Identification of potential confounding factors for the evaluation of clinical outcomes in alpha-1-antitrypsin deficiency-associated liver disease

Alpha-1-Antitrypsin deficiency (AATD) is a common but only rarely recognized genetic condition predisposing to e.g., liver disease. Systematic identification and classification of confounding factors is needed for the evaluation of clinical outcomes in adults with AATD-associated liver disease. A stepwise systematic review was performed to identify relevant guidelines and recommendations, systematic reviews and meta-analyses, and observational studies and randomized clinical trials. Five experts with large long-term experience recruited via purposeful sampling were consulted for validation via open requests and a joint workshop. A list was consented and categorized by clinical relevance and type of influence. Relations were visualized in a directed acyclic graph. Cirrhosis and fibrosis stage, genotype, sex, diabetes, obesity were categorized as very important; age, alcohol and metabolic syndrome were consented to be relevant but less important factors affecting distinct stages of liver disease. Adjusting for diabetes, obesity, alcohol consumption, and metabolic syndrome as confounders; stratifying or testing for interactions with sex and age as potential effect modifiers; and including cirrhosis, fibrosis stage, and genotype as prognostic factors to improve outcome prediction in AATD studies is suggested. Presented results require cautious interpretation due to varying evidence levels of included literature. The results obtained through a transparent and reproducible systematic approach aid future studies to improve design and analytical strategies for AATD-associated liver diseases. They enable a precise and accurate estimation of treatment effects with reduced risk of bias. In practice, this enhances the evidence base for innovative therapies for adults with AATD-associated liver disease. • We performed a systematic literature research followed by an expert validation process to identify potential confounding variables to be considered in nonrandomized studies on adult patients with alpha-1-antitrypsin deficiency-associated liver disease. • Cirrhosis/fibrosis stage, proteinase inhibitor genotype [Pi*Z], male sex, diabetes, and obesity were identified as very important confounders and significant clinical parameters associated with onset and progression of liver disease. • Age, alcohol consumption, and the metabolic syndrome were considered as less important but also relevant confounders due to their impact on liver disease development and progression.