Long-term benefits and harms of early colorectal cancer screening in German individuals with familial cancer risk.

Individuals with a family history of colorectal cancer (CRC) may benefit from early screening with colonoscopy or immunologic fecal occult blood testing (iFOBT). We systematically evaluated the benefit-harm trade-offs of various screening strategies differing by screening test (colonoscopy or iFOBT), interval (iFOBT: annual/biennial; colonoscopy: 10-yearly) and age at start (30, 35, 40, 45, 50 and 55 years) and end of screening (65, 70 and 75 years) offered to individuals identified with familial CRC risk in Germany. A Markov-state-transition model was developed and used to estimate health benefits (CRC-related deaths avoided, life-years gained [LYG]), potential harms (eg, associated with additional colonoscopies) and incremental harm-benefit ratios (IHBR) for each strategy. Both benefits and harms increased with earlier start and shorter intervals of screening. When screening started before age 50, 32-36 CRC-related deaths per 1000 persons were avoided with colonoscopy and 29-34 with iFOBT screening, compared to 29-31 (colonoscopy) and 28-30 (iFOBT) CRC-related deaths per 1000 persons when starting age 50 or older, respectively. For iFOBT screening, the IHBRs expressed as additional colonoscopies per LYG were one (biennial, age 45-65 vs no screening), four (biennial, age 35-65), six (biennial, age 30-70) and 34 (annual, age 30-54; biennial, age 55-75). Corresponding IHBRs for 10-yearly colonoscopy were four (age 55-65), 10 (age 45-65), 15 (age 35-65) and 29 (age 30-70). Offering screening with colonoscopy or iFOBT to individuals with familial CRC risk before age 50 is expected to be beneficial. Depending on the accepted IHBR threshold, 10-yearly colonoscopy or alternatively biennial iFOBT from age 30 to 70 should be recommended for this target group.

Cost-Effectiveness of a Specialized Breathlessness Service Versus Usual Care for Patients With Advanced Diseases.

OBJECTIVES: The Munich Breathlessness Service (MBS) significantly improved control of breathlessness measured by the Chronic Respiratory Questionnaire (CRQ) Mastery in a randomized controlled fast track trial with waitlist group design spanning 8 weeks in Germany. This study aimed to assess the within-trial cost-effectiveness of MBS from a societal perspective. METHODS: Data included generic (5-level version of EQ-5D) health-related quality of life and disease-specific CRQ Mastery. Quality-adjusted life years (QALYs) were calculated based on 5-level version of EQ-5D utilities valued with German time trade-off. Direct medical costs and productivity loss were calculated based on standardized unit costs. Incremental cost-effectiveness ratios (ICER) and cost-effectiveness-acceptance curves were calculated using adjusted mean differences (AMD) in costs (gamma-distributed model) and both effect parameters (Gaussian-distributed model) and performing 1000 simultaneous bootstrap replications. Potential gender differences were investigated in stratified analyses. RESULTS: Between March 2014 and April 2019, 183 eligible patients were enrolled. MBS intervention demonstrated significantly better effects regarding generic (AMD of QALY gains of 0.004, 95% confidence interval [CI] 0.0003 to 0.008) and disease-specific health-related quality of life at nonsignificantly higher costs (AMD of €605 [95% CI -1109 to 2550]). At the end of the intervention, the ICER was €152 433/QALY (95% CI -453 545 to 1 625 903) and €1548/CRQ Mastery point (95% CI -3093 to 10 168). Intervention costs were on average €357 (SD = 132). Gender-specific analyses displayed dominance for MBS in males and higher effects coupled with significantly higher costs in females. CONCLUSIONS: Our results show a high ICER for MBS. Considering dominance for MBS in males, implementing MBS on approval within the German health care system should be considered.

Usability of German hospital administrative claims data for healthcare research: General assessment and use case of multiple myeloma in Munich university hospital in 2015-2017.

