Cited by 1,496Genetic Associations and EpidemiologyAdvanced Causal Inference TechniquesGenetics and Physical Performance

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Evaluating the potential role of pleiotropy in Mendelian randomization studies

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Hemani, Gibran, Bowden, Jack, Davey Smith, George·2018·Human Molecular Genetics

DOI 10.1093/hmg/ddy163PMC PMC6061876

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Abstract

Pleiotropy, the phenomenon of a single genetic variant influencing multiple traits, is likely widespread in the human genome. If pleiotropy arises because the single nucleotide polymorphism (SNP) influences one trait, which in turn influences another ('vertical pleiotropy'), then Mendelian randomization (MR) can be used to estimate the causal influence between the traits. Of prime focus among the many limitations to MR is the unprovable assumption that apparent pleiotropic associations are mediated by the exposure (i.e. reflect vertical pleiotropy), and do not arise due to SNPs influencing the two traits through independent pathways ('horizontal pleiotropy'). The burgeoning treasure trove of genetic associations yielded through genome wide association studies makes for a tantalizing prospect of phenome-wide causal inference. Recent years have seen substantial attention devoted to the problem of horizontal pleiotropy, and in this review we outline how newly developed methods can be used together to improve the reliability of MR.

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Figure 1. (A) The same SNP can associate with multiple traits due to vertical pleiotropy, horizontal pleiotropy and linkage disequilibrium with distinct causal variants depending on the analytical context. To estimate the causal influence of gene expression level (Gene) 1 on Trait 1, SNP 1 is a valid instrument that acts in a vertical pleiotropic manner. But SNP 1 has a horizontal pleiotropic effect when using it to estimate the causal influence of Gene 1 on Trait 2. If SNP 1 was used to instrument Gene 1 to test its effect on Trait 3, it would exhibit a pleiotropic association through linkage disequilibrium with SNP 2. (B) A directed acyclic graph (DAG) in which four SNPs instrument an exposure. The fourth SNP has a horizontal pleiotropic effect of magnitude α. The impact of the horizontal pleiotropic effect is shown in the scatter plot in (C), where the grey slope represents the true causal effect obtained from the three valid instruments, and the red slope represents the IVW estimate when all SNPs are used as instruments.CC BY · PubMed Central

Appendix figure 1. (A) Unobserved confounding (U) makes it impossible to be fully confident that an association between risk factor X and outcome Y represents a measure of causal effect of X on Y. (B) In a perfect RCT, randomization to treatment (T) removes the possibility of confounding, enabling the causal effect of T on Y to be estimated. (C) MR uses genetic variants (G) that explain some variation in the exposure X to estimate the causal effect of X on Y. G must satisfy the instrumental variable assumptions, encoded by the solid arrows (and the strict absence of the dotted arrows) in (C). (D) Instrumental variable methods can also be used in clinical trials when randomization is imperfect because some patients do not receive the treatment they were originally assigned. This is referred to as `non-compliance’. An MR analysis is conceptually and mathematically equivalent to the analysis of RCT data in the presence of non-compliance, where the SNP (G) and exposure (X) proxy for randomization (R) and treatment (T), respectively.CC BY · PubMed Central

