Prostaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2),11^20

& 2000 Harcourt Publishers Ltd

doi:10.1054/plef.2000.0185, available online at http://www.idealibrary.com on

Epidemiology of neurodevelopmental
disorders in children
J. Little
Epidemiology Group, Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK

Summary The epidemiology of mental and behavioural disorders is considered in comparison with spina bifida,
chromosomal anomalies and brain tumours. Descriptive epidemiology is important not only in assessing the frequency of
neurodevelopmental disorders, thereby aiding planning of service provision, but also because variations by geographical
area, over time, and by personal characteristics provide clues regarding etiology.The value of the latter application is
exemplified by research on spina bifida and other neural tube defects (NTDs).The descriptive epidemiology of mental and
behavioural disorders has been less investigated.The descriptive epidemiology of NTDs suggested that diet might be of
etiological importance. Analytical epidemiologic investigation proceeded by testing dietary hypotheses in case-control
and cohort studies. Subsequently, folate supplementation was shown to reduce recurrence risk in a randomized controlled
trial.The analytical epidemiology of other neurodevelopmental disorders is less well understood. Study design issues are
discussed in relation to mental and behavioural disorders. & 2000 Harcourt Publishers Ltd

INTRODUCTION In this paper, aspects of the epidemiology of the mental

A very broad range of disorders may be described as
neurodevelopmental (Table 1). Some are obvious exter-
nally at birth, for example spina bifida, or may be
diagnosed soon after birth by a laboratory test, for
example, chromosomal anomalies. Some become man-
ifest later in childhood, and the diagnosis may take some
time to establish, for example brain tumours. The mental
and behavioural disorders represent `extremes' of con-
tinuous variation in various aspects of learning ability
and social function. It is particularly difficult to define
these disorders because of differences in what is con-
sidered to be `extreme' and because of co-morbidities. It is
useful to consider the epidemiology of these disorders in
childhood because of the need for pediatric, educational
and related services in diagnosis and management. In the
particular context of neoplasms, the predominant sites
and types of cancer observed in childhood differ
substantially from these observed in adult life.
Received 11February 2000
Accepted 17 March 2000
Correspondence to: Professor J. Little, Epidemiology Group, Department of
Medicine and Therapeutics, University of Aberdeen, Foresterhill House
Annexe, Foresterhill, Aberdeen AB25 2ZD, UK.Tel.: +441224 554485; Fax: +44
1224 849153; E-mail: j.little@abdn.ac.uk
and behavioural disorders will be considered in compar-
ison to spina bifida, chromosomal anomalies and brain
tumours.
DESCRIPTIVE EPIDEMIOLOGY
Descriptive epidemiology is the study of the distribution
of disease or health status in populations, and typically
investigates variation and frequency of disorders or
aspects of health status by place, time and person. The
number of cases of a disorder occurring in a population
depends on the size of the population at risk and the
distribution of factors associated with disease occurrence
such as age and gender. Therefore, the measure of
frequency is typically a rate, and sometimes age Ð or
gender-specific rates are presented. In Table 2, data on
the prevalence or incidence rates of a number of
neurodevelopmental disorders in childhood are pre-
sented. In addition to presenting information on the
range of rates reported in the literature, an indication of
the amount of information on which this range is based
is given, together with a comment on geographical
variation.
Spina bifida is a congenital anomaly which is usually
externally obvious at birth. A large number of studies of

