical models, a resulting FHIR resources' network and challenges that we encountered. Challenges mainly related to ISA's genericness, and to different structures and datatypes used in ISA and FHIR. Mapping ISA to FHIR is feasible but requires further analyses of example data and adaptations to better specify target FHIR elements, and enable possible automatized conversions from ISA to FHIR.

Regional and temporal differences in the associations between cardiovascular disease and its classic risk factors: an analysis of 49 cohorts from 11 European countries.

AIMS: The regional and temporal differences in the associations between cardiovascular disease (CVD) and its classic risk factors are unknown. The current study examined these associations in different European regions over a 30-year period. METHODS AND RESULTS: The study sample comprised 553 818 individuals from 49 cohorts in 11 European countries (baseline: 1982-2012) who were followed up for a maximum of 10 years. Risk factors [sex, smoking, diabetes, non-HDL cholesterol, systolic blood pressure (BP), and body mass index (BMI)] and CVD events (coronary heart disease or stroke) were harmonized across cohorts. Risk factor-outcome associations were analysed using multivariable-adjusted Cox regression models, and differences in associations were assessed using meta-regression. The differences in the risk factor-CVD associations between central Europe, northern Europe, southern Europe, and the UK were generally small. Men had a slightly higher hazard ratio (HR) in southern Europe (P = 0.043 for overall difference), and those with diabetes had a slightly lower HR in central Europe (P = 0.022 for overall difference) compared with the other regions. Of the six CVD risk factors, minor HR decreases per decade were observed for non-HDL cholesterol [7% per mmol/L; 95% confidence interval (CI), 3-10%] and systolic BP (4% per 20 mmHg; 95% CI, 1-8%), while a minor HR increase per decade was observed for BMI (7% per 10 kg/m2; 95% CI, 1-13%). CONCLUSION: The results demonstrate that all classic CVD risk factors are still relevant in Europe, irrespective of regional area. Preventive strategies should focus on risk factors with the greatest population attributable risk.

All classic cardiovascular disease (CVD) risk factors are still relevant in Europe, irrespective of regional area. The differences in the associations of CVD risk factors with overt CVD between regions of Europe are generally small. Minor temporal hazard decreases were observed for non-HDL cholesterol and systolic blood pressure, while a minor hazard increase was observed for body mass index.

Are there associations between hip geometry and bone quality? An analysis on 3074 adults from a general population.

INTRODUCTION: Patients with reduced bone mineral density and altered hip geometry are susceptible for hip pathologies. Knowledge on associations between bone properties and hip geometric parameters might facilitate identification of patients at risk for hip pathologies. The aim of the present study was to identify associations of bone properties assessed by quantitative ultrasound (QUS) at the heel and hip geometric parameters like center-edge angle (CE), neck-shaft angle (NSA) and alpha angle. MATERIALS AND METHODS: Hip geometric parameters (CE, NSA and alpha angle) of 3074 participants from the population-based Study of Health in Pomerania were assessed on magnetic resonance imaging. QUS was performed on both calcanei providing broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness-index. Based on the stiffness-index the individual osteoporotic fracture risk (low, moderate or high) was determined. Associations between QUS-based and hip geometric parameters were calculated in linear regression models adjusted for age, sex, body height and weight. Interactions of QUS markers with age and sex on hip geometric parameters were tested. RESULTS: Significant inverse associations between BUA (ß = - 0.068), SOS (ß = - 0.024) as well as stiffness-index (ß = - 0.056) and CE were present, while fracture risk was positively associated with CE (ß for high = 1.28 and moderate = 2.54 vs. low fracture risk). Interactions between BUA and sex as well as between SOS and age were detected in the models for CE. Furthermore, there was an inverse relation between fracture risk and NSA that was restricted to the moderate risk (ß for moderate vs. low fracture risk = - 0.60). There were no significant associations between QUS parameters and alpha angle. CONCLUSIONS: In the general population, several associations between QUS-based bone properties or fracture risk and hip geometry are present. Less dysplastic hips had a lower stiffness-index and a higher fracture risk, whereas more valgus hips had a lower fracture risk.

Chronic pain is associated with less grey matter volume in the anterior cingulum, anterior and posterior insula and hippocampus across three different chronic pain conditions.

