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Epidemiology of neurodevelopmental disorders in children
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 A very broad range of disorders may be described as neurodevelopmental (Table 1). Some are obvious externally at birth, for example spina bifida, or may be diagnosed soon after birth by a laboratory test, for example, chromosomal anomalies. Some become manifest later in childhood, and the diagnosis may take some time to establish, for example brain tumours. The mental and behavioural disorders represent `extremes' of continuous variation in various aspects of learning ability and social function. It is particularly difficult to define these disorders because of differences in what is considered 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: [email protected]
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In this paper, aspects of the epidemiology of the mental and behavioural disorders will be considered in comparison 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 presented. 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
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Table 1 Neurodevelopmental disorders, broad groups as classified in the International Classification of Diseases,10th edition (ICD10) Group
ICD10 Code range
Examples
Congenital anomalies Neoplasms Diseases of the nervous system Mental and behavioural disorders
Q00^Q99 C00^D48 G00^G89 F00^F99
Spina bifida, chromosomal anomalies Brain tumours Cerebral palsy, epilepsy Pervasive developmental disorders, hyperkinetic disorders, conduct disorders
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 disorders such as autism, dyslexia, attention-deficit/hyperactivity 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 instruments 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 neurodevelopmental 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
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 neurodevelopmental disorders in childhood.
Variation by personal characteristics In the context of descriptive epidemiology, variation in the frequency of the various types of neurodevelopmental disorder by personal characteristics refers to characteristics 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 neurodevelopmental 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
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Table 2
Frequency of neurodevelopmental disorders in childhood Amount of information
Measure of frequency
Range of reported frequencies
Comment on geographical variation
Reference
Congenital anomalies Spina bifida
Extensive
EUROCAT199730
Substantial
Births 0.7^9.3 BirthsIA 2.8^10.0 Live births12.3^32.6 Live birthsFDIA 18.6^36.3
Marked
Chromosomal anomalies
Prevalence per10 000 births in Europe1990^4 Prevalence per10 000 births in Europe1990^4
No clear pattern
EUROCAT199730
Neoplasms Brain tumours
Substantial
Age-standardized incidence per million per year in Europe
16^41
No clear pattern
Parkin et al.199831
Diseases of the nervous system Cerebral palsy
Substantial
Prevalence per1000 live births
2
There appears to be little variation
Limited (for childhood)
Incidence per100 000 in England and Wales 5^9 years 10^14 years Prevalence per1000 in England and Wales 5^9 years 10^14 years
Stanley198732; Rudolph's Pediatrics 199633 ; Pharoah et al.199834 Eisenberg19972; Wallace et al.199835
Category
Epilepsy
Schizophrenia
8 surveys in 5 developed countries Limited
Affective illness
Limited
Anxiety disorders
Little
Mental retardation
Extensive, but comparison difficult
3.2 4.1
Prevalence (%)
14^20
Prevalence per10 000
52
Point prevalence (%) prepubertal children adolescents Prevalence (%)
1.5^2.5 4^5 9^21
Prevalence (%)
3
IQ550, prevalence per1000
4
Disorders of psychological development Autism Limited
Prevalence per10 000
3^430
Dyslexia Clumsiness
Prevalence (%) Prevalence (%)
10 6^7
Limited Little
Behavioural and emotional disorders with onset usually occurring in childhood Hyperkinesis (ADHD) Limited Prevalence (%)
11^18
Conduct disorders
6.5
Limited
Prevalence (%)
IA, induced abortions; FD fetal deaths; ADHD, attention deficit hyperactivity disorder.
Moderate^severe psychiatric disorders detected using different instruments in different age ranges Early work appears to have been limited by confusion about relationship with autism
Brandenburg et al.199036 Rudolph's Pediatrics 199633 Rudolph's Pediatrics 199633
Interpretation of data appears to be complicated by changes in classification
Rudolph's Pediatrics 199633
Comparison complicated by differences in definition and classification
Abramowicz & Richardson197537
Comparison complicated by changes in diagnostic criteria, and small size of many studies
Bryson199638; Wing199739 ; Costello199640
DSM IV criteria likely to increase prevalence cf. DSM III
Baumgaertel et al.19953; Wolraich et al.19964 Fombonne199441
Epidemiology of neurodevelopmental disorders in children 13
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Mental and behavioural disorders Mental and behavioural disorders
63.2 53.8
Incidence and prevalence several-fold greater in developing than in developed countries
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Table 3
Variation over time in the frequency of neurodevelopmental disorders in childhood
Category
Variation in frequency
Spina bifida
Long-term trend
Seasonality
Decline
Excess in those conceived towards the Elwood and Little19923; end of winter has ceased to be apparent Little and Elwood19929 No consistent evidence EUROCAT199730
Chromosomal anomalies No clear trend. Prenatal diagnosis may have artificially increased prevalence at birth, by identifying cases that would have been miscarried Brain tumours Increase likely to be due to changes in ascertainment Schizophrenia
Autism
Sharp et al.19996 More frequently born during winter and 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) Little studied; no consistent seasonal excess (limited statistical power, denominator population possibly suboptimal) One study suggests early summer peak (comparison group comprised outpatients with other psychiatric conditions, not births)
No clear evidence. Clinical impression of an increase may be due to changes in referral practice, diagnostic criteria and increased awareness of spectrum of related disorders
Dyslexia
Table 4
Reference
Johnson199942
Wing19968
Fombonne198943; Livingston et al.199344
Variation in the frequency of neurodevelopmental disorders by gender, maternal age and deprivation
Category
Factor
Variation
Reference
Spina bifida
Gender
Elwood & Little199245
Deprivation
Small female predominance (contrasting with very marked female predominance in anencephalus) Small effects ö U-shaped relationship observed in some studies secondary to complex relationships with previous obstetric history Positive association with deprivation in many countries
Chromosomal anomalies
Maternal age
Increased risk with increasing maternal age
EUROCAT199730
Brain tumours
Gender Maternal age Deprivation
Small male excess (1.2:1) No consistent association No consistent association
Sharp et al.19996; Little199948
Schizophrenia
Gender Deprivation
No marked variation May be positive association with deprivation
Rudolph's Pediatrics199633
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
Maternal age
Elwood & Little199246 Little & Elwood199247
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
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p *
p
p p
p p *
p H p p
Spina bifida Chromosomal anomalies Brain tumours Schizophrenia Autism Dyslexia ADHD/CD Continuous outcome variables
p p p p
p p
p p p p
p
p p p p p p p p
Smoking
Nutrient Alcohol status p p p p p p
*Environmental toxins accumulated in food or breast milk ^ methyl mercury, polychlorinated biphenyls (PCBs), dioxins; LBW, low birth weight; ADHD, attention deficit hyperactivity disorder; CD, conduct disorders; RA, rheumatoid arthritis (`protective').
