ADHD and atopic diseases
van der Schans, Jurjen
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ATTENTION-DEFICIT/HYPERACTIVITY DISORDER: A
SYSTEMATIC REVIEW AND META-ANALYSES
Jurjen van der Schans, Rukiye Çiçek, Tjalling W. de Vries, Eelko Hak, Pieter J. Hoekstra.
Published as: Association of atopic diseases and attention-deficit/hyperactivity disorder: A
systematic review and meta-analyses.Van der Schans J, Çiçek R, de Vries TW, Hak E, Hoekstra PJ. Neurosci Biobehav Rev. 2017 Mar;74(Pt A):139-148.
ABSTRACT
Over the last decades, the hypothesis has been raised that an atopic response could lead to the development of attention-deficit/hyperactivity disorder (ADHD). This study systematically reviews the observational cross-sectional and longitudinal studies that assessed the association between atopic disorders including asthma, atopic eczema, allergic rhinitis, and ADHD in children and adolescents. For longitudinal studies, a weighted Mantel-Haenszel odds ratio of these associations was estimated. The majority of cross-sectional and longitudinal studies reported a statistically significant positive association. The meta-analysis of longitudinal studies revealed an overall weighted odds ratio for asthma of 1.34 (95% confidence interval [CI] 1.24-1.44), 1.32 (95% CI 1.20-1.45) for atopic eczema, and 1.52 (95% CI 1.43-1.63) for allergic rhinitis.
Heterogeneity of study data was low (I2: 0%, p=0.46 and p=0.64, respectively) for both studies
examining asthma and eczema but substantial for rhinitis studies (I2: 82%, p=0.004). This current
systematic review provides strong evidence that ADHD is associated with atopic diseases and that individuals have a 30% to 50% greater chance of developing ADHD compared to controls.
INTRODUCTION
In 1975, the hypothesis was already being raised that different food components that could
also act as allergens in an atopic response could lead to the development of hyperactivity.1
Preliminary evidence suggested therapeutic benefits of a hypoallergenic diet for children with attention-deficit/hyperactivity disorder (ADHD), a childhood-onset neurodevelopmental
disorder. 2-4 Multiple hypotheses have been raised regarding the underlying mechanism of the
association between atopy and ADHD. Besides shared risk factors for both diseases, an increase in the cytokines release caused by an allergic inflammation may affect specific regions in the prefrontal cortex and neurotransmitter systems that are known to play a role in the pathology
of ADHD.5
Over the last decade, multiple cross-sectional studies determined an association between the most common atopic diseases (i.e., asthma, atopic eczema, and allergic rhinitis) and
ADHD.6-9. Atopy often precedes ADHD which is the reason that current reasoning is focused
on the onset of ADHD as a consequence of atopy. However, prospective longitudinal data is minimal, therefore, conclusions about temporality should be made with caution.
Until now, the majority of studies found a positive association between atopy in general
and ADHD.10 Studies focussing on specific atopic diseases remain inconclusive. The systematic
review of Schmitt et al.9, however, concluded that it is not atopy in general but only eczema
that is related to ADHD independent of other atopic diseases. In this review, the authors conclude that this positive association between asthma and ADHD was at least partly confounded by eczema which precedes asthma and allergic rhinitis in the atopic procession.
No association was found between allergic rhinitis and ADHD in the review of Schmitt et al. 9,
however, after that review, multiple studies determined a positive association between asthma
and ADHD independent of eczema11-14. Also multiple recent studies found an association
between allergic rhinitis and ADHD.15-17 Yet, there are still substantial differences in the
quality between the recently published studies and, therefore, the associations of the three independent main atopic diseases with ADHD remains conflicting.
The objective of this study was to systematically review the available evidence of the association between the different atopic diseases such as asthma, eczema, and allergic rhinitis with the onset of ADHD in children and adolescents and to estimate the strength of the association in a meta-analysis.
METHODS
The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement
was followed 18. A checklist of the PRISMA statement can be found in Appendix I in
Supplementary material. In an attempt to first update the review of Schmitt et al.9, a qualitative
data synthesis was performed by systematically reviewing the newly available cross-sectional studies examining the co-occurrence of atopy and ADHD. This was followed by a quantitative data synthesis with regard to the available longitudinal studies: through a meta-analysis, the strength of the association was estimated by pooling the studies with a longitudinal design investigating the presence of atopy and the onset of ADHD.