BACKGROUND: Chronic pain of different aetiologies and localization has been associated with less grey matter volume (GMV) in several cortical and subcortical brain areas. Recent meta-analyses reported low reproducibility of GMV alterations between studies and pain syndromes. METHODS: To investigate GMV in common chronic pain conditions defined by body location (chronic back pain, n = 174; migraine, n = 92; craniomandibular disorder, n = 39) compared to controls (n = 296), we conducted voxel-based morphometry and determined GMV from high-resolution cranial MRIs obtained in an epidemiologic survey. Mediation analyses were performed between the presence of chronic pain and GMV testing the mediators stress and mild depression. The predictability of chronic pain was investigated with binomial logistic regression. RESULTS: Whole-brain analyses yielded reduced GMV within the left anterior insula and the anterior cingulate cortex, for a ROI approach additionally the left posterior insula and left hippocampus showing less GMV across all patients with chronic pain. The relationship of pain with GMV in the left hippocampus was mediated by self-reported stressors in the last 12 months. Binomial logistic regression revealed a predictive effect for GMV in the left hippocampus and left anterior insula/temporal pole for the presence of chronic pain. CONCLUSIONS: Chronic pain across three different pain conditions was characterized by less GMV in brain regions consistently described for different chronic pain conditions before. Less GMV in the left hippocampus mediated by experienced stress during the last year might be related to altered pain learning mechanisms in chronic pain patients. SIGNIFICANCE: Grey matter reorganization could serve as a diagnostic biomarker for chronic pain. In a large cohort, we here replicated findings of less grey matter volume across three pain conditions in the left anterior and posterior insula, anterior cingulate and left hippocampus. Less hippocampal grey matter was mediated by experienced stress.

Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics.

Research continues to identify genetic variation, environmental exposures, and their mixtures underlying different diseases and conditions. There is a need for screening methods to understand the molecular outcomes of such factors. Here, we investigate a highly efficient and multiplexable, fractional factorial experimental design (FFED) to study six environmental factors (lead, valproic acid, bisphenol A, ethanol, fluoxetine hydrochloride and zinc deficiency) and four human induced pluripotent stem cell line derived differentiating human neural progenitors. We showcase the FFED coupled with RNA-sequencing to identify the effects of low-grade exposures to these environmental factors and analyse the results in the context of autism spectrum disorder (ASD). We performed this after 5-day exposures on differentiating human neural progenitors accompanied by a layered analytical approach and detected several convergent and divergent, gene and pathway level responses. We revealed significant upregulation of pathways related to synaptic function and lipid metabolism following lead and fluoxetine exposure, respectively. Moreover, fluoxetine exposure elevated several fatty acids when validated using mass spectrometry-based metabolomics. Our study demonstrates that the FFED can be used for multiplexed transcriptomic analyses to detect relevant pathway-level changes in human neural development caused by low-grade environmental risk factors. Future studies will require multiple cell lines with different genetic backgrounds for characterising the effects of environmental exposures in ASD.

Reference values and influencing factors of the glenohumeral subluxation index: a study on 3004 participants.

BACKGROUND: The primary objective of this study was to examine the glenohumeral subluxation index (GHSI) in a large general population cohort and to define reference values. Glenohumeral subluxation is important in the development and prediction of pathological states of the shoulder joint and in total shoulder arthroplasty. Therefore, another objective was to examine the influence of age, sex, body mass index, and body height and weight on GHSI. METHODS: GHSI according to Walch was measured on bilateral magnetic resonance imaging of 3004 participants of the Study of Health in Pomerania (SHIP, aged 21-90 years). SHIP drew a sample of the adult general population of Pomerania (Northeastern Germany). Reference values for GHSI were assessed by quantile regression models. Associations of sex, age, and anthropometric markers with the GHSI were calculated by linear regression models. RESULTS: A reference range between 42% and 55% for men with a mean of 49% ± 4% was defined, while the upper reference limit for women was 1% higher (mean, 50% ± 4%). Age was inversely associated with the GHSI in males (P < 0.001), while no significant association in females was observed (P = .625). Body weight and body mass index were positively associated (P < .001) without effect modification by sex. Heavy mechanical oscillations on the upper extremity showed no significant association with GHSI (P = .268). CONCLUSION: The reference values for GHSI were expanded to a range of 42%-57% on magnetic resonance imaging. Several associations between GHSI and anthropometric properties are present. According to these associations, adjusted formulas are provided to enable individual, patient-specific diagnostics and therapy. Nevertheless, the clinical picture cannot be neglected.

Conducting an Epidemiologic Study and Making It FAIR: Reusable Tools and Procedures from a Population-Based Cohort Study.

