Selection bias in a male-offspring cohort investigating fecundity: is there reason for concern?

Abstract

STUDY QUESTION Is there risk of selection bias in etiological studies investigating prenatal risk factors of poor male fecundity in a cohort of young men? SUMMARY ANSWER The risk of selection bias is considered limited despite a low participation rate. WHAT IS KNOWN ALREADY Participation rates in studies relying on volunteers to provide a semen sample are often very low. Many risk factors for poor male fecundity are associated with participation status, and as men with low fecundity may be more inclined to participate in studies of semen quality, a risk of selection bias exists. STUDY DESIGN, SIZE, DURATION A population-based follow-up study of 5697 young men invited to the Fetal Programming of Semen Quality (FEPOS) cohort nested within the Danish National Birth Cohort (DNBC), 1998–2019. PARTICIPANTS/MATERIALS, SETTING, METHODS Young men (age range: 18 years, 9 months to 21 years, 4 months) born 1998–2000 by mothers included in the DNBC were invited to participate in FEPOS. In total, 1173 men answered a survey in FEPOS (n = 115 participated partly); of those, 1058 men participated fully by also providing a semen and a blood sample at a clinical visit. Differential selection according to parental baseline characteristics in the first trimester, the sons’ own characteristics from the FEPOS survey, and urogenital malformations and diseases in reproductive organs from the Danish registers were investigated using logistic regression. The influence of inverse probability of selection weights (IPSWs) to investigate potential selection bias was examined using a predefined exposure-outcome association of maternal smoking in the first trimester (yes, no) and total sperm count analysed using adjusted negative binomial regression. A multidimensional bias analysis on the same association was performed using a variety of bias parameters to assess different scenarios of differential selection. MAIN RESULTS AND THE ROLE OF CHANCE Participation differed according to most parental characteristics in first trimester but did not differ according to the prevalence of a urogenital malformation or disease in the reproductive organs. Associations between maternal smoking in the first trimester and male fecundity were similar when the regression models were fitted without and with IPSWs. Adjusting for other potential risk factors for poor male fecundity, maternal smoking was associated with 21% (95% CI: −32% to −9%) lower total sperm count. In the bias analysis, this estimate changed only slightly under realistic scenarios. This may be extrapolated to other exposure-outcome associations. LIMITATIONS, REASONS FOR CAUTION We were unable to directly assess markers of male fecundity for non-participants from, for example an external source and therefore relied on potential proxies of fecundity. We did not have sufficient power to analyse associations between prenatal exposures and urogenital malformations. WIDER IMPLICATIONS OF THE FINDINGS The results are reassuring when using this cohort to identify causes of poor male fecundity. The results may be generalized to other similar cohorts. As the young men grow older, they can be followed in the Danish registers, as an external source, to examine, whether participation is associated with the risk of having an infertility diagnosis. STUDY FUNDING/COMPETING INTEREST(S) The project was funded by the Lundbeck Foundation (R170-2014-855), the Capital Region of Denmark, Medical doctor Sofus Carl Emil Friis and spouse Olga Doris Friis’s Grant, Axel Muusfeldt’s Foundation (2016-491), AP Møller Foundation (16-37), the Health Foundation, Dagmar Marshall’s Fond, Aarhus University and Independent Research Fund Denmark (9039-00128B). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

Sleep duration and biomarkers of fecundity in young men: a cross‐sectional study from a population‐based cohort

“…The major strengths of this study included the large sample size of young men from the general population. Although the participation rate was low (19%), potential selection bias due to non‐participation in the FEPOS cohort has been found to be limited, when investigating associations with biomarkers of fecundity using this cohort 31 . Moreover, the men were young and probably unaware of their fecundity, and we considered potential selection bias due to loss‐to‐follow‐up by applying inverse probability weights using parental baseline characteristics 30 .…”

“…We fitted all models with selection weights using baseline parental characteristics (Table S2) and region of participant invitation (Copenhagen/Aarhus) to consider potential selection bias due to non‐participation, 30 as described in detail elsewhere 31 . Robust standard errors were applied to account for the use of the weights and the clustering of siblings.…”

“…Although the participation rate was low (19%), potential selection bias due to non-participation in the FEPOS cohort has been found to be limited, when investigating associations with biomarkers of fecundity using this cohort. 31 Moreover, the men were young and probably unaware of their fecundity, and we considered potential selection bias due to loss-to-followup by applying inverse probability weights using parental baseline characteristics. 30 Finally, sleep duration did not vary between participants and those, who filled in the survey but did not show up for the clinical examination (n = 115).…”

Maternal intake of folate and folic acid during pregnancy and markers of male fecundity: A population‐based cohort study

“…We adjusted for a number of potential confounding factors in addition to precision variables. Although the participation rate was low (19%), potential selection bias because of non‐participation in the FEPOS cohort is not considered to be of concern 33 . In addition, participation was unrelated to maternal intake of total folate, and we further considered potential selection bias because of loss‐to‐follow‐up by applying inverse probability weights 31 .…”

Timing of puberty in relation to semen characteristics, testicular volume, and reproductive hormones: a cohort study

“…Although this is often seen in studies like the present (26), it includes a potential risk of selection bias. Because most young men were not aware of their fecundity at the age of participation (approximately 19 years), participation is probably unrelated to their semen characteristics and reproductive hormone levels, which reduces the risk of selection bias (27). Still, selection weights were applied to reduce this potential risk (25).…”