OBJECTIVES: To assess the usability of German hospital administrative claims data (GHACD) to determine inpatient management patterns, healthcare resource utilization, and quality-of-care in patients with multiple myeloma (PwMM). METHODS: Based on German tertiary hospital's claims data (2015-2017), PwMM aged >18 years were included if they had an International Classification of Diseases, Tenth Revision, code of C90.0 or received anti-MM therapy. Subgroup analysis was performed on stem cell transplantation (SCT) patients. RESULTS: Of 230 PwMM, 59.1% were men; 56.1% were aged ≥65 years. Hypertension and infections were present in 50% and 67.0%, respectively. Seventy percent of PwMM received combination therapy. Innovative drugs such as bortezomib and lenalidomide were given to 36.1% and 10.9% of the patients, respectively. Mean number of admissions and mean hospitalization length/patient were 3.69 (standard deviation (SD) 2.71 (1-16)) and 12.52 (SD 9.55 (1-68.5)) days, respectively. In-hospital mortality was recorded in 12.2%. Seventy-two percent of SCT patients (n = 88) were aged ≤65 years, 22.7% required second transplantation, and 89.8% received platelet transfusion at a mean of 1.42(SD 0.63 (1-3)). CONCLUSION: GHACD provided relevant information essential for healthcare studies about PwMM from routine care settings. Data fundamental for quality-of-care assessment were also captured.

Telemedical cardiac risk assessment by implantable cardiac monitors in patients after myocardial infarction with autonomic dysfunction (SMART-MI-DZHK9): a prospective investigator-initiated, randomised, multicentre, open-label, diagnostic trial.

BACKGROUND: Cardiac autonomic dysfunction after myocardial infarction identifies patients at high risk despite only moderately reduced left ventricular ejection fraction. We aimed to show that telemedical monitoring with implantable cardiac monitors in these patients can improve early detection of subclinical but prognostically relevant arrhythmic events. METHODS: We did a prospective investigator-initiated, randomised, multicentre, open-label, diagnostic trial at 33 centres in Germany and Austria. Survivors of acute myocardial infarction with left ventricular ejection fraction of 36-50% had biosignal analysis for assessment of cardiac autonomic function. Patients with abnormal periodic repolarisation dynamics (≥5·75 deg2) or abnormal deceleration capacity (≤2·5 ms) were randomly assigned (1:1) to telemedical monitoring with implantable cardiac monitors or conventional follow-up. Primary endpoint was time to detection of serious arrhythmic events defined by atrial fibrillation 6 min or longer, atrioventricular block class IIb or higher and fast non-sustained (>187 beats per min; ≥40 beats) or sustained ventricular tachycardia or fibrillation. This study is registered with ClinicalTrials.gov, NCT02594488. FINDINGS: Between May 12, 2016, and July 20, 2020, 1305 individuals were screened and 400 patients at high risk were randomly assigned (median age 64 years [IQR 57-73]); left ventricular ejection fraction 45% [40-48]) to telemedical monitoring with implantable cardiac monitors (implantable cardiac monitor group; n=201) or conventional follow-up (control group; n=199). During median follow-up of 21 months, serious arrhythmic events were detected in 60 (30%) patients of the implantable cardiac monitor group and 12 (6%) patients of the control group (hazard ratio 6·33 [IQR 3·40-11·78]; p<0·001). An improved detection rate by implantable cardiac monitors was observed for all types of serious arrhythmic events: atrial fibrillation 6 min or longer (47 [23%] patients vs 11 [6%] patients; p<0·001), atrioventricular block class IIb or higher (14 [7%] vs 0; p<0·001) and ventricular tachycardia or ventricular fibrillation (nine [4%] patients vs two [1%] patients; p=0·054). INTERPRETATION: In patients at high risk after myocardial infarction and cardiac autonomic dysfunction but only moderately reduced left ventricular ejection fraction, telemedical monitoring with implantable cardiac monitors was highly effective in early detection of subclinical, prognostically relevant serious arrhythmic events. FUNDING: German Centre for Cardiovascular Research (DZHK) and Medtronic Bakken Research Center.