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Method
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Li, B.-H., Yan, S., Li, X., Huang, Q., Luo, L.-S., Wang, X., Huang, J., Jin, Y., & Wang, Y. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.898279 · Cited by 6
“We performed an MR analysis based on three core assumptions: (1) the IVs are robustly related to the exposure of interest, (2) the IVs are not affected by any confounding factors, (3) and the IVs do not influence the outcome via any variable other than the exposure (17).”
Method
Association of mTORC1‑dependent circulating protein levels with cataract formation: a mendelian randomization study
Cai, Y., Liu, K., Wu, P., Yuan, R., He, F., & Zou, J. (2022) · BMC Genomics · doi:10.1186/s12864-022-08925-7 · Cited by 6
“The pleiotropy was divided into vertical and horizontal pleiotropy according to the pathways which SNPs influence the traits[35].”
Background
Identification of potential causal metabolites associated with atopic dermatitis
Jia, Y., Wang, R., Sun, L., Guo, D., Shi, M., Zhang, K., Yang, P., Wang, Y., Liu, F., Chen, G.-C., et al. (2023) · Human Molecular Genetics · doi:10.1093/hmg/ddad005 · Cited by 6
Blood cell traits and risk of glaucoma: A two-sample mendelian randomization study
Song, D.-J., Fan, B., & Li, G. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1142773 · Cited by 6
Univariable and multivariable Mendelian randomization investigating the effects of telomere length on the risk of adverse pregnancy outcomes
Han, X., Wu, T., & Liu, C. Y. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1225600 · Cited by 9
“In addition, the MR-Egger intercept can detect and adjust pleiotropy (39).”
BackgroundMethodInfluential
Mendelian randomization analysis reveals causality of inflammatory bowel disease on risks of Henoch-Schönlein purpura and immune thrombocytopenia
Li, H., Xin, Q., Hong, L., Hu, Y., Lin, L., Guo, M., Jiang, H., He, C., Wang, S., & Li, M. (2023) · Digestive and Liver Disease · doi:10.1016/j.dld.2023.08.044 · Cited by 6
Causal association of nonalcoholic fatty liver disease with 22 extrahepatic cancers: A Mendelian randomization study
Xie, J., Gao, H., Liu, C., Pan, Y., Xu, C., & Xu, L. (2023) · Hepatology Research · doi:10.1111/hepr.13980 · Cited by 6
“23 Thus, we used multiple NAFLD risk variants and performed two sensitivity analyses to ensure the reliability of the MR estimation.”
Method
Unlocking the Medicinal Mysteries: Preventing Lacunar Stroke with Drug Repurposing
Zhang, L., Fan, W., Xia, K., Zhou, Y., Fu, Y., Huang, T., & Fan, D. (2023) · Biomedicines · doi:10.3390/biomedicines12010017 · Cited by 6
“Finally, completely ruling out pleiotropy or an alternative direct causal pathway is a challenge for all MR analyses because there are probably some unknown confounders that could influence lacunar stroke [56].”
Background
The role of blood metabolites in oral cancer: insights from a Mendelian randomization approach
Hu, Z., Xu, Z., Qu, Y., Pan, X., Shi, P., Zhang, D., Zhang, J., Deng, R., & Lin, Z. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1305684 · Cited by 7
“Notably, MR is often likened to a “ natural ” randomized controlled trial (RCT) because alleles are randomly distributed during gamete production, possibly minimizing confounders and biases due to reverse causality (12).”
Background
Exploring genetic associations of Crohn’s disease and ulcerative colitis with extraintestinal cancers in European and East Asian populations
Yu, C., Xu, J., Xu, S., Tang, L., Han, Q., Zeng, X., Huang, Y., Yu, T., & Sun, Z. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1339207 · Cited by 7
“Additionally, leave-one-out analysis was performed to assess the impact of a single SNP ’ s removal on the results (42).”
Method