& 2000 Harcourt Publishers Ltd Prostaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2), 11^20
12 Little
Table 1 Neurodevelopmental disorders, broad groups as classified in the International Classification of Diseases,10th edition (ICD10)
Group ICD10
Code range
Congenital anomalies Q00^Q99
Neoplasms C00^D48
Diseases of the nervous system G00^G89
Mental and behavioural disorders F00^F99
the prevalence at birth in many different geographical
areas based on multiple sources of ascertainment,
together with studies based on vital records or hospital
series for which there is more potential for ascertainment
to be incomplete or biased, have been carried out.1 There
is marked geographical variation in prevalence at birth,
with the British Isles having represented an area of high
risk. Within the British Isles, the frequency increases from
the south and east to the north and west. This remarkable
pattern of geographical variation was one clue which led
investigators to propose a dietary etiology for spina bifida
and related defects.
For the other types of neurodevelopmental disorder,
the diagnosis tends to be less clear cut and there is a
greater need to base ascertainment on multiple sources or
special surveys. In consequence, there have been fewer
studies of these types of disorder and therefore there is
less possibility to investigate geographical variation.
Based on limited information on the incidence or
prevalence of epilepsy in childhood, the frequency of
this disorder appears to be substantially greater in
developing than in developed countries.2 This difference
has been attributed to parasitic infectious disease.
Investigation of the descriptive epidemiology of dis-
orders such as autism, dyslexia, attention-deficit/hyper-
activity disorder (ADHD), and mental and behavioural
disorders has been bedevilled by differences in definition,
changes in diagnostic criteria and by the small size of
many of the studies. This last problem is in part a
consequence of the need to conduct special surveys in
order to have complete ascertainment in a defined
population. Recently, two stage designs have been
employed in which children who show some signs of
the disorder are identified by a simple questionnaire to
parents or teachers, and more detailed diagnostic instru-
ments are then applied in all those above a certain
threshold and a sub-sample of those below a threshold.3,4
Variation over time
Variation over time in the frequency of neurodevelop-
mental disorders in childhood is summarized in Table 3.
There has been a long-term trend of decline in the
prevalence at birth of spina bifida; this is not entirely
attributable to prenatal diagnosis and is thought to reflect
Prostaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2), 11^20
Examples
Spina bifida, chromosomal anomalies
Brain tumours
Cerebral palsy, epilepsy
Pervasive developmental disorders, hyperkinetic disorders, conduct disorders
improvements in maternal diet in the periconceptional
period.5 This decline has predated recent advice from the
Department of Health and from the Health Education/
Health Promotion Authorities regarding folate intake in
the periconceptional period. Increases in the incidence of
brain tumours in children have been reported.6 In the
USA, the primary sites for which an increase in tumour
incidence has been reported are the brain stem and the
cerebrum, and the increase may reflect much more
widespread use of magnetic resonance imaging (MRI)
from the mid 1980s.7 Thus, the increases appear most
likely to be due to changes in detection. Again, clinical
impression of an increase in the frequency of autism may
be due to changes in referral practice, diagnostic criteria
and increased awareness of the spectrum of related
disorders.8
With regard to seasonal variation, studies of spina
bifida and other types of neural tube defects in the 1960s
and 1970s showed an excess in those conceived towards
the end of winter.9 This has ceased to be apparent and is
interpreted as due to improved year round availability of
vegetables and fruits, i.e. the same dietary improvement
which is thought to have contributed to the long-term
trend of decline in prevalence at birth. Seasonal variation
has been much less studied in relation to other neuro-
developmental disorders in childhood.
Variation by personal characteristics
In the context of descriptive epidemiology, variation in
the frequency of the various types of neurodevelopmen-
tal disorder by personal characteristics refers to char-
acteristics recorded in routinely collected data as distinct
from factors on which information is obtained in ad
hoc studies. For example, deprivation may be assessed
on the basis of census indicators relating to the postcode
of residence of the individual, or on the basis of the
occupation of one or other parent at the time of
birth or diagnosis. The main personal characteristics
considered in the descriptive epidemiology of neurode-
velopmental disorders are gender, maternal age and
deprivation (Table 4). There is a consistent weak female
predominance in spina bifida, and a very marked female
predominance in anencephalus, that is the other major
type of neural tube defect in which the affected infant is
& 2000 Harcourt Publishers Ltd
& 2000 Harcourt Publishers Ltd
Table 2 Frequency of neurodevelopmental disorders in childhood
Category Amount of Measure of Range of reported Comment on Reference
information frequency frequencies geographical variation
Congenital anomalies
Spina bifida Extensive Prevalence per10 000 births Births 0.7^9.3 Marked EUROCAT199730
in Europe1990^4 Births‡IA 2.8^10.0
Chromosomal anomalies Substantial Prevalence per10 000 births Live births12.3^32.6 No clear pattern EUROCAT199730
in Europe1990^4 Live births‡FD‡IA
18.6^36.3
Neoplasms
Brain tumours Substantial Age-standardized incidence 16^41 No clear pattern Parkin et al.199831
per million per year in Europe
Diseases of the nervous system
Cerebral palsy Substantial Prevalence per1000 live births 2 There appears to be little variation Stanley198732;
Rudolph's Pediatrics 199633 ;
Pharoah et al.199834
Epilepsy Limited (for Incidence per100 000 Incidence and prevalence Eisenberg19972;
childhood) in England and Wales several-fold greater in developing Wallace et al.199835
5^9 years 63.2 than in developed countries
10^14 years 53.8
Prevalence per1000
in England and Wales
5^9 years 3.2
10^14 years 4.1
Prostaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2), 11^20