p p
RA Thyroid
N-nitroso Disorder in compounds child Diet in childhood Infection/ immunization Head trauma
Obstetric complications (incl. LBW) Periconceptional or gestational Genetic factors Category
Factors postulated to be of importance in the aetiology of neurodevelopmental disorders in children
One of the potential strengths of the cohort study design is that diverse outcomes can be investigated in relation to the exposure or range of exposures on which information is collected at enrolment. This potential advantage is illustrated by the studies of Nichols and Chen,12 in which learning ability, neurological `soft signs' and hyperkinetic±impulsive behaviour were assessed; that of Fergusson et al.,13 in which the outcomes were conduct disorder, substance abuse and depression; and that of Weissman et al.,14 in which conduct disorder, drug abuse and dependence, ADHD, major depression, anxiety disorder and alcohol dependence or abuse were considered. A second strength of the cohort design is that cases and non-cases are derived from the same source population, minimizing the possibility that associations observed are due to selection bias. A third strength is that exposure assessment is not influenced by knowledge of outcome. In addition, information on exposure is collected at or near to the time of exposure, and therefore is not subject to inaccuracies because of poor recall. Potential disadvantages include 1) changes in exposure between enrolment and the assessment of outcome may not be taken into account, unless the design provides for repeated exposure assessment, which imposes logistic difficulties and increases the cost of the study; 2) there may be substantial loss to follow-up during a cohort study. If this is related to exposure or outcome, it may bias the results. For example, if the child of more affluent parents develops ADHD, the parents may move to an area near to a special educational facility, whereas this may
Table 5
Cohort studies
Parental behaviour
under investigation. The major study designs are the randomized controlled trial, the case-control study and the cohort study. Investigation of spina bifida and other neural tube defects in some senses represents a paradigm of analytical epidemiological research in that leads from descriptive epidemiology stimulated the development of cohort and case-control studies and then a randomized controlled trial which showed that folate supplementation reduced recurrence risk.10,11 Factors postulated to be of importance in the etiology of neurodevelopmental disorders in children are summarized in Table 5. Some of these have been investigated in relation to continuous outcome variables, such as neurodevelopmental scores, as distinct from specific disorders. The example of the association between maternal smoking during pregnancy and ADHD/conduct disorders in the offspring illustrates some of the difficulties of research in this area. Five cohort and two case-control studies are available (Table 6).
p
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Table 6
Association between maternal smoking during pregnancy and ADHD/CD in the offspring
Study
Design
Nichols & Chen198112
Cohort study of Learning ability, 29889 children neurological`soft signs', (NCPP), USA hyperkinetic-impulsive behaviour assessed up to 7 years Cohort study of Criminal record by1989 boys born in 1966, Finland Case-control ADHD study of boys aged 6^17 years, USA Cohort study of Oppositional, 1377 twin pairs, aggressive, overactive Netherlands behaviour as assessed by Child Behaviour Checklist at ages 2^3 years Cohort study of Symptoms of CD 1022 subjects of substance abuse and both genders, depression at ages New Zealand 16^18 years
Rantakallio et al.199215 Milberger et al.199649
Orlebeke et al.199750
Fergusson et al.199813
Outcome in offspring
Number of RR (95% CI) offspring DoseAdjusted for offspring of smokers vs nonresponse affected smokers NA
Positive association only for hyperkinetic-impulsive behaviour
355
1.7 (1.4^2.1)
140
2.7 (1.1^7.0)
SES, maternal IQ & ADHD, paternal IQ & ADHD
NA
Higher scores in offspring of mothers who smoked
Birthweight, SES, maternal age, infant feeding
NA
No association when dichotomous outcomes considered. Positive association for CD when score measures of symptoms used. 2.6 (1.0^6.7)
Landgren et al.199851
Case-control study, Sweden
DAMP
62
Weissman et al.199914
Cohort study of 147 offspring with parent with history of major depression or without history of psychiatric illness
Major psychiatric disorders at 3 time points in10-year follow-up
NS
CD in boys 3.2 (1.5^6.9) Drug abuse/ dependency in girls 5.2 (1.6^16.8) ADHD, major depression, anxiety disorder and alcohol dependence/abuse not associated with maternal smoking
Demographic and socioenvironmental variables No
Social & demographic variables
Yes, for SES, child-rearing CD; no behaviour, parental and for other family problems outcomes
Family history of motor clumsiness or language disorder, low birthweight, SES, divorce Parental psychiatric diagnosis, family risk factors, pregnancy, birth and early developmental history
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 information 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
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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 casecontrol studies have been proposed. The main designs of this type are the nested case-control study and the casecohort 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 subsample 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 Table 7
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 doseresponse relationship is considered to be positive evidence 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 variables 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
Familial aggregation of neurodevelopmental disorders in childhood
Category
Spina bifida
Like sex/ MZ
Unlike sex/DZ
*8%
*5% 4%
Reading disability ADHD
30^80% 51%
3%
1 affected child
2 affected children
3^5%
10%
*35% 33%
Risk to offspring Risk to other relatives or parents
Reference
3^5%
Less than to18relatives Little & Nevin199252 but greater than to general population
Raised risk of ? cancer in sibs
Raised risk of cancer
?
