Relatives of probands v. relatives of controls
A family design was used to study the genetic and environmental
sources of overlap between the disorders. We compared the risk of
bipolar disorder and schizophrenia in relatives of probands with
ADHD with risk in relatives of matched controls. To each
proband–relative pair, ten randomly selected control–relative pairs
were matched by birth year and gender of both proband and
relative. This method avoids bias introduced by individuals in
the population registries entering the study at different times (left
truncation) and allows equal follow-up periods of the relatives to
the probands and controls.3 Further, to study specifically the effect
of shared genetic and environmental factors, we adjusted for the
potential existence of aetiologically distinct subsyndromes (e.g.
an ADHD plus bipolar disorder subtype) by excluding from the
proband and control groups anyone with schizophrenia or bipolar
disorder, and by excluding relatives of probands or controls with
ADHD. Shared familial (genetic and environmental) risk factors
are indicated when probands with the index disorder have
relatives with the other two disorders but not the index disorder.9
We analysed first-degree and second-degree relatives separately to
assess whether the observed familial association was due to genetic
and/or shared environmental influences. This set of analyses were
based on the following assumptions: first-degree relatives (who
share 50% of their co-segregating genes) are more similar
genetically than second-degree relatives (who share 25% of their
co-segregating genes), and maternal half-siblings are more similar
with regard to shared environmental exposures than paternal halfsiblings
because children continue to live predominantly with
their mother following parental separation.3
To describe associations, we used odds ratios (ORs) with 95%
confidence intervals obtained from conditional logistic regression
models in PROC PHREG in SAS version 9.3 on Unix. When
studying associations within families, confidence intervals were
obtained with a robust sandwich estimator function to adjust
for non-independence (PROC PHREG, covsandwich option).