@misc{MontiRautenstrauchGhanbarietal.2022, author = {Monti, Remo and Rautenstrauch, Pia and Ghanbari, Mahsa and Rani James, Alva and Kirchler, Matthias and Ohler, Uwe and Konigorski, Stefan and Lippert, Christoph}, title = {Identifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes}, series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Reihe der Digital Engineering Fakult{\"a}t}, journal = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Reihe der Digital Engineering Fakult{\"a}t}, number = {16}, doi = {10.25932/publishup-58607}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-586078}, pages = {16}, year = {2022}, abstract = {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.}, language = {en} } @article{MontiRautenstrauchGhanbarietal.2022, author = {Monti, Remo and Rautenstrauch, Pia and Ghanbari, Mahsa and Rani James, Alva and Kirchler, Matthias and Ohler, Uwe and Konigorski, Stefan and Lippert, Christoph}, title = {Identifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes}, series = {Nature Communications}, volume = {13}, journal = {Nature Communications}, publisher = {Nature Publishing Group UK}, address = {London}, issn = {2041-1723}, doi = {10.1038/s41467-022-32864-2}, pages = {16}, year = {2022}, abstract = {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.}, language = {en} } @article{GaertnerSchneiderArnrichetal.2023, author = {G{\"a}rtner, Thomas and Schneider, Juliana and Arnrich, Bert and Konigorski, Stefan}, title = {Comparison of Bayesian Networks, G-estimation and linear models to estimate causal treatment effects in aggregated N-of-1 trials with carry-over effects}, series = {BMC Medical Research Methodology}, volume = {23}, journal = {BMC Medical Research Methodology}, number = {1}, publisher = {BMC}, address = {London}, issn = {1471-2288}, doi = {10.1186/s12874-023-02012-5}, pages = {12}, year = {2023}, abstract = {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.}, language = {en} } @article{KirchlerKonigorskiNordenetal.2022, author = {Kirchler, Matthias and Konigorski, Stefan and Norden, Matthias and Meltendorf, Christian and Kloft, Marius and Schurmann, Claudia and Lippert, Christoph}, title = {transferGWAS}, series = {Bioinformatics}, volume = {38}, journal = {Bioinformatics}, number = {14}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {1367-4803}, doi = {10.1093/bioinformatics/btac369}, pages = {3621 -- 3628}, year = {2022}, abstract = {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.}, language = {en} } @article{Konigorski2021, author = {Konigorski, Stefan}, title = {Causal inference in developmental medicine and neurology}, series = {Developmental medicine and child neurology}, volume = {63}, journal = {Developmental medicine and child neurology}, number = {5}, publisher = {Wiley-Blackwell}, address = {Oxford}, issn = {0012-1622}, doi = {10.1111/dmcn.14813}, pages = {498 -- 498}, year = {2021}, language = {en} } @article{WiemkerBunovaNeufeldetal.2022, author = {Wiemker, Veronika and Bunova, Anna and Neufeld, Maria and Gornyi, Boris and Yurasova, Elena and Konigorski, Stefan and Kalinina, Anna and Kontsevaya, Anna and Ferreira-Borges, Carina and Probst, Charlotte}, title = {Pilot study to evaluate usability and acceptability of the 'Animated Alcohol Assessment Tool' in Russian primary healthcare}, series = {Digital health}, volume = {8}, journal = {Digital health}, publisher = {Sage Publications}, address = {London}, issn = {2055-2076}, doi = {10.1177/20552076211074491}, pages = {11}, year = {2022}, abstract = {Background and aims: Accurate and user-friendly assessment tools quantifying alcohol consumption are a prerequisite to effective prevention and treatment programmes, including Screening and Brief Intervention. Digital tools offer new potential in this field. We developed the 'Animated Alcohol Assessment Tool' (AAA-Tool), a mobile app providing an interactive version of the World Health Organization's Alcohol Use Disorders Identification Test (AUDIT) that facilitates the description of individual alcohol consumption via culturally informed animation features. This pilot study evaluated the Russia-specific version of the Animated Alcohol Assessment Tool with regard to (1) its usability and acceptability in a primary healthcare setting, (2) the plausibility of its alcohol consumption assessment results and (3) the adequacy of its Russia-specific vessel and beverage selection. Methods: Convenience samples of 55 patients (47\% female) and 15 healthcare practitioners (80\% female) in 2 Russian primary healthcare facilities self-administered the Animated Alcohol Assessment Tool and rated their experience on the Mobile Application Rating Scale - User Version. Usage data was automatically collected during app usage, and additional feedback on regional content was elicited in semi-structured interviews. Results: On average, patients completed the Animated Alcohol Assessment Tool in 6:38 min (SD = 2.49, range = 3.00-17.16). User satisfaction was good, with all subscale Mobile Application Rating Scale - User