Little199948
3%
?
28 relatives: 0.2% 38 relatives: 0.1%
Lombrosso et al.199453; Bailey et al.199554; Szatmari et al.199855
? ?
Cantwell199656 Ryan199957
?
Increased frequency
9 > > > > > > > > > > > > > > > > > =
*60%
Recurrence risk
> > > > > > > > > > > > > > > > > ;
Autism
9 > > > =
> > > ;
Brain tumours
Concordance in twins
41% ?
?
MZ, monozygotic; DZ, dizygotic; ADHD, attention-deficit/hyperactivity disorder.
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Table 8
Genetic susceptibility polymorphisms compared with monogenic disorders
Factor
Susceptibility polymorphism
Monogenic disorder
Gene frequency Penetrance Absolute/relative risk Population attributable risk Role of environment Study setting Study type
Common (41%) Low Low High Critical Population Association
Rare High High Low Modest Family Linkage
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 geneenvironment 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 disorders 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-tetrahydrofolate reductase (MTHFR) polymorphism.25 In relation to other neurodevelopmental disorders in childhood, polymorphisms associated with factors affected by therapeutic 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
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 inference requires integration of evidence from many studies and from different disciplines. Consideration of the principles of causal inference suggests that when planning future studies of the etiology of neurodevelopmental 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.
REFERENCES
CONCLUSION In conclusion, epidemiological investigation of neurodevelopmental 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 caseProstaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2), 11^20
1. Little J., Elwood J. M. Geographical variation. In: Elwood J. M., 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 elementary school sample. J Am Acad Child Adolesc Psychiatry 1995; 34: 629±638. 4. Wolraich M. L., Hannah J. N., Pinnock T. Y., Baumgaertel A., Brown J. Comparison of diagnostic criteria for attention-deficit hyperactivity disorder in a country-wide sample. J Am Acad Child Adolesc Psychiatry 1996; 35: 319±324. 5. Elwood M., Little J. Secular trends In: Elwood J. M., Little J., Elwood J. H., eds. Epidemiology and control of neural tube defects. Oxford: Oxford University Press 1992; 168±194. 6. Sharp L., Cotton S., Little J. Descriptive epidemiology (IARC Scientific Publications 149) In: Little J., ed. Epidemiology of childhood cancer. Lyon: IARC, 1999; 10±66. 7. Smith M. A., Freidlin B., Gloeckler Ries L. A., Simon R. Trends in reported incidence of primary malignant brain tumours in children in the United States. J Natl Cancer Ins 1998; 90: 1269±1277. 8. Wing L. Autistic spectrum disorders. BMJ 1996; 312: 327±328. 9. Little J., Elwood M. Seasonal variation. In: Elwood J. M., Little J., Elwood J. H., eds. Epidemiology and control of neural tube defects Oxford: Oxford University Press, 1992; 195±246.
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Epidemiology of neurodevelopmental disorders in children 19
10. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338: 131±137. 11. Elwood J. M., Elwood J. H., Little J. Diet. In: Elwood J. M., Little J., Elwood J. H., eds. Epidemiology and control of neural tube defects Oxford: Oxford University Press, 1992; 521±603. 12. Nichols P. L., Chen T. C. Minimal brain disfunction: a prospective study Hillsdale, NJ: Lawerence Erlbaum, 1981. 13. Fergusson D. M., Woodward L. J., Horwood L. J. Maternal smoking during pregnancy and psychiatric adjustment in late adolescence. Arch Gen Psychiatry 1998; 55: 721±727. 14. Weissman M. M., Warner V., Wickramaratne P. J., Kandel D. B. Maternal smoking during pregnancy and psychopathology in offspring followed to adulthood. J Amer Acad Child Adolesc Psychiatry 1999; 38: 892±899. 15. Rantakallio P., Laara E., Isohanni M., Moilanen I. M. Maternal smoking during pregnancy and delinquency of the offspring: an association without causation? Int J Epidemiol 1992; 21: 1106±1113. 16. Drews C. D., Greenland S. The impact of differential recall on the results of case-control studies. Int J Epidemiol 1990; 19: 1107±1112. 17. Swan S. H., Shaw G. M., Schulman J. Reporting and selection bias in case-control studies of congenital malformations. Epidemiology 1992; 3: 356±363. 18. Khoury M. J., James L. M., Erickson J. D. On the use of affected controls to address recall bias in case-control studies of birth defects. Teratology 1994; 49: 273±281. 19. Little J. Ascertainment, registration and assessment of exposure. In: Elwood J. M., Little J., Elwood J. H., eds. Epidemiology and control of neural tube defects. Oxford: Oxford University Press, 1992; 37±95. 20. Hill A. B. The environment and disease: association or causation? Proc R Soc Medicine 1965; 58: 295±300. 21. IARC Working Group. IARC Monographs on the Evaluation of Carcinogenic Risks to Human. (Preamble) Lyon: IARC, 1994. 22. Khoury M. J., Beaty T. H., Liang K. Y. Can familial aggregation of disease be explained by familial aggregation of environmental risk factors? Am J Epidemiol 1988; 127: 674±683. 23. Khoury M. J., Dorman J. S. The human genome epidemiology network. Am J Epidemiol 1998; 148: 1±3. 24. Vineis P., Malats N., Boffetta P. Why study metabolic susceptibility to cancer? In: Vineis P., Malats N., Lang M., d'Errico A., Caporaso N., Cuzick J., Boffetta P, eds. Metabolic polymorphisms and susceptibility to cancer (IARC Scientific Publication 148) Lyon: IARC, 1999; 1±3. 25. Botto L. D., Yang Q. Methylene-tetrahydrofolate reductase (MTHFR) and birth defects. http://www.cdc.gov/genetics/ hugenet/reviews/MTHFR.htm Am J Epidemiol 2000; 151: 862±877. 26. Klauck S. M., Poustka F., Benner A., Lesch K. P., Poustka A. Serotonin transporter (5-HTT) gene variants associated with autism? Human Mol Gen 1997; 6: 2233±2238. 27. Waldman I. D., Rowe D. C., Abramowitz A., Kozel S. T., Mohr J. H., Sherman S. L., Cleveland H. H., Sanders M. L., Stever C. Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children; heterogeneity owing to diagnostic subtype and severity. Am J Hum Genet 1998; 63: 1767±1776. 28. Caporaso N. Genetics of smoking-related cancer and mutagen sensitivity. J Natl Cancer Inst 1999; 91: 1097±1098.
