TY - JOUR A1 - Gärtner, Thomas A1 - Schneider, Juliana A1 - Arnrich, Bert A1 - Konigorski, Stefan T1 - Comparison of Bayesian Networks, G-estimation and linear models to estimate causal treatment effects in aggregated N-of-1 trials with carry-over effects JF - BMC Medical Research Methodology N2 - Background The aggregation of a series of N-of-1 trials presents an innovative and efficient study design, as an alternative to traditional randomized clinical trials. Challenges for the statistical analysis arise when there is carry-over or complex dependencies of the treatment effect of interest. Methods In this study, we evaluate and compare methods for the analysis of aggregated N-of-1 trials in different scenarios with carry-over and complex dependencies of treatment effects on covariates. For this, we simulate data of a series of N-of-1 trials for Chronic Nonspecific Low Back Pain based on assumed causal relationships parameterized by directed acyclic graphs. In addition to existing statistical methods such as regression models, Bayesian Networks, and G-estimation, we introduce a carry-over adjusted parametric model (COAPM). Results The results show that all evaluated existing models have a good performance when there is no carry-over and no treatment dependence. When there is carry-over, COAPM yields unbiased and more efficient estimates while all other methods show some bias in the estimation. When there is known treatment dependence, all approaches that are capable to model it yield unbiased estimates. Finally, the efficiency of all methods decreases slightly when there are missing values, and the bias in the estimates can also increase. Conclusions This study presents a systematic evaluation of existing and novel approaches for the statistical analysis of a series of N-of-1 trials. We derive practical recommendations which methods may be best in which scenarios. KW - N-of-1 trials KW - Randomized clinical trials KW - Bayesian Networks; KW - G-estimation KW - Linear model KW - Simulation study KW - Chronic Nonspecific Low KW - Back Pain Y1 - 2023 U6 - https://doi.org/10.1186/s12874-023-02012-5 SN - 1471-2288 VL - 23 IS - 1 PB - BMC CY - London ER - TY - JOUR A1 - Fehr, Jana A1 - Piccininni, Marco A1 - Kurth, Tobias A1 - Konigorski, Stefan T1 - Assessing the transportability of clinical prediction models for cognitive impairment using causal models JF - BMC medical research methodology N2 - Background Machine learning models promise to support diagnostic predictions, but may not perform well in new settings. Selecting the best model for a new setting without available data is challenging. We aimed to investigate the transportability by calibration and discrimination of prediction models for cognitive impairment in simulated external settings with different distributions of demographic and clinical characteristics. Methods We mapped and quantified relationships between variables associated with cognitive impairment using causal graphs, structural equation models, and data from the ADNI study. These estimates were then used to generate datasets and evaluate prediction models with different sets of predictors. We measured transportability to external settings under guided interventions on age, APOE & epsilon;4, and tau-protein, using performance differences between internal and external settings measured by calibration metrics and area under the receiver operating curve (AUC). Results Calibration differences indicated that models predicting with causes of the outcome were more transportable than those predicting with consequences. AUC differences indicated inconsistent trends of transportability between the different external settings. Models predicting with consequences tended to show higher AUC in the external settings compared to internal settings, while models predicting with parents or all variables showed similar AUC. Conclusions We demonstrated with a practical prediction task example that predicting with causes of the outcome results in better transportability compared to anti-causal predictions when considering calibration differences. We conclude that calibration performance is crucial when assessing model transportability to external settings. KW - Alzheimer's Disease KW - Clinical risk prediction KW - DAG KW - Causality; KW - Transportability Y1 - 2023 U6 - https://doi.org/10.1186/s12874-023-02003-6 SN - 1471-2288 VL - 23 IS - 1 PB - BMC CY - London ER - TY - GEN A1 - Monti, Remo A1 - Rautenstrauch, Pia A1 - Ghanbari, Mahsa A1 - Rani James, Alva A1 - Kirchler, Matthias A1 - Ohler, Uwe A1 - Konigorski, Stefan A1 - Lippert, Christoph T1 - Identifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes T2 - Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät N2 - Here we present an exome-wide rare genetic variant association study for 30 blood biomarkers in 191,971 individuals in the UK Biobank. We compare gene- based association tests for separate functional variant categories to increase interpretability and identify 193 significant gene-biomarker associations. Genes associated with biomarkers were ~ 4.5-fold enriched for conferring Mendelian disorders. In addition to performing weighted gene-based variant collapsing tests, we design and apply variant-category-specific kernel-based tests that integrate quantitative functional variant effect predictions for mis- sense variants, splicing and the binding of RNA-binding proteins. For these tests, we present a computationally efficient combination of the likelihood- ratio and score tests that found 36% more associations than the score test alone while also controlling the type-1 error. Kernel-based tests identified 13% more associations than their gene-based collapsing counterparts and had advantages in the presence of gain of function missense variants. We introduce local collapsing by amino acid position for missense variants and use it to interpret associations and identify potential novel gain of function variants in PIEZO1. Our results show the benefits of investigating different functional mechanisms when performing rare-variant association tests, and demonstrate pervasive rare-variant contribution to biomarker variability. T3 - Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät - 16 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-586078 IS - 16 ER - TY - GEN A1 - Zenner, Alexander M. A1 - Böttinger, Erwin A1 - Konigorski, Stefan T1 - StudyMe BT - a new mobile app for user-centric N-of-1 trials T2 - Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät N2 - N-of-1 trials are multi-crossover self-experiments that allow individuals to systematically evaluate the effect of interventions on their personal health goals. Although several tools for N-of-1 trials exist, there is a gap in supporting non-experts in conducting their own user-centric trials. In this study, we present StudyMe, an open-source mobile application that is freely available from https://play.google.com/store/apps/details?id=health.studyu.me and offers users flexibility and guidance in configuring every component of their trials. We also present research that informed the development of StudyMe, focusing on trial creation. Through an initial survey with 272 participants, we learned that individuals are interested in a variety of personal health aspects and have unique ideas on how to improve them. In an iterative, user-centered development process with intermediate user tests, we developed StudyMe that features an educational part to communicate N-of-1 trial concepts. A final empirical evaluation of StudyMe showed that all participants were able to create their own trials successfully using StudyMe and the app achieved a very good usability rating. Our findings suggest that StudyMe provides a significant step towards enabling individuals to apply a systematic science-oriented approach to personalize health-related interventions and behavior modifications in their everyday lives. T3 - Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät - 18 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-589763 IS - 18 ER - TY - JOUR A1 - Monti, Remo A1 - Rautenstrauch, Pia A1 - Ghanbari, Mahsa A1 - Rani James, Alva A1 - Kirchler, Matthias A1 - Ohler, Uwe A1 - Konigorski, Stefan A1 - Lippert, Christoph T1 - Identifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes JF - Nature Communications N2 - Here we present an exome-wide rare genetic variant association study for 30 blood biomarkers in 191,971 individuals in the UK Biobank. We compare gene- based association tests for separate functional variant categories to increase interpretability and identify 193 significant gene-biomarker associations. Genes associated with biomarkers were ~ 4.5-fold enriched for conferring Mendelian disorders. In addition to performing weighted gene-based variant collapsing tests, we design and apply variant-category-specific kernel-based tests that integrate quantitative functional variant effect predictions for mis- sense variants, splicing and the binding of RNA-binding proteins. For these tests, we present a computationally efficient combination of the likelihood- ratio and score tests that found 36% more associations than the score test alone while also controlling the type-1 error. Kernel-based tests identified 13% more associations than their gene-based collapsing counterparts and had advantages in the presence of gain of function missense variants. We introduce local collapsing by amino acid position for missense variants and use it to interpret associations and identify potential novel gain of function variants in PIEZO1. Our results show the benefits of investigating different functional mechanisms when performing rare-variant association tests, and demonstrate pervasive rare-variant contribution to biomarker variability. Y1 - 2022 U6 - https://doi.org/10.1038/s41467-022-32864-2 SN - 2041-1723 VL - 13 PB - Nature Publishing Group UK CY - London ER - TY - JOUR A1 - Zenner, Alexander M. A1 - Böttinger, Erwin A1 - Konigorski, Stefan T1 - StudyMe BT - a new mobile app for user-centric N-of-1 trials JF - Trials N2 - N-of-1 trials are multi-crossover self-experiments that allow individuals to systematically evaluate the effect of interventions on their personal health goals. Although several tools for N-of-1 trials exist, there is a gap in supporting non-experts in conducting their own user-centric trials. In this study, we present StudyMe, an open-source mobile application that is freely available from https://play.google.com/store/apps/details?id=health.studyu.me and offers users flexibility and guidance in configuring every component of their trials. We also present research that informed the development of StudyMe, focusing on trial creation. Through an initial survey with 272 participants, we learned that individuals are interested in a variety of personal health aspects and have unique ideas on how to improve them. In an iterative, user-centered development process with intermediate user tests, we developed StudyMe that features an educational part to communicate N-of-1 trial concepts. A final empirical evaluation of StudyMe showed that all participants were able to create their own trials successfully using StudyMe and the app achieved a very good usability rating. Our findings suggest that StudyMe provides a significant step towards enabling individuals to apply a systematic science-oriented approach to personalize health-related interventions and behavior modifications in their everyday lives. Y1 - 2022 U6 - https://doi.org/10.1186/s13063-022-06893-7 SN - 1745-6215 VL - 23 PB - BioMed Central CY - London ER - TY - JOUR A1 - Kirchler, Matthias A1 - Konigorski, Stefan A1 - Norden, Matthias A1 - Meltendorf, Christian A1 - Kloft, Marius A1 - Schurmann, Claudia A1 - Lippert, Christoph T1 - transferGWAS BT - GWAS of images using deep transfer learning JF - Bioinformatics N2 - Motivation: Medical images can provide rich information about diseases and their biology. However, investigating their association with genetic variation requires non-standard methods. We propose transferGWAS, a novel approach to perform genome-wide association studies directly on full medical images. First, we learn semantically meaningful representations of the images based on a transfer learning task, during which a deep neural network is trained on independent but similar data. Then, we perform genetic association tests with these representations. Results: We validate the type I error rates and power of transferGWAS in simulation studies of synthetic images. Then we apply transferGWAS in a genome-wide association study of retinal fundus images from the UK Biobank. This first-of-a-kind GWAS of full imaging data yielded 60 genomic regions associated with retinal fundus images, of which 7 are novel candidate loci for eye-related traits and diseases. Y1 - 2022 U6 - https://doi.org/10.1093/bioinformatics/btac369 SN - 1367-4803 SN - 1460-2059 VL - 38 IS - 14 SP - 3621 EP - 3628 PB - Oxford Univ. Press CY - Oxford ER -