Mental and behavioural disorders

Mental and behavioural 8 surveys in 5 Prevalence (%) 14^20 Moderate^severe psychiatric Brandenburg et al.199036

Epidemiology of neurodevelopmental disorders in children 13

disorders developed disorders detected using different
countries instruments in different age ranges
Schizophrenia Limited Prevalence per10 000 52 Early work appears to have been Rudolph's Pediatrics 199633
limited by confusion about relationship
with autism
Affective illness Limited Point prevalence (%) Rudolph's Pediatrics 199633
prepubertal children 1.5^2.5
adolescents 4^5
Anxiety disorders Little Prevalence (%) 9^21 Interpretation of data appears to be Rudolph's Pediatrics 199633
complicated by changes in classification
Mental retardation Extensive, but Prevalence (%) 3 Comparison complicated by differences Abramowicz & Richardson197537
comparison difficult in definition and classification
IQ550, prevalence per1000 4
Disorders of psychological development
Autism Limited Prevalence per10 000 3^430 Comparison complicated by changes Bryson199638;
in diagnostic criteria, and small size of Wing199739 ;
many studies Costello199640
Dyslexia Limited Prevalence (%) 10
Clumsiness Little Prevalence (%) 6^7
Behavioural and emotional disorders with onset usually occurring in childhood
Hyperkinesis (ADHD) Limited Prevalence (%) 11^18 DSM IV criteria likely to increase Baumgaertel et al.19953;
prevalence cf. DSM III Wolraich et al.19964
Conduct disorders Limited Prevalence (%) 6.5 Fombonne199441
IA, induced abortions; FD fetal deaths; ADHD, attention deficit hyperactivity disorder.
14 Little

Table 3 Variation over time in the frequency of neurodevelopmental disorders in childhood

Category Variation in frequency
Long-term trend Seasonality Reference
Spina bifida Decline Excess in those conceived towards the Elwood and Little19923;
end of winter has ceased to be apparent Little and Elwood19929
Chromosomal anomalies No clear trend. Prenatal diagnosis may have No consistent evidence EUROCAT199730
artificially increased prevalence at birth, by
identifying cases that would have been
miscarried
Brain tumours Increase likely to be due to changes in Sharp et al.19996
ascertainment
Schizophrenia More frequently born during winter and Johnson199942
early spring than during other seasons:
evidence controversial (not clear
whether studies relate to all ages and/or
whether seasonality in live births has
been taken into account)
Autism No clear evidence. Clinical impression of an Little studied; no consistent seasonal Wing19968
increase may be due to changes in referral excess (limited statistical power,
practice, diagnostic criteria and increased denominator population possibly
awareness of spectrum of related disorders suboptimal)
Dyslexia One study suggests early summer peak Fombonne198943;
(comparison group comprised Livingston et al.199344
outpatients with other psychiatric
conditions, not births)