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29. Khoury M. J., Weinstein A., Panny S., Holtzman N. A., Lindsay P. K., Farrel K., Eisenberg M. Maternal cigarette smoking and oral clefts: a population-based study. Am J Public Health 1987; 77: 623±625. 30. EUROCAT Working Group. Surveillance of Congenital Anomalies in Europe 1980±1994. EUROCAT Report 7. Scientific Institute of Public Health-Louis Pasteur, Brussels, 1997. 31. Parkin D. M., Kramarova A., Draper G. J., Masuyer E., Michaelis J., Neglia J., Qureshi S., Stiller C. A. International incidence of childhood cancer. (IARC Scientific Publications 144). Lyon: IARC, 1998. 32. Stanley F. J. The changing face of cerebral palsy. Dev Med Child Neurol 1987; 29: 263±265. 33. Rudolph A. M., Hoffman J. I. E., Rudolph C. D. Rudolph's pediatrics, 20th edn. Connecticut: Appleton and Lange, 1996. 34. Pharoah P. O., Cooke T., Johnson M. A., King R., Mutch L. Epidemiology of cerebral palsy in England and Scotland, 1984±9. Arch Dis Child Fetal Neonatal Ed 1998; 79: F21±F25. 35. Wallace H., Shorvon S., Tallis R. Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2 052 922 and age-specific fertility rates of women with epilepsy. Lancet 1998; 352: 1970±1973. 36. Brandenburg N. A., Friedman R. M., Silver S. E. The epidemiology of childhood psychiatric disorders: prevalence findings from recent studies. J Am Acad Child Adolesc Psychiatry 1990; 29: 76±83. 37. Abramowicz H. K., Richardson S. A. Epidemiology of severe mental retardation in children: Community studies. Am J Ment Defic 1975; 80: 18±39. 38. Bryson S. E. Brief report: epidemiology of autism. J Autism Dev Disord 1996; 26: 165±167. 39. Wing L. The autistic spectrum. Lancet 1997; 350: 1761±1766. 40. Costello E. J. Epidemiology. J Autism Dev Disord 1996; 26: 126±129. 41. Fombonne E. The Chartres study: I. Prevalence of psychiatric disorders among French school-aged children. Br J Psychiatry 1994; 164: 69±79. 42. Johnson W. G. DNA polymorphism-diet-cofactor-development hypothesis and the gene-teratogen model for schizophrenia and other developmental disorders. Am J Med Genet 1999; 88: 311±323. 43. Fombonne E. Season of birth and childhood psychosis. Br J Psychiatry 1989; 155: 655±661. 44. Livingston R., Adam B. S., Bracha H. S. Season of birth and neurodevelopmental disorders: summer birth is associated with dyslexia. J Amer Acad Child Adolesc Psychiatry 1993; 32: 612±616. 45. Elwood M., Little J. Distribution by sex. In: Elwood J. M., Little J., Elwood J. H., eds. Epidemiology and control of neural tube defects. Oxford: Oxford University Press, 1992; 306±323. 46. Elwood M., Little J. Maternal age and reproductive history. In: Elwood J. M., Little J., Elwood J. H., eds. Epidemiology and control of neural tube defects. Oxford: Oxford University Press, 1992; 391±414. 47. Little J., Elwood J. H. Socio-economic status and occupation. In: Elwood J. M., Little J., Elwood J. H. Epidemiology and control of neural tube defects. Oxford: Oxford University Press, 1992; 306± 323. 48. Little J. Epidemiology of childhood cancer. (IARC Scientific Publication No. 149). Lyon: IARC, 1999. 49. Milberger S., Biederman J., Faraone S. V., Chen L., Jones J. Is maternal smoking during pregnancy a risk factor for attention deficit hyperactivity disorder in children. Am J Psychiatry 1996; 153: 1138±1142.
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50. Orlebeke J. F., Knol D. L., Verhulst F. C. Increase in child behaviour problems resulting from maternal smoking during pregnancy. Arch Environ Health 1997; 52: 317±321. 51. Landgren M., Kjellman B., Gillberg C. Attention deficit disorder with developmental co-ordination disorders. Arch Dis Child 1998; 79: 207±212. 52. Little J., Nevin N. Genetic models. In: Elwood J. M., Little J., Elwood J. H. eds. Epidemiology and control of neural tube defects. Oxford: Oxford University Press, 1992; 677±710. 53. Lombroso P. J., Pauls D. L., Leckman J. F. Genetic mechanisms in childhood psychiatry disorders. J Am Acad Child Adolesc Psychiatry 1994; 33: 921±938.
54. Bailey A., Le Couteur A., Gottesman I., et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25: 63±77. 55. Szatmari P., Jones M. B., Zwaigenbaum L., MacLean J. E. Genetics of autism: overview and new directions. J Autism Dev Dis 1998; 28: 351±368. 56. Cantwell D. P. Attention deficit disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1996; 35: 978±987. 57. Ryan S. G. Genetic susceptibility to neurodevelopmental disorders. J Child Neurol 1999; 14: 187±195.