Conducting large-scale epidemiologic studies requires powerful software for electronic data capture, data management, data quality assessments, and participant management. There is also an increasing need to make studies and the data collected findable, accessible, interoperable, and reusable (FAIR). However, reusable software tools from major studies, underlying such needs, are not necessarily known to other researchers. Therefore, this work gives an overview on the main tools used to conduct the internationally highly networked population-based project Study of Health in Pomerania (SHIP), as well as approaches taken to improve its FAIRness. Deep phenotyping, formalizing processes from data capture to data transfer, with a strong emphasis on cooperation and data exchange have laid the foundation for a broad scientific impact with more than 1500 published papers to date.

Identifying Relevant FHIR Elements for Data Quality Assessment in the German Core Data Set.

The German Medical Informatics Initiative makes clinical routine data available for biomedical research. In total, 37 university hospitals have set up so-called data integration centers to facilitate this data reuse. A standardized set of HL7 FHIR profiles ("MII Core Data Set") defines the common data model across all centers. Regular Projectathons ensure continuous evaluation of the implemented data sharing processes on artificial and real-world clinical use cases. In this context, FHIR continues to rise in popularity for exchanging patient care data. As reusing data from patient care in clinical research requires high trust in the data, data quality assessments are a key point of concern in the data sharing process. To support the setup of data quality assessments within data integration centers, we suggest a process for finding elements of interest from FHIR profiles. We focus on the specific data quality measures defined by Kahn et al.

Brain 18 F-FDG-PET and an optimized cingulate island ratio to differentiate Lewy body dementia and Alzheimer's disease.

BACKGROUND AND PURPOSE: The diagnosis of Dementia with Lewy Bodies (DLB) is challenging due to various clinical presentations and clinical and neuropathological features that overlap with Alzheimer's disease (AD). The use of 18 F-Fluorodeoxyglucose-PET (18 F-FDG-PET) can be limited due to similar patterns in DLB and AD. However, metabolism in the posterior cingulate cortex is known to be relatively preserved in DLB and visual assessment of the "cingulate island sign" became a helpful tool in the analysis of 18F-FDG-PET. The aim of this study was the evaluation of visual and semiquantitative 18F-FDG-PET analyses in the diagnosis of DLB and the differentiation to AD as well as its relation to other dementia biomarkers. METHODS: This retrospective study comprises 81 patients with a clinical diagnosis of DLB or AD that underwent 18 F-FDG-PET/CT. PET scans were analyzed visually and semiquantitatively and results were compared to clinical data, cerebrospinal fluid results, dopamine transporter scintigraphy, and 18F-Florbetaben-PET. Furthermore, different cingulate island ratios were calculated to analyze their diagnostic accuracy. RESULTS: Visual assessment of 18F-FDG-PET showed an accuracy of 62%-77% in differentiating between DLB and AD. Standard uptake values were significantly lower in the primary visual cortex and the lateral occipital cortex of DLB patients compared to AD patients. The cingulate island ratio was significantly higher in the DLB group compared to the AD group and the ratio posterior cingulate cortex to visual cortex plus lateral occipital cortex showed the highest diagnostic accuracy to discriminate between DLB and AD at 81%. CONCLUSIONS: Semiquantitative 18F-FDG-PET imaging and especially the use of an optimized cingulate island ratio are valuable tools to differentiate between DLB and AD.

Usability testing of three visual HMIs for assisted driving: How design impacts driver distraction and mental models.

There is a variety of visual human-machine interfaces (HMI) designed across vehicle manufacturers that support drivers while supervising driving automation features, such as adaptive cruise control (ACC). These various designs communicate the same limited amount of information to drivers about their ACC system and it is unclear which HMI designs impact driver distraction the least or how their design could be modified to help drivers develop more accurate mental models of their ACC system. Using a user-centred design (UCD) approach, we designed a speedometer to inform drivers about some of the system's capabilities and then invited 23 drivers to use ACC in a low-fidelity driving simulator to compare the usability of three HMIs using eye-tracking, response times, and qualitative data. Our attempt at designing an intuitive and more informative speedometer received mixed results, but design recommendations are given regarding the indication of the set target speed, set time gap between vehicles (headway distance), and system mode (conventional or adaptive cruise). Practitioner summary: Manufacturers' heterogeneous designs of their visual HMIs for the ACC systems may impact driver distraction in different ways. We used usability testing to compare three HMIs in a driving simulator and make several design recommendations to indicate speed, time gap, and system mode in a more efficient way. Abbreviations: ACC: adaptive cruise control; ADAS: advanced driving assistance system; HMI: human-machine interface; ISO: international organisation for standardization; OEM: original equipment manufacturer; RSME: rating scale of mental effort; RT: response time; R-TLX: raw task load index; SUS: system usability scale; TGT: total glance time; UCD: user-centred design; UX: user experience; xTGT: extended total glance time.