Natriuretic Peptides and Risk of Type 2 Diabetes: Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium.

OBJECTIVE: Natriuretic peptide (NP) concentrations are increased in cardiovascular diseases (CVDs) but are associated with a lower diabetes risk. We investigated associations of N-terminal pro-B-type NP (NT-proBNP) and midregional proatrial NP (MR-proANP) with incident type 2 diabetes stratified by the presence of CVD. RESEARCH DESIGN AND METHODS: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium, we included 45,477 participants with NT-proBNP measurements (1,707 developed type 2 diabetes over 6.5 years of median follow-up; among these, 209 had CVD at baseline) and 11,537 participants with MR-proANP measurements (857 developed type 2 diabetes over 13.8 years of median follow-up; among these, 106 had CVD at baseline). The associations were estimated using multivariable Cox regression models. RESULTS: Both NPs were inversely associated with incident type 2 diabetes (hazard ratios [95% CI] per 1-SD increase of log NP: 0.84 [0.79; 0.89] for NT-proBNP and 0.77 [0.71; 0.83] for MR-proANP). The inverse association between NT-proBNP and type 2 diabetes was significant in individuals without CVD but not in individuals with CVD (0.81 [0.76; 0.86] vs. 1.04 [0.90; 1.19]; P multiplicative interaction = 0.001). There was no significant difference in the association of MR-proANP with type 2 diabetes between individuals without and with CVD (0.75 [0.69; 0.82] vs. 0.81 [0.66; 0.99]; P multiplicative interaction = 0.236). CONCLUSIONS: NT-proBNP and MR-proANP are inversely associated with incident type 2 diabetes. However, the inverse association of NT-proBNP seems to be modified by the presence of CVD. Further investigations are warranted to confirm our findings and to investigate the underlying mechanisms.

Inequality indices to monitor geographic differences in incidence, mortality and fatality rates over time during the COVID-19 pandemic.

BACKGROUND: It is of interest to explore the variability in how the COVID-19 pandemic evolved geographically during the first twelve months. To this end, we apply inequality indices over regions to incidences, infection related mortality, and infection fatality rates. If avoiding of inequality in health is an important political goal, a metric must be implemented to track geographical inequality over time. METHODS: The relative and absolute Gini index as well as the Theil index are used to quantify inequality. Data are taken from international data bases. Absolute counts are transformed to rates adjusted for population size. RESULTS: Comparing continents, the absolute Gini index shows an unfavorable development in four continents since February 2020. In contrast, the relative Gini as well as the Theil index support the interpretation of less inequality between European countries compared to other continents. Infection fatality rates within the EU as well as within the U.S. express comparable improvement towards more equality (as measured by both Gini indices). CONCLUSIONS: The use of inequality indices to monitor changes in geographic inequality over time for key health indicators is a valuable tool to inform public health policies. The absolute and relative Gini index behave complementary and should be reported simultaneously in order to gain a meta-perspective on very complex dynamics.

Effectiveness of a specialised breathlessness service for patients with advanced disease in Germany: a pragmatic fast-track randomised controlled trial (BreathEase).

BACKGROUND: The effectiveness of the Munich Breathlessness Service (MBS), integrating palliative care, respiratory medicine and physiotherapy, was tested in the BreathEase trial in patients with chronic breathlessness in advanced disease and their carers. METHODS: BreathEase was a single-blinded randomised controlled fast-track trial. The MBS was attended for 5-6 weeks; the control group started the MBS after 8 weeks of standard care. Randomisation was stratified by cancer and the presence of a carer. Primary outcomes were patients' mastery of breathlessness (Chronic Respiratory Disease Questionnaire (CRQ) Mastery), quality of life (CRQ QoL), symptom burden (Integrated Palliative care Outcome Scale (IPOS)) and carer burden (Zarit Burden Interview (ZBI)). Intention-to-treat (ITT) analyses were conducted with hierarchical testing. Effectiveness was investigated by linear regression on change scores, adjusting for baseline scores and stratification variables. Missing values were handled with multiple imputation. RESULTS: 92 patients were randomised to the intervention group and 91 patients were randomised to the control group. Before the follow-up assessment after 8 weeks (T1), 17 and five patients dropped out from the intervention and control groups, respectively. Significant improvements in CRQ Mastery of 0.367 (95% CI 0.065-0.669) and CRQ QoL of 0.226 (95% CI 0.012-0.440) score units at T1 in favour of the intervention group were seen in the ITT analyses (n=183), but not in IPOS. Exploratory testing showed nonsignificant improvements in ZBI. CONCLUSIONS: These findings demonstrate positive effects of the MBS in reducing burden caused by chronic breathlessness in advanced illness across a wide range of patients. Further evaluation in subgroups of patients and with a longitudinal perspective is needed.