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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 A very broad range of disorders may be described as neurodevelopmental (Table 1). Some are obvious externally at birth, for example spina bifida, or may be diagnosed soon after birth by a laboratory test, for example, chromosomal anomalies. Some become manifest later in childhood, and the diagnosis may take some time to establish, for example brain tumours. The mental and behavioural disorders represent `extremes' of continuous variation in various aspects of learning ability and social function. It is particularly difficult to define these disorders because of differences in what is considered 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: [email protected]
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In this paper, aspects of the epidemiology of the mental and behavioural disorders will be considered in comparison 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 presented. 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
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Table 1 Neurodevelopmental disorders, broad groups as classified in the International Classification of Diseases,10th edition (ICD10) Group
ICD10 Code range
Examples
Congenital anomalies Neoplasms Diseases of the nervous system Mental and behavioural disorders
Q00^Q99 C00^D48 G00^G89 F00^F99
Spina bifida, chromosomal anomalies Brain tumours Cerebral palsy, epilepsy Pervasive developmental disorders, hyperkinetic disorders, conduct disorders
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 disorders such as autism, dyslexia, attention-deficit/hyperactivity 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 instruments 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 neurodevelopmental 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
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 neurodevelopmental disorders in childhood.
Variation by personal characteristics In the context of descriptive epidemiology, variation in the frequency of the various types of neurodevelopmental disorder by personal characteristics refers to characteristics 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 neurodevelopmental 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
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Table 2
Frequency of neurodevelopmental disorders in childhood Amount of information
Measure of frequency
Range of reported frequencies
Comment on geographical variation
Reference
Congenital anomalies Spina bifida
Extensive
EUROCAT199730
Substantial
Births 0.7^9.3 BirthsIA 2.8^10.0 Live births12.3^32.6 Live birthsFDIA 18.6^36.3
Marked
Chromosomal anomalies
Prevalence per10 000 births in Europe1990^4 Prevalence per10 000 births in Europe1990^4
No clear pattern
EUROCAT199730
Neoplasms Brain tumours
Substantial
Age-standardized incidence per million per year in Europe
16^41
No clear pattern
Parkin et al.199831
Diseases of the nervous system Cerebral palsy
Substantial
Prevalence per1000 live births
2
There appears to be little variation
Limited (for childhood)
Incidence per100 000 in England and Wales 5^9 years 10^14 years Prevalence per1000 in England and Wales 5^9 years 10^14 years
Stanley198732; Rudolph's Pediatrics 199633 ; Pharoah et al.199834 Eisenberg19972; Wallace et al.199835
Category
Epilepsy
Schizophrenia
8 surveys in 5 developed countries Limited
Affective illness
Limited
Anxiety disorders
Little
Mental retardation
Extensive, but comparison difficult
3.2 4.1
Prevalence (%)
14^20
Prevalence per10 000
52
Point prevalence (%) prepubertal children adolescents Prevalence (%)
1.5^2.5 4^5 9^21
Prevalence (%)
3
IQ550, prevalence per1000
4
Disorders of psychological development Autism Limited
Prevalence per10 000
3^430
Dyslexia Clumsiness
Prevalence (%) Prevalence (%)
10 6^7
Limited Little
Behavioural and emotional disorders with onset usually occurring in childhood Hyperkinesis (ADHD) Limited Prevalence (%)
11^18
Conduct disorders
6.5
Limited
Prevalence (%)
IA, induced abortions; FD fetal deaths; ADHD, attention deficit hyperactivity disorder.
Moderate^severe psychiatric disorders detected using different instruments in different age ranges Early work appears to have been limited by confusion about relationship with autism
Brandenburg et al.199036 Rudolph's Pediatrics 199633 Rudolph's Pediatrics 199633
Interpretation of data appears to be complicated by changes in classification
Rudolph's Pediatrics 199633
Comparison complicated by differences in definition and classification
Abramowicz & Richardson197537
Comparison complicated by changes in diagnostic criteria, and small size of many studies
Bryson199638; Wing199739 ; Costello199640
DSM IV criteria likely to increase prevalence cf. DSM III
Baumgaertel et al.19953; Wolraich et al.19964 Fombonne199441
Epidemiology of neurodevelopmental disorders in children 13
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Mental and behavioural disorders Mental and behavioural disorders
63.2 53.8
Incidence and prevalence several-fold greater in developing than in developed countries
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Table 3
Variation over time in the frequency of neurodevelopmental disorders in childhood
Category
Variation in frequency
Spina bifida
Long-term trend
Seasonality
Decline
Excess in those conceived towards the Elwood and Little19923; end of winter has ceased to be apparent Little and Elwood19929 No consistent evidence EUROCAT199730
Chromosomal anomalies No clear trend. Prenatal diagnosis may have artificially increased prevalence at birth, by identifying cases that would have been miscarried Brain tumours Increase likely to be due to changes in ascertainment Schizophrenia
Autism
Sharp et al.19996 More frequently born during winter and 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) Little studied; no consistent seasonal excess (limited statistical power, denominator population possibly suboptimal) One study suggests early summer peak (comparison group comprised outpatients with other psychiatric conditions, not births)
No clear evidence. Clinical impression of an increase may be due to changes in referral practice, diagnostic criteria and increased awareness of spectrum of related disorders
Dyslexia
Table 4
Reference
Johnson199942
Wing19968
Fombonne198943; Livingston et al.199344
Variation in the frequency of neurodevelopmental disorders by gender, maternal age and deprivation
Category
Factor
Variation
Reference
Spina bifida
Gender
Elwood & Little199245
Deprivation
Small female predominance (contrasting with very marked female predominance in anencephalus) Small effects ö U-shaped relationship observed in some studies secondary to complex relationships with previous obstetric history Positive association with deprivation in many countries
Chromosomal anomalies
Maternal age
Increased risk with increasing maternal age
EUROCAT199730
Brain tumours
Gender Maternal age Deprivation
Small male excess (1.2:1) No consistent association No consistent association
Sharp et al.19996; Little199948
Schizophrenia
Gender Deprivation
No marked variation May be positive association with deprivation
Rudolph's Pediatrics199633
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
Maternal age
Elwood & Little199246 Little & Elwood199247
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
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p *
p
p p
p p *
p H p p
Spina bifida Chromosomal anomalies Brain tumours Schizophrenia Autism Dyslexia ADHD/CD Continuous outcome variables
p p p p
p p
p p p p
p
p p p p p p p p
Smoking
Nutrient Alcohol status p p p p p p
*Environmental toxins accumulated in food or breast milk ^ methyl mercury, polychlorinated biphenyls (PCBs), dioxins; LBW, low birth weight; ADHD, attention deficit hyperactivity disorder; CD, conduct disorders; RA, rheumatoid arthritis (`protective').