Causal association between depression and intracranial aneurysms: a bidirectional two-sample Mendelian randomization study
Wu, J., Sun, H., & Ma, J. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1346703 · Cited by 6
“We assessed potential heterogeneity with Cochran’s Q (25).”
Method
Causal effect of serum 25 hydroxyvitamin D concentration on cardioembolic stroke: Evidence from two-sample Mendelian randomization
Habibi, D., Teymoori, F., Ebrahimi, N., Fateh, S. T., Bonab, L. N. H., Saeidian, A. H., Taloubaghi, A. S., Asgarian, S., Hosseinpanah, F., Hakonarson, H. H., et al. (2024) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2024.02.013 · Cited by 6
Causal Association Between Diabetes, Body Mass Index and Lichen Sclerosus: A Bidirectional Two-Sample Mendelian Randomization Analysis
Liu, L., Zhang, Q., Chang, J., & Yang, K. (2024) · Clinical Cosmetic and Investigational Dermatology · doi:10.2147/ccid.s450399 · Cited by 6
“16–18 In view of the uncertain causality of the relationships between DM, BMI, and LS, the present study applied MR to evaluate their correlation using data from the large Genome-Wide Association Study (GWAS).”
Method
Genetically predicted fatty liver disease and risk of psychiatric disorders: A mendelian randomization study
Wei-ming, X., Zhang, H.-F., Feng, Y.-H., Li, S.-J., & Xie, B.-Y. (2024) · World Journal of Clinical Cases · doi:10.12998/wjcc.v12.i14.2359 · Cited by 6
“The primary analytical method used to examine causal associations was the random-effect inverse-variance-weighted model[31].”
RETRACTED: Causal effects of genetically determined metabolites on androgenetic alopecia: A two‐sample Mendelian randomization analysis
Du, Y., Lu, C., Bi, L., Wang, C., Zhao, M., Ding, Y., & Fan, W. (2024) · Skin Research and Technology · doi:10.1111/srt.13732 · Cited by 6
Retracted
Bi‐directional two‐sample Mendelian randomization identifies causal association of depression with temporomandibular disorders
Que, H., Zhang, Q., Xu, S., Chu, T., Xu, L., & Wang, Y. (2024) · Journal of Oral Rehabilitation · doi:10.1111/joor.13771 · Cited by 6
Female genital prolapse and risk of psychiatric disorders: A two-sample Mendelian randomization analysis
Zhou, Q., Guo, Y., Lu, L., Lu, M., Li, G., & Peng, G.-L. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.08.196 · Cited by 5
Causal association between glaucoma and risk of retinal vascular occlusion: a Mendelian randomization study
Wang, Z., Xu, K., Zhang, X., Wei, R., & Li, Z. (2024) · Journal of International Medical Research · doi:10.1177/03000605241286985 · Cited by 6
Causal Effects of Circulating Cytokines on the Risk of Psoriasis Vulgaris: A Mendelian Randomization Study
Zhao, P., Zhang, J., Liu, B., Tang, Y., Wang, L., Wang, G., Wu, H., Yang, C., Li, X., & Li, B. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.941961 · Cited by 6
Causal effects of serum sex hormone binding protein levels on the risk of amyotrophic lateral sclerosis: a mendelian randomization study
Ou, Y., Liu, Y., Wu, B., Tan, L., & Yu, J. (2022) · Annals of Translational Medicine · doi:10.21037/atm-22-1156 · Cited by 5
“MR-Egger regression is not constrained to have a slope of zero; therefore, its causal estimate represents a genotype-outcome dose-response relationship that takes pleiotropic effects into account (26,28) .”
A Mendelian randomization study of the effect of tea intake on breast cancer
Deng, Y., Ge, W., Xu, H., & Zhang, J. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.956969 · Cited by 6
Maternal genetic risk for depression and child human capital
Menta, G., Lepinteur, A., Clark, A. E., Ghislandi, S., & D’Ambrosio, C. (2022) · Journal of Health Economics · doi:10.1016/j.jhealeco.2022.102718 · Cited by 7
“Genetic variants can be used as a conditionally-exogenous source of variation in a variety of contexts, such as Mendelian Randomisation (see Koellinger and De Vlaming, 2019, and Hemani et al. , 2018, for reviews of some recent developments).”