Incorporation of Multiple Sources into IT - and Data Protection Concepts: Lessons Learned from the FARKOR Project.

The IT- and data protection concept of the FAmiliäres Risiko für das KOloRektale Karzinom (FARKOR) project will be presented. FARKOR is a risk adapted screening-project in Bavaria, Germany focusing on young adults with familial colorectal cancer (CRC). For each participant, data from different sources have to be integrated: Treatment records centrally administered by the resident doctors association (KVB), data from health insurance companies (HIC), and patient reported lifestyle data. Patient privacy rights must be observed. Record Linkage is performed by a central independent trust center. Data are decrypted, integrated and analyzed in a secure part of the scientific evaluation center with no connection to the internet (SECSP). The presented concept guarantees participants privacy through different identifiers, separation of responsibilities, data pseudonymization, public-private key encryption of medical data and encrypted data transfer.

Evaluating the effects of a risk-adapted screening program for familial colorectal cancer in individuals between 25 and 50 years of age: study protocol for the prospective population-based intervention study FARKOR.

BACKGROUND: Colorectal cancer (CRC) is the second most common malignant disease and the second most common cause of cancer death in Germany. Official CRC screening starts at age 50. As there is evidence that individuals with a family history of CRC have an increased risk of developing CRC before age 50, there are recommendations to start screening for this group earlier. This study aims to evaluate the clinical and economic effects of a risk-adapted screening program for CRC in individuals between 25 and 50 years of age with potentially increased familial CRC risk. METHODS: FARKOR (Familiäres Risiko für das Kolorektale Karzinom) is a population-based prospective intervention study. All members of cooperating statutory health insurance companies between 25 and 50 years of age living in a model region in Germany (federal state of Bavaria, 3.5 million inhabitants in this age group) can participate in the program between October 2018 and March 2020. Recruitment takes place through physicians and through a public campaign. Additionally, insurances contact recently diagnosed CRC patients in order to encourage their relatives to participate in the program. Physicians assess a participant's familial history of CRC using a short questionnaire. All participants with a family history of CRC are invited to a shared decision making process to decide on further screening options consisting of either undergoing an immunological test for fecal occult blood or colonoscopy. Comprehensive data collection based on self-reported lifestyle information, medical documentation and health administrative databases accompanies the screening program. Longterm benefits, harms and the cost-effectiveness of the risk-adapted CRC screening program will be assessed by decision analytic modeling. DISCUSSION: The data collected in this study will add important pieces of information that are still missing in the evaluation of the effects and the cost-effectiveness of a risk-adapted CRC screening strategy for individuals under 50 years of age. TRIAL REGISTRATION: German Clinical Trials Register, DRKS-IDDRKS00015097.

Effectiveness of a complex intervention to improve participation and activities in nursing home residents with joint contractures (JointConEval): study protocol of a multicentre cluster-randomised controlled trial [DRKS-ID:DRKS00015185].