p p
RA Thyroid
N-nitroso Disorder in compounds child Diet in childhood Infection/ immunization Head trauma
Obstetric complications (incl. LBW) Periconceptional or gestational Genetic factors Category
Factors postulated to be of importance in the aetiology of neurodevelopmental disorders in children
One of the potential strengths of the cohort study design is that diverse outcomes can be investigated in relation to the exposure or range of exposures on which information is collected at enrolment. This potential advantage is illustrated by the studies of Nichols and Chen,12 in which learning ability, neurological `soft signs' and hyperkinetic±impulsive behaviour were assessed; that of Fergusson et al.,13 in which the outcomes were conduct disorder, substance abuse and depression; and that of Weissman et al.,14 in which conduct disorder, drug abuse and dependence, ADHD, major depression, anxiety disorder and alcohol dependence or abuse were considered. A second strength of the cohort design is that cases and non-cases are derived from the same source population, minimizing the possibility that associations observed are due to selection bias. A third strength is that exposure assessment is not influenced by knowledge of outcome. In addition, information on exposure is collected at or near to the time of exposure, and therefore is not subject to inaccuracies because of poor recall. Potential disadvantages include 1) changes in exposure between enrolment and the assessment of outcome may not be taken into account, unless the design provides for repeated exposure assessment, which imposes logistic difficulties and increases the cost of the study; 2) there may be substantial loss to follow-up during a cohort study. If this is related to exposure or outcome, it may bias the results. For example, if the child of more affluent parents develops ADHD, the parents may move to an area near to a special educational facility, whereas this may
Table 5
Cohort studies
Parental behaviour
under investigation. The major study designs are the randomized controlled trial, the case-control study and the cohort study. Investigation of spina bifida and other neural tube defects in some senses represents a paradigm of analytical epidemiological research in that leads from descriptive epidemiology stimulated the development of cohort and case-control studies and then a randomized controlled trial which showed that folate supplementation reduced recurrence risk.10,11 Factors postulated to be of importance in the etiology of neurodevelopmental disorders in children are summarized in Table 5. Some of these have been investigated in relation to continuous outcome variables, such as neurodevelopmental scores, as distinct from specific disorders. The example of the association between maternal smoking during pregnancy and ADHD/conduct disorders in the offspring illustrates some of the difficulties of research in this area. Five cohort and two case-control studies are available (Table 6).
p
Epidemiology of neurodevelopmental disorders in children 15
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Table 6
Association between maternal smoking during pregnancy and ADHD/CD in the offspring
Study
Design
Nichols & Chen198112
Cohort study of Learning ability, 29889 children neurological`soft signs', (NCPP), USA hyperkinetic-impulsive behaviour assessed up to 7 years Cohort study of Criminal record by1989 boys born in 1966, Finland Case-control ADHD study of boys aged 6^17 years, USA Cohort study of Oppositional, 1377 twin pairs, aggressive, overactive Netherlands behaviour as assessed by Child Behaviour Checklist at ages 2^3 years Cohort study of Symptoms of CD 1022 subjects of substance abuse and both genders, depression at ages New Zealand 16^18 years
Rantakallio et al.199215 Milberger et al.199649
Orlebeke et al.199750
Fergusson et al.199813
Outcome in offspring
Number of RR (95% CI) offspring DoseAdjusted for offspring of smokers vs nonresponse affected smokers NA
Positive association only for hyperkinetic-impulsive behaviour
355
1.7 (1.4^2.1)
140
2.7 (1.1^7.0)
SES, maternal IQ & ADHD, paternal IQ & ADHD
NA
Higher scores in offspring of mothers who smoked
Birthweight, SES, maternal age, infant feeding
NA
No association when dichotomous outcomes considered. Positive association for CD when score measures of symptoms used. 2.6 (1.0^6.7)
Landgren et al.199851
Case-control study, Sweden
DAMP
62
Weissman et al.199914
Cohort study of 147 offspring with parent with history of major depression or without history of psychiatric illness
Major psychiatric disorders at 3 time points in10-year follow-up
NS
CD in boys 3.2 (1.5^6.9) Drug abuse/ dependency in girls 5.2 (1.6^16.8) ADHD, major depression, anxiety disorder and alcohol dependence/abuse not associated with maternal smoking
Demographic and socioenvironmental variables No
Social & demographic variables
Yes, for SES, child-rearing CD; no behaviour, parental and for other family problems outcomes
Family history of motor clumsiness or language disorder, low birthweight, SES, divorce Parental psychiatric diagnosis, family risk factors, pregnancy, birth and early developmental history
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 information 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
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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 casecontrol studies have been proposed. The main designs of this type are the nested case-control study and the casecohort 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 subsample 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 Table 7
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 doseresponse relationship is considered to be positive evidence 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 variables 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
Familial aggregation of neurodevelopmental disorders in childhood
Category
Spina bifida
Like sex/ MZ
Unlike sex/DZ
*8%
*5% 4%
Reading disability ADHD
30^80% 51%
3%
1 affected child
2 affected children
3^5%
10%
*35% 33%
Risk to offspring Risk to other relatives or parents
Reference
3^5%
Less than to18relatives Little & Nevin199252 but greater than to general population
Raised risk of ? cancer in sibs
Raised risk of cancer
?