Table 4 Variation in the frequency of neurodevelopmental disorders by gender, maternal age and deprivation
Category Factor Variation Reference
Spina bifida Gender Small female predominance (contrasting with very marked Elwood & Little199245
female predominance in anencephalus)
Maternal age Small effects ö U-shaped relationship observed in some studies Elwood & Little199246
secondary to complex relationships with previous obstetric history
Deprivation Positive association with deprivation in many countries Little & Elwood199247
Chromosomal anomalies Maternal age Increased risk with increasing maternal age EUROCAT199730
Brain tumours Gender Small male excess (1.2:1) Sharp et al.19996;
Maternal age No consistent association Little199948
Deprivation No consistent association
Schizophrenia Gender No marked variation Rudolph's Pediatrics199633
Deprivation May be positive association with deprivation
Autism Gender Marked male predominance (4^5:1) Rudolph's Pediatrics199633
Dyslexia Gender Marked male predominance (4:1) Rudolph's Pediatrics199633
ADHD Gender Male predominance (3:1) Rudolph's Pediatrics199633
ADHD; attention-deficit/hyperactivity disorder.

usually born dead or usually dies soon after birth if the
pregnancy continues to term. By contrast, marked male
predominance has been observed for autism, dyslexia and
ADHD. For the latter disorders, the extent to which
knowledge of the gender of the child influences diagnosis
is unclear. There is a well established association between
increased maternal age and chromosomal anomalies, but
the underlying biological basis is still not understood. No
clear association between maternal age and other types of
neurodevelopmental disorders appears to have been
identified.
ANALYTICAL EPIDEMIOLOGY
Analytical epidemiology is based on hypothesis-testing
studies requiring the collection of detailed data on
individuals. A very important aspect of the hypothesis
testing is the demonstration of the internal validity of a
study by excluding bias, confounding and chance as
possible explanations of the associations observed.
One reason why the data on individuals tend to
be detailed is that these are used in the assessment
of potential confounding of the primary relationship

Prostaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2), 11^20 & 2000 Harcourt Publishers Ltd
 Epidemiology of neurodevelopmental disorders in children 15

under investigation. The major study designs are

behaviour
the randomized controlled trial, the case-control

Parental

*Environmental toxins accumulated in food or breast milk ^ methyl mercury, polychlorinated biphenyls (PCBs), dioxins; LBW, low birth weight; ADHD, attention deficit hyperactivity
study and the cohort study. Investigation of spina
bifida and other neural tube defects in some senses

p
represents a paradigm of analytical epidemiological

RA

p
Disorder in
research in that leads from descriptive epidemiology

Thyroid
stimulated the development of cohort and case-control

compounds child
studies and then a randomized controlled trial which

p
showed that folate supplementation reduced recurrence
risk.10,11

N-nitroso
Factors postulated to be of importance in the etiology
of neurodevelopmental disorders in children are sum-

p
marized in Table 5. Some of these have been investigated
in relation to continuous outcome variables, such as

childhood
neurodevelopmental scores, as distinct from specific

Diet in
disorders.

p
*
The example of the association between maternal
smoking during pregnancy and ADHD/conduct disorders

immunization
in the offspring illustrates some of the difficulties of

Infection/
research in this area. Five cohort and two case-control
studies are available (Table 6).

p
p
p
p
p
Factors postulated to be of importance in the aetiology of neurodevelopmental disorders in children

Cohort studies
trauma
Head

One of the potential strengths of the cohort study design

p
is that diverse outcomes can be investigated in relation to
complications

the exposure or range of exposures on which information

(incl. LBW)

is collected at enrolment. This potential advantage is

Obstetric

illustrated by the studies of Nichols and Chen,12 in which

learning ability, neurological `soft signs' and hyperki-
p
p
p

p
netic±impulsive behaviour were assessed; that of Fergus- p
son et al.,13 in which the outcomes were conduct
Periconceptional or gestational

disorder, substance abuse and depression; and that of

Smoking

Weissman et al.,14 in which conduct disorder, drug abuse

and dependence, ADHD, major depression, anxiety dis-
p
p
p

p
p

order and alcohol dependence or abuse were considered.