Version scores averaging >3 out of 5 points. A majority of patients (53\%) and practitioners (93\%) would recommend the tool to 'many people' or 'everyone'. Assessed alcohol consumption was plausible, with a low number (14\%) of logically impossible entries. Most patients reported the Animated Alcohol Assessment Tool to reflect all vessels (78\%) and all beverages (71\%) they typically used. Conclusion: High acceptability ratings by patients and healthcare practitioners, acceptable completion time, plausible alcohol usage assessment results and perceived adequacy of region-specific content underline the Animated Alcohol Assessment Tool's potential to provide a novel approach to alcohol assessment in primary healthcare. After its validation, the Animated Alcohol Assessment Tool might contribute to reducing alcohol-related harm by facilitating Screening and Brief Intervention implementation in Russia and beyond.}, language = {en} } @article{FehrPiccininniKurthetal.2023, author = {Fehr, Jana and Piccininni, Marco and Kurth, Tobias and Konigorski, Stefan}, title = {Assessing the transportability of clinical prediction models for cognitive impairment using causal models}, series = {BMC medical research methodology}, volume = {23}, journal = {BMC medical research methodology}, number = {1}, publisher = {BMC}, address = {London}, issn = {1471-2288}, doi = {10.1186/s12874-023-02003-6}, pages = {14}, year = {2023}, abstract = {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.}, language = {en} } @misc{KonigorskiWernickeSlosareketal.2023, author = {Konigorski, Stefan and Wernicke, Sarah and Slosarek, Tamara and Zenner, Alexander Maximilian and Strelow, Nils and Ruether, Darius Ferenc and Henschel, Florian and Manaswini, Manisha and Pottb{\"a}cker, Fabian and Edelman, Jonathan Antonio and Owoyele, Babajide and Danieletto, Matteo and Golden, Eddye and Zweig, Micol and Nadkarni, Girish N. and B{\"o}ttinger, Erwin}, title = {StudyU: A Platform for Designing and Conducting Innovative Digital N-of-1 Trials}, series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Reihe der Digital Engineering Fakult{\"a}t}, journal = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Reihe der Digital Engineering Fakult{\"a}t}, number = {12}, doi = {10.25932/publishup-58037}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-580370}, pages = {12}, year = {2023}, abstract = {N-of-1 trials are the gold standard study design to evaluate individual treatment effects and derive personalized treatment strategies. Digital tools have the potential to initiate a new era of N-of-1 trials in terms of scale and scope, but fully functional platforms are not yet available. Here, we present the open source StudyU platform, which includes the StudyU Designer and StudyU app. With the StudyU Designer, scientists are given a collaborative web application to digitally specify, publish, and conduct N-of-1 trials. The StudyU app is a smartphone app with innovative user-centric elements for participants to partake in trials published through the StudyU Designer to assess the effects of different interventions on their health. Thereby, the StudyU platform allows clinicians and researchers worldwide to easily design and conduct digital N-of-1 trials in a safe manner. We envision that StudyU can change the landscape of personalized treatments both for patients and healthy individuals, democratize and personalize evidence generation for self-optimization and medicine, and can be integrated in clinical practice.}, language = {en} } @misc{ZennerBoettingerKonigorski2022, author = {Zenner, Alexander M. and B{\"o}ttinger, Erwin and Konigorski, Stefan}, title = {StudyMe}, series = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Reihe der Digital Engineering Fakult{\"a}t}, journal = {Zweitver{\"o}ffentlichungen der Universit{\"a}t Potsdam : Reihe der Digital Engineering Fakult{\"a}t}, number = {18}, doi = {10.25932/publishup-58976}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-589763}, pages = {15}, year = {2022}, abstract = {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.}, language = {en} } @article{CopeBaukmannKlingeretal.2021, author = {Cope, Justin L. and Baukmann, Hannes A. and Klinger, J{\"o}rn E. and Ravarani, Charles N. J. and B{\"o}ttinger, Erwin and Konigorski, Stefan and Schmidt, Marco F.