BACKGROUND: Nursing home residents are frequently affected by joint contractures, which impacts their participation and daily activities. A complex intervention, the Participation Enabling Care in Nursing (PECAN), was previously developed and pilot tested to address their needs. Its effectiveness and safety will be evaluated in the present study. METHODS/DESIGN: This multicentre cluster-randomised controlled trial will be conducted in 32 nursing homes spread over two regions of Germany. A total of 578 residents over 65 years old with joint contractures will be included. To compare the effect of the PECAN intervention with optimised standard care (usual care and an information session), randomisation will take place at a cluster level. The individually tailored intervention was designed using the biopsychosocial model in the International Classification of Functioning, Disability and Health (ICF) to reduce activity limitations and participation restrictions resulting from existing joint contractures by addressing barriers and by strengthening supportive factors on an individual level and an organisational level. The implementation strategy comprises a facilitators' workshop, a peer mentoring approach including a peer mentor visit and telephone peer counselling, an in-house information event, an information session for the nursing team and a training session on collegial consultation for the facilitators. The in-house information event will also take place in the nursing homes of the control group. The primary outcome is the residents' participation and activities after 12 months of follow-up as assessed using the PaArticular Scales. The secondary outcome is the residents' quality of life. A cost-effectiveness analysis (costs per additional resident who experienced a decrease of ten points in the participation or activities subscale of the PaArticular Scales) and a cost-utility analysis (costs per additional quality adjusted life year) will be conducted. We will investigate barriers and facilitators in a comprehensive process evaluation. DISCUSSION: We expect a clinically relevant improvement of participation and activities in residents with joint contractures. Our findings will provide important insights regarding participation in the situation of the affected individuals. TRIAL REGISTRATION: DRKS, DRKS00015185 . Registered on 1 August 2018. Universal Trial Number U1111-1218-1555. Registered on 26 July 2018.

A Web-based survey among adults aged 40-54 years was time effective and yielded stable response patterns.

OBJECTIVE: We want to present information about response patterns obtained by Web-based survey in a large-scale epidemiological study. STUDY DESIGN AND SETTING: Within the RAPS (Risk Adapted Prevention Strategies for colorectal cancer [CRC]) study, we invited 160,000 randomly selected persons aged 40-54 years in three large German cities from 2015 to 2016 to complete a Web-based questionnaire on CRC risk factors and screening (97 items, average time for completion 15 minutes). Invitation letters and up to two reminder letters were sent to each individual. RESULTS: A total of 21.4% of women and 18.0% of men completed the questionnaire. Overall cumulative response rates were 7.5%, 14.3%, and 19.6% after the initial invitation letter, and the first and second reminder, respectively, with prevalence of and associations of key epidemiological parameters (such as family history of cancer, previous colonoscopy, etc.) being remarkably stable across waves of responses. For example, the sex and age distribution of the sample did not change with additional answers gained from additional letters. CONCLUSION: Web-based questionnaires are feasible, cost-effective, and time effective in the setting of large-scale epidemiological studies. Although response patterns were remarkably stable over several rounds of reminders with substantially increasing cumulative response rates, future research should address possibilities to further enhance response rates.

[Risk Prediction Using Routine Data: Development and Validation of Multivariable Models Predicting 30- and 90-day Mortality after Surgical Treatment of Colorectal Cancer]. / Risikoberechnung mit Routinedaten? Entwicklung und Validierung multivariabler Modelle zur Prädiktion der 30- und 90-Tage-Mortalität nach chirurgischer Behandlung kolorektaler Karzinome.