CD, conduct disorders; RA, rheumatoid arthritis (`protective').
Nutrient Alcohol

A second strength of the cohort design is that cases and

non-cases are derived from the same source population,
p

minimizing the possibility that associations observed are

due to selection bias. A third strength is that exposure
status

assessment is not influenced by knowledge of outcome.

p
p
p
p

In addition, information on exposure is collected at or

Genetic

near to the time of exposure, and therefore is not subject

factors

to inaccuracies because of poor recall. Potential dis-

p
p
p
p
H
p
p

advantages include 1) changes in exposure between

enrolment and the assessment of outcome may not be
Chromosomal anomalies

taken into account, unless the design provides for

repeated exposure assessment, which imposes logistic
Continuous outcome

difficulties and increases the cost of the study; 2) there

Schizophrenia

may be substantial loss to follow-up during a cohort

Brain tumours
Spina bifida

study. If this is related to exposure or outcome, it may bias

ADHD/CD
Category

variables

disorder;
Dyslexia

the results. For example, if the child of more affluent

Table 5

Autism

parents develops ADHD, the parents may move to an area

near to a special educational facility, whereas this may

& 2000 Harcourt Publishers Ltd Prostaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2), 11^20
16 Little

Table 6 Association between maternal smoking during pregnancy and ADHD/CD in the offspring
Study Design Outcome in offspring Number of RR (95% CI) offspring Dose- Adjusted for
offspring of smokers vs non- response
affected smokers
Nichols & Chen198112 Cohort study of Learning ability, NA Positive association Demographic and
29889 children neurological`soft signs', only for hyper- socioenvironmental
(NCPP), USA hyperkinetic-impulsive kinetic-impulsive variables
behaviour assessed up behaviour
to 7 years
Rantakallio et al.199215 Cohort study of Criminal record by1989 355 1.7 (1.4^2.1) No Social & demographic
boys born in variables
1966, Finland
Milberger et al.199649 Case-control ADHD 140 2.7 (1.1^7.0) SES, maternal IQ &
study of boys ADHD, paternal IQ &
aged 6^17 years, ADHD
USA
Orlebeke et al.199750 Cohort study of Oppositional, NA Higher scores in Birthweight, SES,
1377 twin pairs, aggressive, overactive offspring of mothers maternal age, infant
Netherlands behaviour as assessed who smoked feeding
by Child Behaviour
Checklist at ages 2^3
years
Fergusson et al.199813 Cohort study of Symptoms of CD NA No association Yes, for SES, child-rearing
1022 subjects of substance abuse and when dichotomous CD; no behaviour, parental and
both genders, depression at ages outcomes considered. for other family problems
New Zealand 16^18 years Positive association outcomes
for CD when score
measures of
symptoms used.
Landgren et al.199851 Case-control DAMP 62 2.6 (1.0^6.7) Family history of motor
study, Sweden clumsiness or language
disorder, low
birthweight, SES,
divorce
Weissman et al.199914 Cohort study of Major psychiatric NS CD in boys 3.2 (1.5^6.9) Parental psychiatric
147 offspring disorders at 3 time Drug abuse/ diagnosis, family risk
with parent with points in10-year dependency in girls 5.2 factors, pregnancy,
history of major follow-up (1.6^16.8) birth and early
depression or developmental history
without history ADHD, major
of psychiatric depression, anxiety
illness disorder and alcohol
dependence/abuse
not associated with
maternal smoking
ADHD, attention-deficit/hyperactivity disorder; CD, conduct disorder; RR, relative risk; CI, confidence interval; SES, socioeconomic status;
DAMP, deficits in attention, motor control and perception.

not be the case for less affluent parents. The proportion of
the population which smokes decreases with increasing
affluence. Loss to follow-up of the more affluent might
therefore produce an artifactual association between
smoking and ADHD in this circumstances; 3) cohort
studies typically require collection of exposure informa-
tion from many hundreds or thousands of subjects and
follow-up over several years. In consequence, they are
expensive. In certain circumstances, this problem can be
reduced by restricting the cohort to subjects at high risk
of the disorder of interest, e.g. by studying sibling
recurrence risks; 4) as a consequence of the logistical
problems of cohort studies, the information on potential
confounding factors may be limited. One approach to
solving the logistical problems of cohort studies is to link
records. For example, this was done in the study of
Rantakallio et al.15 There has been debate about the
ethical and legal basis of using sources of information for
purposes other than originally collected. Another issue
relates to the quality of information available in routine
data sets.
Case-control studies
The main strengths of case control studies are 1) that they
are efficient in terms of size and time. Typically they
include hundreds of subjects rather than thousands of
subjects and take about three years to conduct; 2) diverse

Prostaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2), 11^20 & 2000 Harcourt Publishers Ltd
 Epidemiology of neurodevelopmental disorders in children 17

exposures can be assessed, and this enables detailed
assessment of possible confounding; 3) the assessment of
outcome is unlikely to be influenced by knowledge of
exposure (although this possibility cannot entirely be
discounted if a great deal of publicity about a relationship
between exposure and a disorder were to prompt health
officials to examine exposed individuals differently from
non-exposed individuals). The potential weaknesses of
case-control studies are 1) inappropriate control selection
or poor participation of controls may result in selection
bias; 2) when exposure assessment is based on recalled
information, this may be inaccurate. In addition it is
possible that the accuracy of recall differs between cases
and controls, i.e. that there is recall bias. On the basis of
theoretical considerations, it has been shown that recall
bias has to be extreme to influence the results.16±18 In
some studies, recall bias has been assessed by comparing
prospectively collected and recalled information in the
same subjects. These investigations do not provide
evidence of a severe uni-directional bias in recall of
exposure.19
In view of the possible logistic difficulties of collecting
high-quality data on exposure on large numbers of
subjects in a cohort study, and also in the context of
increasing interest in the use of biomarkers of exposure
and of genetic susceptibility in epidemiological studies,
study designs that combine features of cohort and case-
control studies have been proposed. The main designs of
this type are the nested case-control study and the case-
cohort study. In both of these, biological samples and
exposure information are collected from a cohort and are
stored. Later, the biological samples are analyzed for all
cases after a predefined period of follow-up and for a sub-
sample of the cohort. In the nested case-control study, the
sub-sample comprises subjects without the disease of
interest sampled from the cohort at the time each case is
diagnosed. In the case-cohort design, the sub-sample is a
sample of subjects taken at the time of enrolment into the
cohort. It is possible also to collect more detailed
exposure information from cases and the sub-sample of
the cohort. The statistical analysis may be limited either
to the cases and comparison sub-sample, or may be
complemented by inclusion of data from the rest of the
cohort in a two-stage analysis.
In relation to the studies summarized in Table 6, further
issues relate to the wide confidence intervals of the
relative risks observed in some of the studies. This
suggests that the studies had limited statistical power to
detect a relationship between maternal smoking and the
various disorders in the offspring. In interpreting the
results of analytical epidemiological studies, a dose-
response relationship is considered to be positive evi-
dence that an association may be causal. In most of the
studies, the possibility of a dose-response relationship
was not investigated. In regard to potential confounding
factors, most of the studies assessed demographic vari-
ables and socio-economic status. However, it might be
argued that many types of parental lifestyle might be
relevant to the etiology of ADHD/conduct disorders and
that the adjustment may not adequately have dealt with
confounding.
In making causal inference, a number of criteria have
been specified.20,21 One of the most important of these is
consistency of association. It is difficult to integrate the
evidence provided by the studies in Table 6 because of
the different classifications of outcome used. Future
research would benefit from planning of studies using
similar protocols in different geographical areas.
GENETIC SUSCEPTIBILITY
Many of the childhood neurodevelopmental disorders
show evidence of familial aggregation (Table 7). Although
many of these disorders have occurred in association

Table 7 Familial aggregation of neurodevelopmental disorders in childhood

Category Concordance in twins Recurrence risk Risk to offspring Risk to other relatives Reference
or parents
Like sex/ Unlike 1 affected 2 affected
MZ sex/DZ child children
Spina bifida *8% *5% 3^5% 10% 3^5% Less than to18relatives Little & Nevin199252
but greater than to
general population
;
>
>
>
=
>
>
>
9

Brain tumours 4% Raised risk of ? Raised risk of ? Little199948

cancer in sibs cancer
Autism *60% 3% 3% ? ? 28 relatives: 0.2% Lombrosso et al.199453;
38 relatives: 0.1% Bailey et al.199554;
Szatmari et al.199855
;
>
>
>
>
>
>
>
>
>
>
>
>
>
>
>
>
>
=
>
>
>
>
>
>
>
>
>
>
>
>
>
>
>
>
>
9

Reading disability 30^80% *35% 41% ? Cantwell199656

ADHD 51% 33% Increased ? ? ? Ryan199957
frequency
MZ, monozygotic; DZ, dizygotic; ADHD, attention-deficit/hyperactivity disorder.

