Read the following paper, and answer the questions below:

Heeringa J, van der Kuip DAM, Hofman A, Kors JA, van Herpen G, Stricker BHC, et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. European Heart Journal 2006;27(8):949-53.

Question 1:

(a) What study design does this study employ? [1 mark]

(b) What are the characteristics of this type of study design? [2 marks]

(c) What justification do the authors give for conducting this study? [2 marks]

(d) What is the overall prevalence of atrial fibrillation in (i) men and (ii) women? (You are not required to report 95% confidence intervals) [2 marks]

(e) What is the relative risk of atrial fibrillation in women aged 80-84 compared to women aged 60-64? (You are not required to report 95% confidence intervals) [2 marks]

(f) How would you interpret the relative risk in 1 (e)? [3 marks]

(g) Is the relative risk for this study better described as a risk ratio or a rate ratio? Why? [2 marks]

(h) What is the main conclusion of this paper relating to (i) prevalence of atrial fibrillation and (ii) incidence of atrial fibrillation [2 marks]

(i) The authors note that there are differences in the incidence rate of atrial fibrillation in comparisons with similar population-based studies, like the Framingham Study and the Cardiovascular Health Study. Summarise these differences, and describe the reasons for why the authors think the incidence rate in the Rotterdam Study differs from previous studies. [6 marks]

Question 2:

Heeringa et al. (2006) indicate in the Methods section of the paper that 343 participants were not available for analysis for logistical reasons. Assume that a research assistant has since located the data for these participants, and included them with the existing data so that there are an additional (i) 188 male cases with 12,899 male person years at risk and (ii) 155 female cases with 13,335 female person years at risk.

(a) What is the revised incidence rate (per 1,000 person years) of atrial fibrillation for males? (You are not required to report 95% confidence intervals) [3 marks]

(b) What is the revised incidence rate (per 1,000 person years) of atrial fibrillation for females? (You are not required to report 95% confidence intervals) [3 marks]

Question 3:

Diabetes is a risk factor for atrial fibrillation. In another study using a similar design to Heeringa et al. (2006), researchers investigated the association between diabetes and atrial fibrillation, stratified by sex. These data are given in the table below.

Table: Incidence of Atrial Fibrillation (AF) by diabetes status, stratified by sex

(a) Use the data in the table to assess the association between diabetes and atrial fibrillation, stratified by sex. Is sex best characterised as a confounder or an effect measure modifier of the relationship between diabetes and atrial fibrillation? Explain.  [16 marks]

(b) What is the attributable risk of diabetes in males? [4 marks]

(c) How would you interpret the finding in 3 (b)? [3 marks]

Question 4:

Read the following paper, and answer the questions below:

Wilcox AJ, Lie RT, Solvoll K, Taylor J, McConnaughey DR, Abyholm F, et al. Folic acid supplements and risk of facial clefts: national population based case-control study. BMJ 2007;334(7591):464.

(a) What study design does this study employ? [1 mark]

(b) How does this study design differ from the study design in Question 1? [2 marks]

(c) What justification do the authors provide for conducting this study? [2 marks]

(d) What was the overall adjusted OR of cleft lip with or without cleft palate in those consuming ≥400μg of folic acid per day compared to no consumption of folic acid. [1 mark]

(e) How would you interpret the finding in 4 (d)? [3 marks]

 (f) The authors state that the controls in this study are population-based controls – are they? Why or why not?  [5 marks]

 (g) Reflect upon your answer in (f). The authors could have conveniently recruited controls (those without orofacial clefts, but presenting for other reasons) from the surgical centres at the same time as recruiting cases. What might be the effect of using control participants from the surgical centres on the magnitude of the reported OR between folic acid intake and facial clefts? Would the OR move closer or further away from the null value of 1.00? Explain. [5 marks]

Question 5:

In a study using the same design as Wilcox et al., researchers investigated cleft lip with or without cleft palate by smoking status in those participants who reported consuming folic acid supplements. In this sub-group there were 42 cases of cleft lip with or without cleft palate and 55 controls who were current smokers; and there were 72 cases of cleft lip with or without cleft palate and 190 controls who were non-smokers.

(a) Construct a 2×2 table and calculate an appropriate measure of the strength of association between smoking and cleft lip with or without cleft palate in those who consumed folic acid supplements during pregnancy. [5 marks]

(b) How would you interpret the finding in 5(a)? [3 marks]

(c) What proportion of cleft lip with or without cleft palate in the population is potentially preventable, assuming a causal association between smoking and cleft lip? [4 marks]

Question 6

Table: Data from an observational study of obesity and IHD, stratified by FTO genotype

The data in the table above come from an observational study investigating whether obesity (E) is associated with the incidence of ischaemic heart disease (D). Study subjects were categorised as either obese (E=1) or not obese (E=0), and were assessed for presence (D=1) or absence (D=0) of IHD at follow-up. Participants were also categorised as having the FTO genotype (E*=1 or E*=0), a common genetic variant that has been shown to be strongly associated with obesity. The FTO genotype has no effect on IHD other than through its effect on obesity status. A range of other measured confounders (C) were also collected in this study, to investigate the extent to which the association between obesity and IHD incidence might be attributable to other non-causal factors. FTO genotype is inherited independently of the presence or absence of measured confounders.

Propose a causal diagram that describes how obesity, FTO genotype, and counfounders are associated with IHD. [6 marks]