Thyroid Function and the Risk of Atrial Fibrillation
Roberts, J. D. (2019) · JAMA Cardiology · doi:10.1001/jamacardio.2018.4614 · Cited by 6
Bayesian network analysis incorporating genetic anchors complements conventional Mendelian randomization approaches for exploratory analysis of causal relationships in complex dataPreprint
Howey, R., Shin, S.-Y., Relton, C. L., Smith, G. D., & Cordell, H. J. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/639864 · Cited by 7
“In the MR literature a large (and growing) set 96 of sensitivity analyses allow relaxation of some of the assumptions required for 97 identification [32].”
Background
Validation of lipid-related therapeutic targets for coronary heart disease prevention using human geneticsPreprint
Gordillo‐Marañón, M., Zwierzyna, M., Charoen, P., Drenos, F., Chopade, S., Shah, T., Engmann, J., Casas, J. P., Chaturvedi, N., Papacosta, O., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.11.11.377747 · Cited by 6
Using clustering of genetic variants in Mendelian randomization to interrogate the causal pathways underlying multimorbidityPreprint
Liang, X., Mounier, N., Apfel, N., Khalid, S., Frayling, T. M., & Bowden, J. (2023) · medRxiv · doi:10.1101/2023.03.18.23287164 · Cited by 6
“61 62 For example, amajor concern inMR is violation of the exclusion restriction due to pleiotropy, the 63 general phenomenon whereby a SNP affects multiple traits [5] and therefore is associated with 64 the outcome through pathways other than the exposure.”
BackgroundSelf-citation
RE: Exploring the cross-cancer effect of circulating proteins and discovering potential intervention targets for 13 site-specific cancers
Yarmolinsky, J., Tzoulaki, I., Gunter, M. J., Travis, R. C., Smith, G. D., & Smith-Byrne, K. (2024) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djae064 · Cited by 6
Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans
Brigos-Barril, E., Vasallo, C., Farré, X., Morcillo-Suárez, C., Polo-Alonso, S., Rodríguez-Fernández, B., Valenzuela, A., Sarabia, C., Bosch, E., Laayouni, H., et al. (2026) · Nature Ecology & Evolution · doi:10.1038/s41559-026-03140-z · Cited by 6
“This pattern is consistent with a directional influence of disease liability on longevity 27,64 and is also compatible with vertical pleiotropy 65 .”
Central corneal thickness and the risk of primary open-angle glaucoma: a Mendelian randomisation mediation analysis
Katsimpris, A., Baumeister, S., Baurecht, H., Tatham, A. J., & Nolde, M. (2024) · British Journal of Ophthalmology · doi:10.1136/bjo-2023-324996 · Cited by 5
“Moreover, by summing the coefficients of determination (R 2 ) obtained from the associations between the selected SNPs and CCT, we calculated the percentage of variability in CCT that can be accounted for by the selected 24 SNPs.”
Causal Associations Between Sleep Traits and Low Grip Strength: A Bidirectional Mendelian Randomization Study
Tai, Y., Wang, H., Dai, Y., & Liang, Y. (2024) · Nature and Science of Sleep · doi:10.2147/nss.s480491 · Cited by 6
“In the sensitivity analyses, the MR-PRESSO results for chronotype showed rs76277841 played a contradictory role with other SNPs.”
MethodInfluential
Brain multi-omic Mendelian randomisation to identify novel drug targets for gliomagenesis
Thornton, Z. A., Andrews, L., Zhao, H., Zheng, J., Paternoster, L., Robinson, J. W., & Kurian, K. M. (2024) · Human Molecular Genetics · doi:10.1093/hmg/ddae168 · Cited by 6
Adiposity and domain-specific stroke recovery: A Mendelian randomization study
Wang, M., Daghlas, I., Aldridge, C., Zhang, Z., & Ren, Y. (2025) · European Stroke Journal · doi:10.1177/23969873251319916 · Cited by 5
“23,24 The intercept from the MR-Egger regression was used to assess the presence of directional horizontal pleiotropy with a p 0.05 indicating significant pleiotropy.”