Little199948
3%
?
28 relatives: 0.2% 38 relatives: 0.1%
Lombrosso et al.199453; Bailey et al.199554; Szatmari et al.199855
? ?
Cantwell199656 Ryan199957
?
Increased frequency
9 > > > > > > > > > > > > > > > > > =
*60%
Recurrence risk
> > > > > > > > > > > > > > > > > ;
Autism
9 > > > =
> > > ;
Brain tumours
Concordance in twins
41% ?
?
MZ, monozygotic; DZ, dizygotic; ADHD, attention-deficit/hyperactivity disorder.
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Table 8
Genetic susceptibility polymorphisms compared with monogenic disorders
Factor
Susceptibility polymorphism
Monogenic disorder
Gene frequency Penetrance Absolute/relative risk Population attributable risk Role of environment Study setting Study type
Common (41%) Low Low High Critical Population Association
Rare High High Low Modest Family Linkage
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 geneenvironment 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 disorders 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-tetrahydrofolate reductase (MTHFR) polymorphism.25 In relation to other neurodevelopmental disorders in childhood, polymorphisms associated with factors affected by therapeutic 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
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 inference requires integration of evidence from many studies and from different disciplines. Consideration of the principles of causal inference suggests that when planning future studies of the etiology of neurodevelopmental 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.
REFERENCES
CONCLUSION In conclusion, epidemiological investigation of neurodevelopmental 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 caseProstaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2), 11^20
1. Little J., Elwood J. M. Geographical variation. In: Elwood J. M., 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 elementary school sample. J Am Acad Child Adolesc Psychiatry 1995; 34: 629±638. 4. Wolraich M. L., Hannah J. N., Pinnock T. Y., Baumgaertel A., Brown J. Comparison of diagnostic criteria for attention-deficit hyperactivity disorder in a country-wide sample. J Am Acad Child Adolesc Psychiatry 1996; 35: 319±324. 5. Elwood M., Little J. Secular trends In: Elwood J. M., Little J., Elwood J. H., eds. Epidemiology and control of neural tube defects. Oxford: Oxford University Press 1992; 168±194. 6. Sharp L., Cotton S., Little J. Descriptive epidemiology (IARC Scientific Publications 149) In: Little J., ed. Epidemiology of childhood cancer. Lyon: IARC, 1999; 10±66. 7. Smith M. A., Freidlin B., Gloeckler Ries L. A., Simon R. Trends in reported incidence of primary malignant brain tumours in children in the United States. J Natl Cancer Ins 1998; 90: 1269±1277. 8. Wing L. Autistic spectrum disorders. BMJ 1996; 312: 327±328. 9. Little J., Elwood M. Seasonal variation. In: Elwood J. M., Little J., Elwood J. H., eds. Epidemiology and control of neural tube defects Oxford: Oxford University Press, 1992; 195±246.
& 2000 Harcourt Publishers Ltd
Epidemiology of neurodevelopmental disorders in children 19
10. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338: 131±137. 11. Elwood J. M., Elwood J. H., Little J. Diet. In: Elwood J. M., Little J., Elwood J. H., eds. Epidemiology and control of neural tube defects Oxford: Oxford University Press, 1992; 521±603. 12. Nichols P. L., Chen T. C. Minimal brain disfunction: a prospective study Hillsdale, NJ: Lawerence Erlbaum, 1981. 13. Fergusson D. M., Woodward L. J., Horwood L. J. Maternal smoking during pregnancy and psychiatric adjustment in late adolescence. Arch Gen Psychiatry 1998; 55: 721±727. 14. Weissman M. M., Warner V., Wickramaratne P. J., Kandel D. B. Maternal smoking during pregnancy and psychopathology in offspring followed to adulthood. J Amer Acad Child Adolesc Psychiatry 1999; 38: 892±899. 15. Rantakallio P., Laara E., Isohanni M., Moilanen I. M. Maternal smoking during pregnancy and delinquency of the offspring: an association without causation? Int J Epidemiol 1992; 21: 1106±1113. 16. Drews C. D., Greenland S. The impact of differential recall on the results of case-control studies. Int J Epidemiol 1990; 19: 1107±1112. 17. Swan S. H., Shaw G. M., Schulman J. Reporting and selection bias in case-control studies of congenital malformations. Epidemiology 1992; 3: 356±363. 18. Khoury M. J., James L. M., Erickson J. D. On the use of affected controls to address recall bias in case-control studies of birth defects. Teratology 1994; 49: 273±281. 19. Little J. Ascertainment, registration and assessment of exposure. In: Elwood J. M., Little J., Elwood J. H., eds. Epidemiology and control of neural tube defects. Oxford: Oxford University Press, 1992; 37±95. 20. Hill A. B. The environment and disease: association or causation? Proc R Soc Medicine 1965; 58: 295±300. 21. IARC Working Group. IARC Monographs on the Evaluation of Carcinogenic Risks to Human. (Preamble) Lyon: IARC, 1994. 22. Khoury M. J., Beaty T. H., Liang K. Y. Can familial aggregation of disease be explained by familial aggregation of environmental risk factors? Am J Epidemiol 1988; 127: 674±683. 23. Khoury M. J., Dorman J. S. The human genome epidemiology network. Am J Epidemiol 1998; 148: 1±3. 24. Vineis P., Malats N., Boffetta P. Why study metabolic susceptibility to cancer? In: Vineis P., Malats N., Lang M., d'Errico A., Caporaso N., Cuzick J., Boffetta P, eds. Metabolic polymorphisms and susceptibility to cancer (IARC Scientific Publication 148) Lyon: IARC, 1999; 1±3. 25. Botto L. D., Yang Q. Methylene-tetrahydrofolate reductase (MTHFR) and birth defects. http://www.cdc.gov/genetics/ hugenet/reviews/MTHFR.htm Am J Epidemiol 2000; 151: 862±877. 26. Klauck S. M., Poustka F., Benner A., Lesch K. P., Poustka A. Serotonin transporter (5-HTT) gene variants associated with autism? Human Mol Gen 1997; 6: 2233±2238. 27. Waldman I. D., Rowe D. C., Abramowitz A., Kozel S. T., Mohr J. H., Sherman S. L., Cleveland H. H., Sanders M. L., Stever C. Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children; heterogeneity owing to diagnostic subtype and severity. Am J Hum Genet 1998; 63: 1767±1776. 28. Caporaso N. Genetics of smoking-related cancer and mutagen sensitivity. J Natl Cancer Inst 1999; 91: 1097±1098.