Monitoring and management of chronic kidney disease in ambulatory care - analysis of clinical and claims data from a population-based study.

BACKGROUND: Although chronic kidney disease (CKD) is highly prevalent in the general population, little research has been conducted on CKD management in ambulatory care. Objective was to assess management and quality of care by evaluating CKD coding in ambulatory care, patient diagnosis awareness, frequency of monitoring and whether appropriate patients are referred to nephrology. METHODS: Clinical data from the population-based cohort Study of Health in Pomerania (SHIP-START) were matched with claims data of the Association of Statutory Health Insurance Physicians. Quality of care was evaluated according international and German recommendations. RESULTS: Data from 1778 participants (56% female, mean age 59 years) were analysed. 10% had eGFR < 60 ml/min/1.73m2 (mean age 74 years), 15% had albuminuria. 21% had CKD as defined by KDIGO. 20% of these were coded and 7% self-reported having CKD. Coding increased with GFR stage (G3a 20%, G3b 61%, G4 75%, G5 100%). Serum creatinine and urinary dip stick testing were billed in the majority of all participants regardless of renal function. Testing frequency partially surpassed recommendations. Nephrology consultation was billed in few cases with stage G3b-G4. CONCLUSION: CKD coding increased with stage and was performed reliably in stages ≥ G4, while CKD awareness was low. Adherence to monitoring and referral criteria varied, depending on the applicability of monitoring criteria. For assessing quality of care, consent on monitoring, patient education, referral criteria and coordination of care needs to be established, accounting for patient related factors, including age and comorbidity. TRIAL REGISTRATION: This study was prospectively registered as DRKS00009812 in the German Clinical Trials Register (DRKS).

The Role of PSMA PET/CT in the Primary Diagnosis and Follow-Up of Prostate Cancer-A Practical Clinical Review.

The importance of PSMA PET/CT in both primary diagnostics and prostate cancer recurrence has grown steadily since its introduction more than a decade ago. Over the past years, a vast amount of data have been published on the diagnostic accuracy and the impact of PSMA PET/CT on patient management. Nevertheless, a large heterogeneity between studies has made reaching a consensus difficult; this review aims to provide a comprehensive clinical review of the available scientific literature, covering the currently known data on physiological and pathological PSMA expression, influencing factors, the differences and pitfalls of various tracers, as well as the clinical implications in initial TNM-staging and in the situation of biochemical recurrence. This review has the objective of providing a practical clinical overview of the advantages and disadvantages of the examination in various clinical situations and the body of knowledge available, as well as open questions still requiring further research.

Validation of Cardiovascular Risk Prediction by the Arriba Instrument.

BACKGROUND: It is recommended in cardiovascular prevention guidelines that treatment should be based on overall cardiovascular risk. The arriba instrument has been widely used for this purpose in Germany. The aim of this study is to validate risk prediction by arriba with the aid of morbidity and mortality data from the population- based Study of Health in Pomerania. METHODS: In a longitudinal analysis, the arriba instrument was used to calculate the 10-year overall cardiovascular risk at baseline for subjects who had not sustained any prior cardiovascular event. Cardiovascular event rates were determined from follow-up data, and discrimination and calibration measures for the risk determination algorithm were calculated. RESULTS: Data from 1973 subjects (mean age 51 ± 13 years, 48% men) were included in the analysis. After a median follow-up of 10.9 years, cardiovascular events had occurred in 196 subjects, or 9.8%. The ratio of predicted to observed event rate was 0.8 (95% confidence interval: [0.5; 1.1]), 1.3 [1.0; 1.8], and 1.1 [0.8; 1.4] for subjects at low, intermediate, and high cardiovascular risk, respectively. Arriba underestimated cardiovascular event rates in women and overestimated them in persons aged 30-44 and 45-59. The area under curve was 0.84 [95% CI 0.81; 0.86]. CONCLUSION: The discrimination scores of the arriba instrument resemble those of SCORE-Germany and PROCAM, but a better adjustment to the target population would be desirable. The results support the recommendation of the German Guideline for Cardiovascular Risk Counseling in General Practice for the use of the arriba instrument. An unresolved problem is the failure to consider intervention effects, resulting in an overall mild overestimation of risk.