AIMS: Quality control, benchmarking, and pay for performance (P4P) require valid indicators and statistical models allowing adjustment for differences in risk profiles of the patient populations of the respective institutions. Using hospital remuneration data for measuring quality and modelling patient risks has been criticized by clinicians. Here we explore the potential of prediction models for 30- and 90-day mortality after colorectal cancer surgery based on routine data. STUDY DESIGN: Full census of a major statutory health insurer. SETTING: Surgical departments throughout the Federal Republic of Germany. PATIENTS: 4283 and 4124 insurants with major surgery for treatment of colorectal cancer during 2013 and 2014, respectively. PREDICTORS: Age, sex, primary and secondary diagnoses as well as tumor locations as recorded in the hospital remuneration data according to §301 SGB V. OUTCOMES: 30- and 90-day mortality. STATISTICAL ANALYSIS: Elixhauser comorbidities, Charlson conditions, and Charlson scores were generated from the ICD-10 diagnoses. Multivariable prediction models were developed using a penalized logistic regression approach (logistic ridge regression) in a derivation set (patients treated in 2013). Calibration and discrimination of the models were assessed in an internal validation sample (patients treated in 2014) using calibration curves, Brier scores, receiver operating characteristic curves (ROC curves) and the areas under the ROC curves (AUC). RESULTS: 30- and 90-day mortality rates in the learning-sample were 5.7 and 8.4%, respectively. The corresponding values in the validation sample were 5.9% and once more 8.4%. Models based on Elixhauser comorbidities exhibited the highest discriminatory power with AUC values of 0.804 (95% CI: 0.776 -0.832) and 0.805 (95% CI: 0.782-0.828) for 30- and 90-day mortality. The Brier scores for these models were 0.050 (95% CI: 0.044-0.056) and 0.067 (95% CI: 0.060-0.074) and similar to the models based on Charlson conditions. Regardless of the model, low predicted probabilities were well calibrated, while higher predicted values tended to be overestimates. CONCLUSION: The reasonable results regarding discrimination and calibration notwithstanding, models based on hospital remuneration data may not be helpful for P4P. Routine data do not offer information regarding a wide range of quality indicators more useful than mortality. As an alternative, models based on clinical registries may allow a wider, more valid perspective.

A Bayesian scoring rule on clustered event data for familial risk assessment - An example from colorectal cancer screening.

Colorectal cancer screening is well established. The identification of high risk populations is the key to implement effective risk-adjusted screening. Good statistical approaches for risk prediction do not exist. The family's colorectal cancer history is used for identification of high risk families and usually assessed by a questionnaire. This paper introduces a prediction algorithm to designate a family for colorectal cancer risk and discusses its statistical properties. The new algorithm uses Bayesian reasoning and a detailed family history illustrated by a pedigree and a Lexis diagram. The algorithm is able to integrate different hereditary mechanisms that define complex latent class or random factor structures. They are generic and do not reflect specific genetic models. This is comparable to strategies in complex segregation analysis. Furthermore, the algorithm can integrate different statistical penetrance models for right censored event data. Computational challenges related to the handling of the likelihood are discussed. Simulation studies assess the predictive quality of the new algorithm in terms of ROC curves and corresponding AUCs. The algorithm is applied to data of a recent study on familial colorectal cancer risk. Its predictive performance is compared to that of a questionnaire currently used in screening for familial colorectal cancer. The results of the proposed algorithm are robust against different inheritance models. Using the simplest hereditary mechanism, the simulation study provides evidence that the algorithm improves detection of families with high cancer risk in comparison to the currently used questionnaire. The applicability of the algorithm goes beyond the field of colorectal cancer.

Applying for, reviewing and funding public health research in Germany and beyond.

Public health research is complex, involves various disciplines, epistemological perspectives and methods, and is rarely conducted in a controlled setting. Often, the added value of a research project lies in its inter- or trans-disciplinary interaction, reflecting the complexity of the research questions at hand. This creates specific challenges when writing and reviewing public health research grant applications. Therefore, the German Research Foundation (DFG), the largest independent research funding organization in Germany, organized a round table to discuss the process of writing, reviewing and funding public health research. The aim was to analyse the challenges of writing, reviewing and granting scientific public health projects and to improve the situation by offering guidance to applicants, reviewers and funding organizations. The DFG round table discussion brought together national and international public health researchers and representatives of funding organizations. Based on their presentations and discussions, a core group of the participants (the authors) wrote a first draft on the challenges of writing and reviewing public health research proposals and on possible solutions. Comments were discussed in the group of authors until consensus was reached. Public health research demands an epistemological openness and the integration of a broad range of specific skills and expertise. Applicants need to explicitly refer to theories as well as to methodological and ethical standards and elaborate on why certain combinations of theories and methods are required. Simultaneously, they must acknowledge and meet the practical and ethical challenges of conducting research in complex real life settings. Reviewers need to make the rationale for their judgments transparent, refer to the corresponding standards and be explicit about any limitations in their expertise towards the review boards. Grant review boards, funding organizations and research ethics committees need to be aware of the specific conditions of public health research, provide adequate guidance to applicants and reviewers, and ensure that processes and the expertise involved adequately reflect the topic under review.