& 2000 Harcourt Publishers Ltd
29. Khoury M. J., Weinstein A., Panny S., Holtzman N. A., Lindsay P. K., Farrel K., Eisenberg M. Maternal cigarette smoking and oral clefts: a population-based study. Am J Public Health 1987; 77: 623±625. 30. EUROCAT Working Group. Surveillance of Congenital Anomalies in Europe 1980±1994. EUROCAT Report 7. Scientific Institute of Public Health-Louis Pasteur, Brussels, 1997. 31. Parkin D. M., Kramarova A., Draper G. J., Masuyer E., Michaelis J., Neglia J., Qureshi S., Stiller C. A. International incidence of childhood cancer. (IARC Scientific Publications 144). Lyon: IARC, 1998. 32. Stanley F. J. The changing face of cerebral palsy. Dev Med Child Neurol 1987; 29: 263±265. 33. Rudolph A. M., Hoffman J. I. E., Rudolph C. D. Rudolph's pediatrics, 20th edn. Connecticut: Appleton and Lange, 1996. 34. Pharoah P. O., Cooke T., Johnson M. A., King R., Mutch L. Epidemiology of cerebral palsy in England and Scotland, 1984±9. Arch Dis Child Fetal Neonatal Ed 1998; 79: F21±F25. 35. Wallace H., Shorvon S., Tallis R. Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2 052 922 and age-specific fertility rates of women with epilepsy. Lancet 1998; 352: 1970±1973. 36. Brandenburg N. A., Friedman R. M., Silver S. E. The epidemiology of childhood psychiatric disorders: prevalence findings from recent studies. J Am Acad Child Adolesc Psychiatry 1990; 29: 76±83. 37. Abramowicz H. K., Richardson S. A. Epidemiology of severe mental retardation in children: Community studies. Am J Ment Defic 1975; 80: 18±39. 38. Bryson S. E. Brief report: epidemiology of autism. J Autism Dev Disord 1996; 26: 165±167. 39. Wing L. The autistic spectrum. Lancet 1997; 350: 1761±1766. 40. Costello E. J. Epidemiology. J Autism Dev Disord 1996; 26: 126±129. 41. Fombonne E. The Chartres study: I. Prevalence of psychiatric disorders among French school-aged children. Br J Psychiatry 1994; 164: 69±79. 42. Johnson W. G. DNA polymorphism-diet-cofactor-development hypothesis and the gene-teratogen model for schizophrenia and other developmental disorders. Am J Med Genet 1999; 88: 311±323. 43. Fombonne E. Season of birth and childhood psychosis. Br J Psychiatry 1989; 155: 655±661. 44. Livingston R., Adam B. S., Bracha H. S. Season of birth and neurodevelopmental disorders: summer birth is associated with dyslexia. J Amer Acad Child Adolesc Psychiatry 1993; 32: 612±616. 45. Elwood M., Little J. Distribution by sex. In: Elwood J. M., Little J., Elwood J. H., eds. Epidemiology and control of neural tube defects. Oxford: Oxford University Press, 1992; 306±323. 46. Elwood M., Little J. Maternal age and reproductive history. In: Elwood J. M., Little J., Elwood J. H., eds. Epidemiology and control of neural tube defects. Oxford: Oxford University Press, 1992; 391±414. 47. Little J., Elwood J. H. Socio-economic status and occupation. In: Elwood J. M., Little J., Elwood J. H. Epidemiology and control of neural tube defects. Oxford: Oxford University Press, 1992; 306± 323. 48. Little J. Epidemiology of childhood cancer. (IARC Scientific Publication No. 149). Lyon: IARC, 1999. 49. Milberger S., Biederman J., Faraone S. V., Chen L., Jones J. Is maternal smoking during pregnancy a risk factor for attention deficit hyperactivity disorder in children. Am J Psychiatry 1996; 153: 1138±1142.
Prostaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2), 11^20
20
Little
50. Orlebeke J. F., Knol D. L., Verhulst F. C. Increase in child behaviour problems resulting from maternal smoking during pregnancy. Arch Environ Health 1997; 52: 317±321. 51. Landgren M., Kjellman B., Gillberg C. Attention deficit disorder with developmental co-ordination disorders. Arch Dis Child 1998; 79: 207±212. 52. Little J., Nevin N. Genetic models. In: Elwood J. M., Little J., Elwood J. H. eds. Epidemiology and control of neural tube defects. Oxford: Oxford University Press, 1992; 677±710. 53. Lombroso P. J., Pauls D. L., Leckman J. F. Genetic mechanisms in childhood psychiatry disorders. J Am Acad Child Adolesc Psychiatry 1994; 33: 921±938.
54. Bailey A., Le Couteur A., Gottesman I., et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25: 63±77. 55. Szatmari P., Jones M. B., Zwaigenbaum L., MacLean J. E. Genetics of autism: overview and new directions. J Autism Dev Dis 1998; 28: 351±368. 56. Cantwell D. P. Attention deficit disorder: a review of the past 10 years. J Am Acad Child Adolesc Psychiatry 1996; 35: 978±987. 57. Ryan S. G. Genetic susceptibility to neurodevelopmental disorders. J Child Neurol 1999; 14: 187±195.
Prostaglandins, Leukotrienes and Essential FattyAcids (2000) 63(1/2), 11^20
& 2000 Harcourt Publishers Ltd