https://orcid.org/0000-0001-7859-0483
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Abstract
Sequencing read-count data often exhibit sparsity (zero-count inflation) and overdispersion. As most sequencing techniques provide an arbitrary total count, taxon-specific counts should be treated under the compositional data-analytic framework. There is increasing interest in the role of gut microbiome composition in mediating the effects of exposures on health. Previous compositional mediation approaches have focused on identifying mediating taxa among a number of candidates. We here consider compositional causal mediation when a priori knowledge is available about the hierarchy for a restricted number of taxa, building on a single hypothesis structured as contrasts between appropriate sub-compositions. Based on the assumed causal graph and the theory of multiple contemporaneous mediators, we define non-parametric estimands for overall and coordinate-wise mediation effects and show how they are estimated based on parametric linear models. The mediators have straightforward and coherent interpretations, related to causal questions about interrelationships between the sub-compositions. We perform a simulation study focusing on the impact of sparsity on estimation. While unbiased, the estimators' precision depends on sparsity and the relative magnitudes of exposure-to-mediator and mediator-to-outcome effects in a complex manner. In the empirical application we find an inverse association of fibre intake on insulin level, mainly attributable to the direct effects.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Ethical approval and patient consent
The empirical study was approved by the associated university and hospital district ethical authorities. Written informed consent was obtained from the participants.
Data availability statement
The details of the simulation study, including the extensive simulation codes, are available upon request from the corresponding author. The empirical dataset comprises health related participant data and their use is therefore restricted under the regulations on professional secrecy (Act on the Openness of Government Activities, 612/1999) and on sensitive personal data (Personal Data Act, 523/1999, implementing the EU data protection directive 95/46/EC). Due to these legal restrictions, the data from this study can not be stored in public repositories or otherwise made publicly available. However, data access may be permitted on a case by case basis upon request only. Data sharing requires a data-sharing agreement. Investigators can submit an expression of interest to the corresponding author.
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Funding
Notes on contributors
Noora Kartiosuo
Noora Kartiosuo holds a MSc in statistics and is as a doctoral researcher at the Department of Mathematics and Statistics at the University of Turku, Finland. She also works as a biostatistician at the Centre for Population Health Research at University of Turku. Her research interests include omics data, methods for understanding the role of omics in health, mediation questions and modelling of longitudinal life-course data. Department of Mathematics and Statistics, University of Turku, FI-20014 Turun Yliopisto, FINLAND.
Jaakko Nevalainen
Jaakko Nevalainen is currently Head of the Health Sciences Unit and Professor in Biostatistics at Tampere University, Finland. His theoretical interests in statistics are in nonparametric methods and the analysis of clustered & high-dimensional data with non-standard structures. He has been active in collaborative research in the particularly in the fields of nutrition, diabetes, and prostate cancer, their epidemiology and economics, as well as in making use of modern data sources like multicellular imaging, health registers and loyalty card data. Currently, he is a principal investigator for the LoCard study consortia (www.locard.fi) in which new computational methodologies are used to understand food purchase patterns, their impacts on people, planet, and prosperity, and ways to steer them to a transition to a more sustainable future. Nevalainen has contributed to statistical theory and novel applications of methodology in new contexts. His work has been published in leading journals like JAMA, JASA, Statistics in Medicine, American Journal of Clinical Nutrition, International Journal of Epidemiology and Diabetologia and he has authored > 160 articles. Health Sciences Unit, Tampere University, FI-33014 Tampere University, FINLAND.
Olli Raitakari
Olli Raitakari is the Director of the Centre for Population Health Research at the Turku University and Turku University Hospital. He is coordinating two large Finnish studies into cardiovascular risk. The national Cardiovascular Risk in Young Finns study (http://med.utu.fi/cardio/youngfinnsstudy/) is one the largest long-standing observational cohort studies globally that has followed a cohort of individuals from childhood to adulthood. He is also the Director of the STRIP Study, an ongoing intervention study commenced in early 90's, when >1,000 infants were recruited to an intervention to receive detailed individualised dietary counselling (http://stripstudy.utu.fi/english.html). Raitakari has introduced vascular epidemiology, genetic epidemiology and population omics approaches in these cohorts. His work has allowed the development, modification and validation of the techniques involved in the measurement of subclinical atherosclerotic changes in the vasculature. The research has contributed to the understanding of pre-clinical development of atherosclerosis in young individuals. As a demonstration of the international recognition and impact of this work, many of his studies have been widely cited in updated pediatric guidelines on cardiovascular prevention both in Europe and in US. He has authored over 1,200 articles. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Kiinamyllynkatu 10, FI-20520 Turku, FINLAND.
Katja Pahkala
Katja Pahkala is a professor in preventive medicine, is an Academy of Finland research fellow and director of the Paavo Nurmi Centre. Pahkala has devoted her research career to examining early life determinants of cardiometabolic health with the ultimate aim to improve primordial prevention of cardiometabolic diseases. She is a long-standing senior researcher and the vice director of the Research Centre of Applied and Preventive Cardiovascular Medicine at the University of Turku. She is also the vice principal investigator of the globally unique atherosclerosis prevention trial, the STRIP study (Special Turku Coronary Risk Factor Intervention Project, http://stripstudy.utu.fi/english.html). Since 2018, she has been a member of the executive committee and a local co-principal investigator of the multi-center Cardiovascular Risk in Young Finns Study (YFS, http://med.utu.fi/cardio/youngfinnsstudy/). Pahkala started as the director of Paavo Nurmi Centre, a centre of expertise in exercise medicine, in 2024. Her work aims to provide novel scientific evidence on the early determinants and the importance of the prevention of cardiometabolic diseases beginning from childhood to inform preventive guidelines and actions. Pahkala has 169 peer-reviewed international publications. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Kiinamyllynkatu 10FI-20520 Turku, FINLAND.
Kari Auranen
Kari Auranen is a professor of statistics at the University of Turku, Finland. Previously, he was affiliated with the Finnish National Institute for Health and Welfare, working on various vaccination-related research and policy questions. In 2006–2012 he acted as the scientific manager of the Pneumo.