Influential
Association of Plasma Angiogenin With Risk of Incident End-Stage Kidney Disease in Individuals With Type 2 Diabetes
Gurung, R. L., Liu, J., Liu, S., Lee, J., Zheng, H., Chan, C., Ang, K., & Lim, S. C. (2025) · Diabetes · doi:10.2337/db24-0699 · Cited by 5
A gut microbiome-kidney-heart axis predictive of future cardiovascular diseases
Chechi, K., Chakaroun, R., Myridakis, A., Forslund, S. K., Fromentin, S., Nielsen, T., Aron‐Wisnewsky, J., Belda, E., Prifti, E., Lassen, P. B., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-69405-0 · Cited by 6
“One of the key sources of potential bias in the MR approach is the violation of exclusion-restriction assumption or phenomenon of horizontal pleiotropy 87 .”
Causal relationship between psoriasis vulgaris and dementia: Insights from Mendelian randomization analysis
Zhang, Z., Xu, W., Zheng, Y., Chen, C., Kang, X., Chen, D., Cheng, F., & Wang, X. (2023) · Experimental Dermatology · doi:10.1111/exd.14984 · Cited by 5
“39 The number of distributions in the MR-PRESSO analysis was set to 1000.”
Method
Association of Chronic Obstructive Pulmonary Disease with Risk of Psychiatric Disorders: A Two-Sample Mendelian Randomization Study
Zhang, Q., Zhang, H., & Xu, Q. (2024) · International Journal of COPD · doi:10.2147/copd.s442725 · Cited by 6
Alzheimer’s disease as a causal risk factor for diabetic retinopathy: a Mendelian randomization study
Ouyang, F., Yuan, P., Ju, Y., Chen, W., Peng, Z., & Xu, H. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1340608 · Cited by 6
An exploration into the causal relationships between educational attainment, intelligence, and wellbeing: an observational and two-sample Mendelian randomisation study
Armitage, J. M., Wootton, R. E., Davis, O. S. P., & Haworth, C. M. A. (2024) · npj Mental Health Research · doi:10.1038/s44184-024-00066-x · Cited by 7
“Fortunately,therearemeasuresthatcanbetakentoimprovethe reliabilityofMR,includingrunningalternativeversionsofMRthatmake differentassumptionsaboutpleiotropy,aswellasmultivariableMR 54 .”
MethodInfluential
Causal association and shared genetics between telomere length and COVID-19 outcomes: New evidence from the latest large-scale summary statistics
Zhang, J., Wen, J., Dai, Z., Zhang, H., Zhang, N., Lei, R., Liu, Z., Luo, P., & Cheng, Q. (2024) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2024.05.012 · Cited by 5
“Thus, the weighted median and MR Egger methods were also employed, as they are more resistant to the effects of horizontal pleiotropy despite a potential reduction in statistical power [42].”
Deciphering the brain-gut axis: elucidating the link between cerebral cortex structures and functional gastrointestinal disorders via integrated Mendelian randomization
Xu, Z., Ning, F., Zhang, X., Wang, Q., Zhang, Y., Guo, Y., & Jia, H. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1398412 · Cited by 6
Mendelian randomization analysis reveals a causal relationship between preterm birth and myopia risk
Lin, B., Chen, L.-L., & Li, D. (2024) · Frontiers in Pediatrics · doi:10.3389/fped.2024.1404184 · Cited by 5
“To clarify further, if the results of the genetic pleiotropy test had shown a P -value 0.05, it would imply the presence of some inextricable association between the variables that could not be eliminated (15).”
BackgroundInfluential
Autoimmune diseases and COPD risk: A Mendelian randomization study
Ma, X., Sun, Y., Mou, H., & Zhang, W. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112791 · Cited by 5
The relationship between metabolite mediated immune regulatory imbalance and the occurrence of malignant tumors of bone and articular cartilage: a Mendelian randomization study