Functioning and disability in people living with spinal cord injury in high- and low-resourced countries: a comparative analysis of 14 countries.

OBJECTIVES: We examined whether persons with spinal cord injury (SCI) from countries with differential resources and resource distribution differ in the level and structure of functioning and disability. METHODS: We analysed cross-sectional data of 1,048 persons with SCI from 14 countries based on the International Classification of Functioning, Disability and Health (ICF). We used penalized logistic regression to identify ICF categories distinguishing lower- and higher-resourced countries. Hierarchical linear models were employed to predict the number of problems in functioning. The association structure of ICF categories was compared between higher- and lower-resourced countries using graphical models. RESULTS: A total of 96 ICF categories separated lower- and higher-resourced countries. Differences were not univocal. Lower resources and unequal distribution were predictive of more functional problems in persons with higher age or tetraplegia. In the graphical models, few associations between ICF categories persisted across countries. CONCLUSION: Higher-resourced countries do not score higher in all ICF categories. Countries' economic resources and their distribution are significant predictors of disability in vulnerable groups such as tetraplegics and the elderly. Functioning is multi-dimensional and structures of association suggest that country-specific pathways towards disability exist.

Graphical models illustrated complex associations between variables describing human functioning.

OBJECTIVE: To examine whether graphical modeling is a potentially useful method for the study of human functioning using data collected by means of the International Classification of Functioning, Disability and Health (ICF). STUDY DESIGN AND SETTING: The applicability of the method was examined in a convenience sample of 616 patients from a cross-sectional multicentric study undergoing early postacute rehabilitation. Functioning was qualified using 115 second-level ICF categories. The modeling was carried out on a data set with imputed missing values. The least absolute shrinkage and selection operator (LASSO) for generalized linear models was used to identify conditional dependencies between the ICF categories. Bootstrap aggregating was used to enhance the accuracy and validity of model selection. RESULTS: The resulting graph showed highly meaningful relationships. For example, one structure centered around speaking and included three paths addressing conversation, speech functions, and mental functions of language. CONCLUSION: Graphical modeling of human functioning using data collected by means of the ICF yields clinically meaningful results. The structures found may be the basis for the identification of suitable targets for rehabilitation interventions, the identification of confounders and intermediate variables, and the selection of parsimonious sets of variables for multivariate epidemiological modeling.

GlobalANCOVA: exploration and assessment of gene group effects.

MOTIVATION: Several authors have studied expression in gene sets with specific goals: overrepresentation of interesting genes in functional groups, predictive power for class membership and searches for groups where the constituent genes show coordinated changes in expression under the experimental conditions. The purpose of this article is to follow the third direction. One important aspect is that the gene sets under analysis are known a priori and are not determined from the experimental data at hand. Our goal is to provide a methodology that helps to identify the relevant structural constituents (phenotypical, experimental design, biological component) that determine gene expression in a group. RESULTS: Gene-wise linear models are used to formalize the structural aspects of a study. The full model is contrasted with a reduced model that lacks the relevant design component. A comparison with respect to goodness of fit is made and quantified. An asymptotic test and a permutation test are derived to test the null hypothesis that the reduced model sufficiently explains the observed expression within the gene group of interest. Graphical tools are available to illustrate and interpret the results of the analysis. Examples demonstrate the wide range of application. AVAILABILITY: The R-package GlobalAncova (http://www.bioconductor.org) offers data and functions as well as a vignette to guide the user through specific analysis steps.