Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization.

BACKGROUND: Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). METHODS: Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. RESULTS: In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p = < 0.001) and increasing NSP (IVW OR = 2.2, 95%CI (1.3, 3.8) per SD, p = < 0.001) on OPC risk. These effects were largely robust to sensitivity analyses accounting for horizontal pleiotropy. However, negative control analysis suggested potential violation of the core MR assumptions and subsequent CAUSE analysis implicated pleiotropy of the genetic instruments used to proxy sexual behaviours. Finally, there was some attenuation of the univariable MR results in the multivariable models (AFS IVW OR = 0.7, 95%CI (0.4, 1.2), p = 0.21; NSP IVW OR = 0.9, 95%CI (0.5 1.7), p = 0.76). CONCLUSIONS: Despite using genetic variants strongly related sexual behaviour traits in large-scale GWAS, we found evidence for correlated pleiotropy. This emphasizes a need for multivariable approaches and the triangulation of evidence when performing MR of complex behavioural traits.

Bedside assessment of quadriceps muscle by ultrasound after admission for acute exacerbations of chronic respiratory disease.

RATIONALE: Hospitalization represents a major event for the patient with chronic respiratory disease. There is a high risk of readmission, which over the longer term may be related more closely to the underlying condition of the patient, such as skeletal muscle dysfunction. OBJECTIVES: We assessed the risk of hospital readmission at 1 year, including measures of lower limb muscle as part of a larger clinical trial. METHODS: Patients hospitalized with an exacerbation of chronic respiratory disease underwent measures of muscle function including quadriceps ultrasound. Independent factors influencing time to hospital readmission or death were identified. Patients were classified into four quartiles based on quadriceps size and compared. MEASUREMENTS AND MAIN RESULTS: One hundred and ninety-one patients (mean age, 71.6 [SD, 9.1] yr) were recruited. One hundred and thirty (68%) were either readmitted or died. Factors associated with readmission or death were age (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.08; P = 0.015), Medical Research Council (MRC) dyspnea grade (OR, 4.57; 95% CI, 2.62-7.95; P < 0.001), home oxygen use (OR, 12.4; 95% CI, 4.53-33.77; P < 0.001), quadriceps (rectus femoris) cross-sectional area (Qcsa) (OR, 0.34; 95% CI, 0.17-0.65; P = 0.001), and hospitalization in the previous year (OR, 4.82; 95% CI, 2.42-9.58; P < 0.001). In the multivariate analyses, home oxygen use (OR, 4.80; 95% CI, 1.68-13.69; P = 0.003), MRC dyspnea grade (OR, 2.57; 95% CI, 1.44-4.59; P = 0.001), Qcsa (OR, 0.46; 95% CI, 0.22-0.95; P = 0.035), and previous hospitalization (OR, 3.04; 95% CI, 1.47-6.29; P = 0.003) were independently associated with readmission or death. Patients with the smallest muscle spent more days in hospital than those with largest muscle (28.1 [SD, 33.9] vs. 12.2 [SD, 23.5] d; P = 0.007). CONCLUSIONS: Smaller quadriceps muscle size, as measured by ultrasound in the acute care setting, is an independent risk factor for unscheduled readmission or death, which may have value both in clinical practice and for risk stratification.