Additional file 2 of Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization
Creators: name: Gormley, Mark
name: Dudding, Tom
name: Kachuri, Linda
name: Burrows, Kimberley
name: Chong, Amanda H. W.
name: Martin, Richard M.
name: Thomas, Steven J.
name: Tyrrell, Jessica
name: Ness, Andrew R.
name: Brennan, Paul
name: Munafò, Marcus R.
name: Pring, Miranda
name: Boccia, Stefania
name: Olshan, Andrew F.
name: Diergaarde, Brenda
name: Hung, Rayjean J.
name: Liu, Geoffrey
name: Tajara, Eloiza H.
name: Severino, Patricia
name: Toporcov, Tatiana N.
name: Lacko, Martin
name: Waterboer, Tim
name: Brenner, Nicole
name: Smith, George Davey
name: Vincent, Emma E.
name: Richmond, Rebecca C.
Publisher: name: figshare
Year: 2022
Subjects: subject: Medicine
subject: Sociology
subject: FOS: Sociology
subject: 111714 Mental Health
subject: FOS: Health sciences

description: Additional file 2: Supplementary information and Supplementary Tables and Figures. Table S1. Univariable Mendelian randomization results for age at first sex and number of sexual partners on risk of oropharyngeal cancer using a more stringent r2 &lt; 0.001. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; IVW, inverse variance weighted; SE, standard error; OR, odds ratio; CI, confidence intervals; SNPs, single nucleotide polymorphisms. NSP OR represents the exponential change in odds of oropharyngeal squamous cell carcinoma per SD increase (0.94) in number of sexual partners. AFS OR represents the exponential change in odds of oropharyngeal squamous cell carcinoma per SD change (7.3-month delay) in age at first sex. Table S2. Univariable Mendelian randomization results of age at first sex with HPV seropositivity including sensitivity analyses. Abbreviations: IVW, inverse variance weighted; SE, standard error; OR, odds ratio; CI, confidence intervals; SNPs, single nucleotide polymorphisms. OR represents the exponential change in odds of HPV seropositivity per SD change (7.3-month delay) in age at first sex. GWAS were run for four HPV markers derived from UK Biobank, with HPV16 seropositivity described: if antigen L1 &gt; 175; if antigen E6 &gt; 120 or antigen E7 &gt; 150. Table S3. Mendelian randomization results of number of sexual partners with HPV seropositivity including sensitivity analyses. Abbreviations: IVW, inverse variance weighted; SE, standard error; OR, odds ratio; CI, confidence intervals; SNPs, single nucleotide polymorphisms. OR represents the exponential change in odds of HPV seropositivity per SD increase (0.94) in number of sexual partners. GWAS were run for four HPV markers derived from UK Biobank, with HPV16 seropositivity described: if antigen L1 &gt; 175; if antigen E6 &gt; 120 or antigen E7 &gt; 150. Table S4. Assessing weak instrument bias (F-statistic) and proportion of variance in the phenotype (R2) explained by age at first sex and number of sexual partners genetic instruments. Abbreviations: AFS, age at first sex; NSP, number of sexual partners. Table S5. Assessing heterogeneity and directional pleiotropy of single nucleotide polymorphism effect estimates for age at first sex and number of sexual partners on oropharyngeal cancer risk. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; Q, Cochran’s Q-statistic; df, degrees of freedom; SE, standard error; P, p-value. Table S6. MR-PRESSO outliers detected results for age at first sex and number of sexual partners instruments on oropharyngeal cancer risk. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; Q-stat, Cochran’s Q statistic. Table S7. MR-PRESSO results for age at first sex and number of sexual partners instruments on oropharyngeal cancer risk. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; RSSobs, residual sum of squares observations. Table S8. Outlier corrected results for age at first sex and number of sexual partners instruments on combined oropharyngeal cancer. Abbreviations: IVW, inverse variance weighted; OR, odds ratio; CI, confidence intervals; SNPs, single nucleotide polymorphisms. NSP OR represents the exponential change in odds of oropharyngeal squamous cell carcinoma per SD increase (0.94) in number of sexual partners. AFS OR represents the exponential change in odds of oropharyngeal squamous cell carcinoma per SD change (7.3-month delay) in age at first sex. Table S9. SIMEX correction MR-Egger regression results for age at first sex and number of sexual partners instruments on oropharyngeal cancer risk (where I2 &lt; 0.90). Abbreviations: AFS, age at first sex; NSP, number of sexual partners; I2, I-squared statistic; OR, odds ratio; CI, confidence intervals; P, p-value. Table S10. Univariable Mendelian randomization examining effects of age at first sex on positive and negative controls. Abbreviations: SE, standard error; OR, odds ratio; P, p-value; CI, confidence intervals; AFS, age at first sex. AFS OR represents the exponential change in odds of cervical or lung cancer per SD change (7.3-month delay) in age at first sex. Table S11. Univariable Mendelian randomization examining effects of number of sexual partners on positive and negative controls. Abbreviations: SE, standard error; OR, odds ratio; P, p-value; CI, confidence intervals; NSP, number of sexual partners; NSP OR represents the exponential change in odds of cervical or lung cancer per SD increase (0.94) in number of sexual partners. Table S12. Assessing directional pleiotropy through MR-Egger intercept for univariable MR positive and negative control analyses. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; SE, standard error; P, p-value. Table S13. Assessing heterogeneity of single nucleotide polymorphism effect estimates in inverse variance weighted and MR-Egger regression for univariable MR positive and negative control analyses. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; Q, Cochran’s Q-statistic; IVW, inverse variance weighted; df, degrees of freedom; P, p-value. Table S14. MR-PRESSO outliers detected results for age at first sex and number of sexual partners instruments on positive and negative controls. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; Q-stat, Cochran’s Q statistic. Table S15. Outlier corrected results for age at first sex and number of sexual partners instruments on positive and negative controls. Abbreviations: SE, standard error; OR, odds ratio; P, p-value; CI, confidence intervals; AFS, age at first sex; NSP, number of sexual partners. AFS OR represents the exponential change in odds of cervical or lung cancer per SD change (7.3-month delay) in age at first sex. NSP OR represents the exponential change in odds cervical or lung cancer per SD increase (0.94) in number of sexual partners. Table S16. Causal Analysis Using Summary Effect estimates (CAUSE) results for age at first sex on risk of oropharyngeal cancer. Abbreviations: OPC, oropharyngeal cancer; ELPD, expected log pointwise posterior density; se, standard error; γ (gamma), estimate of causal effect if causal model is correct; η (eta), estimate of correlated pleiotropy; q, proportion of effect due to correlated pleiotropy; CI, confidence intervals; NA, non-applicable. Table S17. Causal Analysis Using Summary Effect estimates (CAUSE) results for number of sexual partners on risk of oropharyngeal cancer. Abbreviations: OPC, oropharyngeal cancer; ELPD, expected log pointwise posterior density; se, standard error; γ (gamma), estimate of causal effect if causal model is correct; η (eta), estimate of correlated pleiotropy; q, proportion of effect due to correlated pleiotropy; CI, confidence intervals; NA, non-applicable. Table S18. Overlapping single nucleotide polymorphisms identified between genetic instruments used in multivariable Mendelian randomization. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; RT, risk tolerance; CSI, comprehensive smoking index; SI, smoking initiation; DPW, drinks per week. Table S19. LD Score Regression results for all exposures. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; CSI, comprehensive smoking index; SI, smoking initiation; DPW, drinks per week; RT, risk tolerance; rg, genetic correlation; SE, bootstrap standard error of genetic correlation, h2 obs = estimated SNP heritability of the second exposure , h2 obs se = bootstrap standard error of the SNP heritability estimate, h2 int = LD score regression intercept for the second exposure, h2 int se = bootstrap standard error of the intercept, gcov int = estimated genetic covariance between exposure 1 and 2, gcov int se = bootstrap standard error of the genetic covariance. Table S20. Assessing directional pleiotropy through MR-Egger intercept for multivariable MR analysis on oropharyngeal cancer. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; SE, standard error; P, p-value; CSI, comprehensive smoking index; SI, smoking initiation; DPW, drinks per week; RT, risk tolerance. Table S21. Bidirectional Mendelian randomization analysis for age at first sex on other risk factors. Abbreviations: AFS, age at first sex; SNP, single nucleotide polymorphism; SE, standard error; CSI, comprehensive smoking index; SI, smoking initiation; DPW, drinks per week; RT, risk tolerance; EA, educational attainment. Table S22. Bidirectional Mendelian randomization analysis for number of sexual partners on other risk factors. Abbreviations: NSP, number of sexual partners; SNP, single nucleotide polymorphism; SE, standard error; CSI, comprehensive smoking index; SI, smoking initiation; DPW, drinks per week; RT, risk tolerance; EA, educational attainment. Table S23. Multivariable Mendelian randomization for age at first sex and number of sexual partners with risk lung cancer. Abbreviations: IVW, inverse variance weighted; OR, odds ratio; CI, confidence intervals; P, p-value; Q-stat, Cochran’s Q statistic; F-stat, conditional F-statistic. AFS OR represents the exponential change in odds of oropharyngeal squamous cell carcinoma per SD change (7.3-month delay) in age at first sex. NSP OR represents the exponential change in odds of oropharyngeal squamous cell carcinoma per SD increase (0.94) in number of sexual partners. Table S24. Assessing directional pleiotropy through MR-Egger intercept for multivariable MR analysis on lung and cervical cancer. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; SE, standard error; P, p-value; CSI, comprehensive smoking index; SI, smoking initiation; DPW, drinks per week; RT, risk tolerance. Figure S1 Forest plots showing Mendelian randomization results for age at first sex and number of sexual partners single nucleotide polymorphisms with risk of oropharyngeal cancer in GAME-ON. Effect estimates are reported on the log odds scale with 95% confidence intervals. A. Age at first sex point estimate represents the exponential change in odds oropharyngeal squamous cell carcinoma per SD change (7.3 month delay) in age at first sex. B. Number of sexual partners point estimate represents the exponential change in odds of oropharyngeal squamous cell carcinoma per SD increase (0.94) in number of sexual partners. Figure S2 Scatter plots for age at first sex and number of sexual partners single nucleotide polymorphisms effect on oropharyngeal cancer in GAME-ON. Scatter plots for A. age at first sex and B. number of sexual partners single nucleotide polymorphisms effect on oropharyngeal cancer in GAME-ON. Coloured lines indicating Mendelian Randomization test as described in the key above. Figure S3 Leave one out plots for age at first sex and number of sexual partners single nucleotide polymorphisms effect on oropharyngeal cancer in GAME-ON. Leave one out plots for A. age at first sex and B. number of sexual partners. Figure S4 Scatter and leave one out plots for age at first sex and number of sexual partners single nucleotide polymorphisms effect on risk of cervical cancer. Scatter and leave one out plots for A. age at first sex and B. number of sexual partners single nucleotide polymorphisms effect on cervical cancer. Coloured lines indicating Mendelian Randomization test as described in the key above. Figure S5 Scatter and leave one out plots for age at first sex and number of sexual partners single nucleotide polymorphisms effect on risk of C. trachomatis seropositivity. Scatter and leave one out plots for A. age at first sex and B. number of sexual partners single nucleotide polymorphisms effect on Chlamydia trachomatis seropositivity. Coloured lines indicating Mendelian Randomization test as described in the key above. Figure S6 Scatter and leave one out plots for age at first sex and number of sexual partners single nucleotide polymorphisms effect on risk of lung cancer. Scatter and leave one out plots for A. age at first sex and B. number of sexual partners single nucleotide polymorphisms effect on lung cancer. Coloured lines indicating Mendelian Randomization test as described in the key above. Figure S7 Scatter and leave one out plots for age at first sex and number of sexual partners single nucleotide polymorphisms effect on risk of oral cancer. Scatter and leave one out plots for A. age at first sex and B. number of sexual partners single nucleotide polymorphisms effect on oral cancer. Coloured lines indicating Mendelian Randomization test as described in the key above. Figure S8 Causal Analysis Using Summary Effect estimates (CAUSE) results for age at first sex on oropharyngeal cancer. Plots showing sharing, causal and expected log pointwise posterior density (ELPD) models for age at first sex on oropharyngeal cancer. Causal Analysis Using Summary Effect estimates (CAUSE) suggests there is relatively similar evidence for sharing (correlated pleiotropy) and causal models compared to the null (no effect) model. Comparing both shared and causal models, there is limited evidence that the causal model fits the data better than the sharing model, indicating that correlated pleiotropy could not be discounted. Gamma, estimate of causal effect if causal model is correct; Eta estimate of correlated pleiotropy. Figure S9 Causal Analysis Using Summary Effect estimates (CAUSE) results for number of sexual partners on oropharyngeal cancer. Plots showing sharing, causal and expected log pointwise posterior density (ELPD) models for number of sexual partners on oropharyngeal cancer. Neither shared nor causal models appear to fit in comparison to the null model, providing limited evidence for a causal effect of number of sexual partners on oropharyngeal cancer risk. Gamma, estimate of causal effect if causal model is correct; Eta estimate of correlated pleiotropy. Figure S10 Heat map of LD Score regression results for all exposures. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; CSI, comprehensive smoking index; SI, smoking initiation; DPW, drinks per week; EA, educational attainment; RT, risk tolerance. Figure S11 Heat map of LD Score regression results for all number of sexual partners and age at first sex on HPV-seropositivity. Abbreviations: AFS, age at first sex; NSP, number of sexual partners; HPV, human papilloma virus. Figure S12 Forest plot showing multivariable Mendelian randomization results for age at first sex and number of sexual partners single nucleotide polymorphisms with risk of lung cancer. Effect estimates on oropharyngeal cancer risk are reported on the log odds scale with 95% confidence intervals. UVMR, univariable Mendelian randomization; MVMR, multivariable Mendelian randomization. A. Age at first sex OR represents the change in odds of lung cancer per SD change (7.3-month delay) in age at first sex. B. Number of sexual partners OR represents the change in odds of lung cancer per SD change (0.94) in number of sexual partners. Comprehensive smoking index (dark orange), smoking initiation (teal blue), alcoholic drinks per week (yellow), risk tolerance (green), educational attainment (light orange). The MVMR effect is the MR effect after accounting for this variable.