}, title = {Interaction-based feature selection algorithm outperforms polygenic risk score in predicting Parkinson's Disease status}, series = {Frontiers in genetics}, volume = {12}, journal = {Frontiers in genetics}, publisher = {Frontiers Media}, address = {Lausanne}, issn = {1664-8021}, doi = {10.3389/fgene.2021.744557}, pages = {9}, year = {2021}, abstract = {Polygenic risk scores (PRS) aggregating results from genome-wide association studies are the state of the art in the prediction of susceptibility to complex traits or diseases, yet their predictive performance is limited for various reasons, not least of which is their failure to incorporate the effects of gene-gene interactions. Novel machine learning algorithms that use large amounts of data promise to find gene-gene interactions in order to build models with better predictive performance than PRS. Here, we present a data preprocessing step by using data-mining of contextual information to reduce the number of features, enabling machine learning algorithms to identify gene-gene interactions. We applied our approach to the Parkinson's Progression Markers Initiative (PPMI) dataset, an observational clinical study of 471 genotyped subjects (368 cases and 152 controls). With an AUC of 0.85 (95\% CI = [0.72; 0.96]), the interaction-based prediction model outperforms the PRS (AUC of 0.58 (95\% CI = [0.42; 0.81])). Furthermore, feature importance analysis of the model provided insights into the mechanism of Parkinson's disease. For instance, the model revealed an interaction of previously described drug target candidate genes TMEM175 and GAPDHP25. These results demonstrate that interaction-based machine learning models can improve genetic prediction models and might provide an answer to the missing heritability problem.}, language = {en} } @article{ZennerBoettingerKonigorski2022, author = {Zenner, Alexander M. and B{\"o}ttinger, Erwin and Konigorski, Stefan}, title = {StudyMe}, series = {Trials}, volume = {23}, journal = {Trials}, publisher = {BioMed Central}, address = {London}, issn = {1745-6215}, doi = {10.1186/s13063-022-06893-7}, pages = {15}, year = {2022}, abstract = {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.}, language = {en} } @article{KonigorskiWernickeSlosareketal.2022, author = {Konigorski, Stefan and Wernicke, Sarah and Slosarek, Tamara and Zenner, Alexander M. and Strelow, Nils and Ruether, Darius F. and Henschel, Florian and Manaswini, Manisha and Pottb{\"a}cker, Fabian and Edelman, Jonathan A. and Owoyele, Babajide and Danieletto, Matteo and Golden, Eddye and Zweig, Micol and Nadkarni, Girish N. and B{\"o}ttinger, Erwin}, title = {StudyU: a platform for designing and conducting innovative digital N-of-1 trials}, series = {Journal of medical internet research}, volume = {24}, journal = {Journal of medical internet research}, number = {7}, publisher = {Healthcare World}, address = {Richmond, Va.}, issn = {1439-4456}, doi = {10.2196/35884}, pages = {12}, year = {2022}, abstract = {N-of-1 trials are the gold standard study design to evaluate individual treatment effects and derive personalized treatment strategies. Digital tools have the potential to initiate a new era of N-of-1 trials in terms of scale and scope, but fully functional platforms are not yet available. Here, we present the open source StudyU platform, which includes the StudyU Designer and StudyU app. With the StudyU Designer, scientists are given a collaborative web application to digitally specify, publish, and conduct N-of-1 trials. The StudyU app is a smartphone app with innovative user-centric elements for participants to partake in trials published through the StudyU Designer to assess the effects of different interventions on their health. Thereby, the StudyU platform allows clinicians and researchers worldwide to easily design and conduct digital N-of-1 trials in a safe manner. We envision that StudyU can change the landscape of personalized treatments both for patients and healthy individuals, democratize and personalize evidence generation for self-optimization and medicine, and can be integrated in clinical practice.}, language = {en} } @article{EhrigWagnerWolteretal.2023, author = {Ehrig, Lukas and Wagner, Ann-Christin and Wolter, Heike and Correll, Christoph U. and Geisel, Olga and Konigorski, Stefan}, title = {FASDetect as a machine learning-based screening app for FASD in youth with ADHD}, series = {npj Digital Medicine}, volume = {6}, journal = {npj Digital Medicine}, number = {1}, publisher = {Macmillan Publishers Limited}, address = {Basingstoke}, issn = {2398-6352}, doi = {10.1038/s41746-023-00864-1}, pages = {9}, year = {2023}, abstract = {Fetal alcohol-spectrum disorder (FASD) is underdiagnosed and often misdiagnosed as attention-deficit/hyperactivity disorder (ADHD). Here, we develop a screening tool for FASD in youth with ADHD symptoms. To develop the prediction model, medical record data from a German University outpatient unit are assessed including 275 patients aged 0-19 years old with FASD with or without ADHD and 170 patients with ADHD without FASD aged 0-19 years old. We train 6 machine learning models based on 13 selected variables and evaluate their performance. Random forest models yield the best prediction models with a cross-validated AUC of 0.92 (95\% confidence interval [0.84, 0.99]). Follow-up analyses indicate that a random forest model with 6 variables - body length and head circumference at birth, IQ, socially intrusive behaviour, poor memory and sleep disturbance - yields equivalent predictive accuracy. We implement the prediction model in a web-based app called FASDetect - a user-friendly, clinically scalable FASD risk calculator that is freely available at https://fasdetect.dhc-lab.hpi.de.}, language = {en} }