Long, K., Gong, A., Zheng, T., Liu, S., Ying, Z., & Cong, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1433219 · Cited by 5
Using clustering of genetic variants in Mendelian randomization to interrogate the causal pathways underlying multimorbidity from a common risk factor
Liang, X., Mounier, N., Apfel, N., Khalid, S., Frayling, T. M., & Bowden, J. (2024) · Genetic Epidemiology · doi:10.1002/gepi.22582 · Cited by 8
“A major source of excess heterogeneity is undoubtedly horizontal pleiotropy , the phenomenon whereby a variant affects multiple traits and therefore is associated with the outcome through pathways other than via the exposure (Burgess et al., 2019; Hemani et al., 2018).”
Self-citation
Intraocular pressure, primary open-angle glaucoma and the risk of retinal vein occlusion: A Mendelian randomization mediation analysis
Katsimpris, A., Baumeister, S., Voulgari, N., Baurecht, H., Kandarakis, S., & Nolde, M. (2024) · Eye · doi:10.1038/s41433-024-03303-x · Cited by 5
Association between diet-derived antioxidants and asthma: Insights from the NHANES survey 2003–2018 and Mendelian randomization analysis
Chen, L., Chen, C., Lin, M., Li, S., Xue, Y., & Chen, T. (2024) · Heart & Lung · doi:10.1016/j.hrtlng.2024.09.014 · Cited by 5
No genetic causal relationship between lung function and osteoporosis ― evidence from a mendelian randomization study
Jiang, R., Li, Z., Zhang, C., Zhang, G., Luo, F., Qu, Q., Tu, S., Huang, Z., Wang, Z., & Zhang, Z. (2024) · Scientific Reports · doi:10.1038/s41598-024-76116-3 · Cited by 5
“The IVW approach was applied as the main statistical analysis approach, however, it may yield biased estimates when there is directional or unbalanced horizontal pleiotropy 27 .”
Method
Assessing the causal associations of atrial fibrillation with serum uric acid level and gout: insights from a bidirectional mendelian randomization study
Zhu, S., Zhang, M., Cheng, S., Wang, C., & Deng, F. (2024) · BMC Cardiovascular Disorders · doi:10.1186/s12872-024-04319-7 · Cited by 5
Glucagon-like peptide-1 receptor agonists, inflammation, and kidney diseases: evidence from Mendelian randomization
Yao, Y.-X., Tang, C., Si, F., Lv, J., Shi, S.-F., Zhou, S., Liu, L., & Zhang, H. (2025) · Renal Failure · doi:10.1080/0886022x.2025.2478488 · Cited by 5
“When heterogeneity existed, the IVW random effects model was employed, otherwise, the fixed effects model was used [17].”

Authors: Hemani, G., Bowden, J., & Davey Smith, G.
Affiliations: University of Bristol (GB)
MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol
Corresponding author: Hemani, Gibran
ORCID: Hemani, Gibran
Bowden, Jack
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2018-05-16
Volume: 27
Issue: R2
Pages: R195-R208
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/ddy163
PMC: PMC6061876
OpenAlex: W2810852503
Cited by: 1,496
References: 113
Citations by year: 2026: 129 · 2025: 266 · 2024: 422 · 2023: 209 · 2022: 169 · 2021: 131 · 2020: 101 · 2019: 62 · 2018: 7
FWCI: 10.71
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Human Molecular Genetics (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Bristol Research (University of Bristol) (submittedVersion, cc-by)
Funders: Wellcome Trust (208806/Z/17/Z)
Medical Research Council (MC_UU_12013/1)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
Keywords: pleiotropy, Mendelian randomization, horizontal pleiotropy, single nucleotide polymorphisms, causal inference, phenome-wide association study, genetic variants
MeSH terms: Animals, Humans, Phenotype, Genetic Variation, Reproducibility of Results, Genome, Human, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Mendelian Randomization Analysis, Genetic Pleiotropy

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Evaluating the potential role of pleiotropy in Mendelian randomization studies

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