A Versatile and Efficient Novel Approach for Mendelian Randomization Analysis with Application to Assess the Causal Effect of Fetal Hemoglobin on Anemia in Sickle Cell Anemia
Mendelian randomization (MR) is increasingly employed as a technique to assess the causation of a risk factor on an outcome using observational data. The two-stage least-squares (2SLS) procedure is commonly used to examine the causation using genetic variants as the instrument variables. The validit...
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| Format: | Article |
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MDPI AG
2022-10-01
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| Series: | Mathematics |
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| Online Access: | https://www.mdpi.com/2227-7390/10/20/3743 |
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| author | Janaka S. S. Liyanage Jeremie H. Estepp Kumar Srivastava Sara R. Rashkin Vivien A. Sheehan Jane S. Hankins Clifford M. Takemoto Yun Li Yuehua Cui Motomi Mori Stephen Burgess Michael R. DeBaun Guolian Kang |
| author_facet | Janaka S. S. Liyanage Jeremie H. Estepp Kumar Srivastava Sara R. Rashkin Vivien A. Sheehan Jane S. Hankins Clifford M. Takemoto Yun Li Yuehua Cui Motomi Mori Stephen Burgess Michael R. DeBaun Guolian Kang |
| author_sort | Janaka S. S. Liyanage |
| collection | DOAJ |
| description | Mendelian randomization (MR) is increasingly employed as a technique to assess the causation of a risk factor on an outcome using observational data. The two-stage least-squares (2SLS) procedure is commonly used to examine the causation using genetic variants as the instrument variables. The validity of 2SLS relies on a representative sample randomly selected from a study cohort or a population for genome-wide association study (GWAS), which is not always true in practice. For example, the extreme phenotype sequencing (EPS) design is widely used to investigate genetic determinants of an outcome in GWAS as it bears many advantages such as efficiency, low sequencing or genotyping cost, and large power in detecting the involvement of rare genetic variants in disease etiology. In this paper, we develop a novel, versatile, and efficient approach, namely MR analysis under Extreme or random Phenotype Sampling (MREPS), for one-sample MR analysis based on samples drawn through either the random sampling design or the nonrandom EPS design. In simulations, MREPS provides unbiased estimates for causal effects, correct type I errors for causal effect testing. Furthermore, it is robust under different study designs and has high power. These results demonstrate the superiority of MREPS over the widely used standard 2SLS approach. We applied MREPS to assess and highlight the causal effect of total fetal hemoglobin on anemia risk in patients with sickle cell anemia using two independent cohort studies. A user-friendly Shiny app web interface was implemented for professionals to easily explore the MREPS. |
| first_indexed | 2024-03-09T19:52:09Z |
| format | Article |
| id | doaj.art-663a3c0165484446b5c51efee9ce90f4 |
| institution | Directory Open Access Journal |
| issn | 2227-7390 |
| language | English |
| last_indexed | 2024-03-09T19:52:09Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Mathematics |
| spelling | doaj.art-663a3c0165484446b5c51efee9ce90f42023-11-24T01:06:32ZengMDPI AGMathematics2227-73902022-10-011020374310.3390/math10203743A Versatile and Efficient Novel Approach for Mendelian Randomization Analysis with Application to Assess the Causal Effect of Fetal Hemoglobin on Anemia in Sickle Cell AnemiaJanaka S. S. Liyanage0Jeremie H. Estepp1Kumar Srivastava2Sara R. Rashkin3Vivien A. Sheehan4Jane S. Hankins5Clifford M. Takemoto6Yun Li7Yuehua Cui8Motomi Mori9Stephen Burgess10Michael R. DeBaun11Guolian Kang12Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartments of Global Pediatric Medicine and Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Pediatrics, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA 30322, USADepartment of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADepartment of Biostatistics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USADepartment of Statistics and Probability, Michigan State University, East Lansing, MI 48824, USADepartment of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USAMRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UKDepartment of Pediatrics, Vanderbilt-Meharry Sickle Cell Disease Center of Excellence, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USAMendelian randomization (MR) is increasingly employed as a technique to assess the causation of a risk factor on an outcome using observational data. The two-stage least-squares (2SLS) procedure is commonly used to examine the causation using genetic variants as the instrument variables. The validity of 2SLS relies on a representative sample randomly selected from a study cohort or a population for genome-wide association study (GWAS), which is not always true in practice. For example, the extreme phenotype sequencing (EPS) design is widely used to investigate genetic determinants of an outcome in GWAS as it bears many advantages such as efficiency, low sequencing or genotyping cost, and large power in detecting the involvement of rare genetic variants in disease etiology. In this paper, we develop a novel, versatile, and efficient approach, namely MR analysis under Extreme or random Phenotype Sampling (MREPS), for one-sample MR analysis based on samples drawn through either the random sampling design or the nonrandom EPS design. In simulations, MREPS provides unbiased estimates for causal effects, correct type I errors for causal effect testing. Furthermore, it is robust under different study designs and has high power. These results demonstrate the superiority of MREPS over the widely used standard 2SLS approach. We applied MREPS to assess and highlight the causal effect of total fetal hemoglobin on anemia risk in patients with sickle cell anemia using two independent cohort studies. A user-friendly Shiny app web interface was implemented for professionals to easily explore the MREPS.https://www.mdpi.com/2227-7390/10/20/3743Mendelian randomizationextreme phenotype sequencingcausal inferencegenome-wide association studiesnext generation sequencing studies |
| spellingShingle | Janaka S. S. Liyanage Jeremie H. Estepp Kumar Srivastava Sara R. Rashkin Vivien A. Sheehan Jane S. Hankins Clifford M. Takemoto Yun Li Yuehua Cui Motomi Mori Stephen Burgess Michael R. DeBaun Guolian Kang A Versatile and Efficient Novel Approach for Mendelian Randomization Analysis with Application to Assess the Causal Effect of Fetal Hemoglobin on Anemia in Sickle Cell Anemia Mathematics Mendelian randomization extreme phenotype sequencing causal inference genome-wide association studies next generation sequencing studies |
| title | A Versatile and Efficient Novel Approach for Mendelian Randomization Analysis with Application to Assess the Causal Effect of Fetal Hemoglobin on Anemia in Sickle Cell Anemia |
| title_full | A Versatile and Efficient Novel Approach for Mendelian Randomization Analysis with Application to Assess the Causal Effect of Fetal Hemoglobin on Anemia in Sickle Cell Anemia |
| title_fullStr | A Versatile and Efficient Novel Approach for Mendelian Randomization Analysis with Application to Assess the Causal Effect of Fetal Hemoglobin on Anemia in Sickle Cell Anemia |
| title_full_unstemmed | A Versatile and Efficient Novel Approach for Mendelian Randomization Analysis with Application to Assess the Causal Effect of Fetal Hemoglobin on Anemia in Sickle Cell Anemia |
| title_short | A Versatile and Efficient Novel Approach for Mendelian Randomization Analysis with Application to Assess the Causal Effect of Fetal Hemoglobin on Anemia in Sickle Cell Anemia |
| title_sort | versatile and efficient novel approach for mendelian randomization analysis with application to assess the causal effect of fetal hemoglobin on anemia in sickle cell anemia |
| topic | Mendelian randomization extreme phenotype sequencing causal inference genome-wide association studies next generation sequencing studies |
| url | https://www.mdpi.com/2227-7390/10/20/3743 |
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