Fitness Consequences of Advanced Ancestral Age over Three Generations in Humans

A rapid rise in age at parenthood in contemporary societies has increased interest in reports of higher prevalence of de novo mutations and health problems in individuals with older fathers, but the fitness consequences of such age effects over several generations remain untested. Here, we use extensive pedigree data on seven pre-industrial Finnish populations to show how the ages of ancestors for up to three generations are associated with fitness traits. Individuals whose fathers, grandfathers and great-grandfathers fathered their lineage on average under age 30 were ~13% more likely to survive to adulthood than those whose ancestors fathered their lineage at over 40 years. In addition, females had a lower probability of marriage if their male ancestors were older. These findings are consistent with an increase of the number of accumulated de novo mutations with male age, suggesting that deleterious mutations acquired from recent ancestors may be a substantial burden to fitness in humans. However, possible non-mutational explanations for the observed associations are also discussed

Algorithm linking patients and general practices in Denmark using the Danish National Health Service Register

Maiken Ina Siegismund Kjaersgaard,1 Peter Vedsted,2 Erik Thorlund Parner,1 Bodil Hammer Bech,3 Mogens Vestergaard,2,4 Kaare Rud Flarup,2 Morten Fenger-Grøn,2 1Section for Biostatistics, 2Research Unit for General Practice, 3Section for Epidemiology, 4Section for General Medical Practice, Department of Public Health, Aarhus University, Aarhus, Denmark Background: The patient list system in Denmark assigns virtually all residents to a general practice. Nevertheless, historical information on this link between patient and general practice is not readily available for research purposes. Objectives: To develop, implement, and evaluate the performance of an algorithm linking individual patients to their general practice by using information from the Danish National Health Service Register and the Danish Civil Registration System. Materials and methods: The National Health Service Register contains information on all services provided by general practitioners from 1990 and onward. On the basis of these data and information on migration history and death obtained from the Civil Registration System, we developed an algorithm that allocated patients to a general practice on a monthly basis. We evaluated the performance of the algorithm between 2002 and 2007. During this time period, we had access to information on the link between patients and general practices. Agreement was assessed by the proportion of months for which the algorithm allocated patients to the correct general practice. We also assessed the proportion of all patients in the patient list system for which the algorithm was able to suggest an allocation. Results: The overall agreement between algorithm and patient lists was 98.6%. We found slightly higher agreement for women (98.8%) than for men (98.4%) and lower agreement in the age group 18–34 years (97.1%) compared to all other age groups (≥98.6%). The algorithm had assigned 83% of all patients in the patient list system after 1 year of follow-up, 91% after 2 years of follow-up, and peaked at 94% during the fourth year. Conclusion: We developed an algorithm that enables valid and nearly complete linkage between patients and general practices. The algorithm performs better in subgroups of patients with high health care needs. The algorithm constitutes a valuable tool for primary health care research. Keywords: general practice, medical record linkage, patient list, primary care, register

Adverse pregnancy outcomes after exposure to methylphenidate or atomoxetine during pregnancy

Søren Pauli Bro,1 Maiken Ina Siegismund Kjaersgaard,2 Erik Thorlund Parner,2 Merete Juul Sørensen,3 Jørn Olsen,4 Bodil Hammer Bech,4 Lars Henning Pedersen,4,5 Jakob Christensen,6,7 Mogens Vestergaard11Research Unit and Section for General Practice, Department of Public Health, 2Section for Biostatistics, Department of Public Health, Aarhus University, 3Regional Center for Child and Adolescent Psychiatry, Aarhus University Hospital, 4Section for Epidemiology, Department of Public Health, 5Department of Clinical Medicine – Obstetrics and Gynecology, Aarhus University, 6Department of Clinical Pharmacology, 7Department of Neurology, Aarhus University Hospital, Aarhus, DenmarkObjective: To determine if prenatal exposure to methylphenidate (MPH) or atomoxetine (ATX) increases the risk of adverse pregnancy outcomes in women with attention deficit/hyperactivity disorder (ADHD).Materials and methods: This was a population-based cohort study of all pregnancies in Denmark from 1997 to 2008. Information on use of ADHD medication, ADHD diagnosis, and pregnancy outcomes was obtained from nationwide registers.Results: We identified 989,932 pregnancies, in which 186 (0.02%) women used MPH/ATX and 275 (0.03%) women had been diagnosed with ADHD but who did not take MPH/ATX. Our reference pregnancies had no exposure to MPH/ATX and no ADHD diagnosis. Exposure to MPH/ATX was associated with an increased risk of spontaneous abortion (SA; ie, death of an embryo or fetus in the first 22 weeks of gestation) (adjusted relative risk [aRR] 1.55, 95% confidence interval [CI] 1.03–2.36). The risk of SA was also increased in pregnancies where the mother had ADHD but did not use MPH/ATX (aRR 1.56, 95% CI 1.11–2.20). The aRR of Apgar scores <10 was increased among exposed women (aRR 2.06, 95% CI 1.11–3.82) but not among unexposed women with ADHD (aRR 0.99, 95% CI 0.48–2.05).Conclusion: MPH/ATX was associated with a higher risk of SA, but our study indicated that it may at least partly be explained by confounding by indication. Treatment with MPH/ATX was however associated with low Apgar scores <10, an association not found among women with ADHD who did not use MPH/ATX.Keywords: attention deficit/hyperactivity disorder, ADHD, methylphenidate, atomoxetine, pregnancy outcome