& 2000 Harcourt Publishers Ltd Prostaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2), 11^20
18 Little
Table 8 Genetic susceptibility polymorphisms compared with monogenic disorders
Factor Susceptibility polymorphism
Gene frequency Common (41%)
Penetrance Low
Absolute/relative risk Low
Population attributable risk High
Role of environment Critical
Study setting Population
Study type Association
Modified from Caporaso.28
with specific genetic syndromes, these syndromes
account only for a small fraction of cases in each category,
and do not account for the observed familial aggregation.
In addition, the familial aggregation is greater than can be
accounted for by familial aggregation of environmental
exposures.22 Therefore, it is possible that the familial
aggregation is to a large extent attributable to gene-
environment and gene±gene interactions. In relation to
gene-environment interaction, the characteristics of
genetic susceptibility polymorphisms are compared with
monogenic disorders in Table 8. The relationship between
genetic susceptibility polymorphisms and chronic dis-
orders is attracting increasing emphasis.23,24 In relation to
spina bifida and other neural tube defects, considerable
work has been done on the 5,10-methylene-tetrahydro-
folate reductase (MTHFR) polymorphism.25 In relation to
other neurodevelopmental disorders in childhood, poly-
morphisms associated with factors affected by therapeu-
tic agents have been investigated, notably the serotonin
transporter gene (5-HTT) in relation to autism26 and the
dopamine transporter gene (DAT1) in relation to ADHD.27
In the cancer field in particular, polymorphisms of the
genes controlling enzymes important in phase I and
phase II metabolism have been investigated, particularly
in the context of possible interactions with tobacco
smoke and alcohol.28 In terms of planning future
research, it is important to consider that in the presence
of an interaction between genetic and environmental
factors, failure to take both sets of factors into account
leads to bias in the estimation of disease risk.29
CONCLUSION
In conclusion, epidemiological investigation of neurode-
velopmental disorders in childhood has been complicated
by difficulties in classification and diagnosis. These have
impeded clarification of geographical and time variations
in frequency, and the consideration of these patterns in
developing hypotheses about etiology. In regard to
analytical epidemiological studies, there are a number
of methodological issues which need to be taken into
account in attempting to make any synthesis of the
evidence or in planning of future research. These include
1) exposure assessment in the context of cohort and case-
Prostaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2), 11^20
Monogenic disorder
Rare
High
High
Low
Modest
Family
Linkage
control studies, and consideration of the fact that
both the intrauterine and postnatal environment
may be relevant; 2) potential confounding, particularly
in view of the close interrelationships of many aspects of
lifestyle; 3) statistical power; and 4) gene-environment
interaction.
No one study will demonstrate the cause of any specific
neurodevelopmental disorder in childhood. Causal infer-
ence requires integration of evidence from many studies
and from different disciplines. Consideration of the
principles of causal inference suggests that when plan-
ning future studies of the etiology of neurodevelopmen-
tal disorders in childhood, it would be appropriate to
consider multicentre, multidisciplinary research with a
view to carrying out combined analysis with exploration
of heterogeneity of results between centres. The further
application of the results of these studies to primary
prevention will also require evaluation.
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Little J., Elwood J. H., eds. Epidemiology and Control of Neural
Tube Defects. Oxford University Press, Oxford 1992; 96±145.
2. Eisenberg L. Global burden of disease. Lancet 1997; 350: 143.
3. Baumgaertel A., Wolraich M. L., Dietrich M. Comparison of
diagnostic criteria for attention deficit disorders in a German
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