Selection criteria for eligible studies
Observational studies with the objective to assess the association between one of the three main atopic diseases (i.e., asthma, eczema, and/or allergic rhinitis) and ADHD in children and adolescents (under the age of 18 years old) were included. Any of the atopic diseases were defined as the exposure variable and ADHD as the outcome variable in accordance with the general order of development in children. Studies were included if they examined the prevalence and/or incidence of ADHD in relationship to one or more of the three atopic diseases in children/adolescents. Studies were only included when there was a comparative reference group available either matched or unmatched to the case or exposed group. Any exposure assessment method of asthma, eczema, and/or allergic rhinitis was included. Regarding the outcome measure, any method of assessment of ADHD and/or ADHD symptoms, all types, i.e., predominantly inattentive or predominantly hyperactive-impulsive and the combined type, were included in the narrative review as well as the quantitative meta-analysis. Studies were excluded if there was no quantitative information available on the association between any of the atopic diseases and ADHD. Either crude data on exposure and outcome or the odds ratio of the association between an atopic disease and ADHD needed to be reported. If there was an overlapping or similar dataset used in different published articles, the dataset with the shorter follow-up or substandard study quality was excluded. Studies published only as an abstract, not written in a peer reviewed journal, or not written in English were also excluded.
Search strategy and study selection
Medline, Embase, and PsychINFO were searched from the inception of each database until September 18, 2015. The following search terms were used in combination and modified according to the requirements of the database.
• Attention-Deficit/Hyperactivity Disorder, ADHD, Attention-Deficit Disorder, Hyperkinetic Disorder
• Allergic asthma, Allergic rhinitis, Atopic dermatitis, Eczema, Asthma, Rhinitis, Dermatitis, Conjunctivitis, Urticaria, Immunoglobulin E, Allergy, Allerg*, Atopy, Atopic
The complete search terms are located in Appendix II in Supplementary material. Two authors (JVDS and RC) independently scanned the outcomes of the search based on the abstracts and titles. Those studies according with the eligibility criteria were retrieved as full text and reviewed for inclusion. Disagreement between authors concerning eligibility and inclusion was resolved with a discussion followed by mutual consensus. All references of the included articles were reviewed in order to identify other studies.
Data extraction
The data of each included article, if available, was extracted on a custom-made data form by the first author (JVDS) and checked by the second author (RC). This form comprised information on the study design, study characteristics, crude unadjusted study outcome (2x2 contingency table), study outcome adjusted for confounding factors (odds ratios), information on confounders, and the assessment method of both the atopic disease and ADHD.
Disagreement between authors concerning data extraction was resolved with a discussion followed by mutual consensus. If necessary, data was calculated from the available information in the article. The odds ratios of the association between asthma, eczema, or rhinitis and ADHD were the main outcome variable. If the point estimate of the adjusted outcome was presented as a hazard ratio, the outcome as an odds ratio was interpreted. Although it is noted that the hazard ratio and the odds ratio are different estimates, at low incidence, the hazard
ratio provides a conservative approximation of the odds ratio 19. If there was only information
available on separate types of ADHD, these types were combined into one general ADHD outcome measure. All information was abstracted from the manuscripts; there was no contact with the authors.
Data abstraction for the meta-analysis
The independent association of the three atopic diseases with the development of ADHD
was investigated. Cross-sectional studies do not assess the development of a disease20 and
were, therefore, not informative for the meta-analysis. For this reason, the studies with a cross-sectional design for the meta-analysis were excluded.
With the Cochrane Revman 5.3 software, the relative weight of the outcome data to the total dataset was calculated for each study. In those studies where the outcome was adjusted for confounding factors such as age, gender, and comorbid atopy, the adjusted ORs were utilized to calculate the summary estimate. Crude data were pooled with the random effect model meta-analyses using the generic inverse variance method to determine the weighted Mantel-Haenszel odds ratio with the 95% confidence interval (95% CI). Statistical heterogeneity was
assessed by calculating the I-squared (I2) value. The I2-value represents the total variance of
the pooled estimate explained by the heterogeneity. 21 In accordance with the Cochrane
handbook for systematic reviews of interventions, the I2 thresholds for low (≤40%), moderate
(40%-60%) , substantial(50%-90%), and considerable (≥75%) heterogeneity were established.22
Possible publication bias was assessed by plotting a Funnel plot.
Sensitivity analyses
In addition to the main analyses of the association between atopic diseases and ADHD, a sensitivity analysis was performed in order to estimate the strength of the association in different scenarios. Information regarding the quality of the included studies was determined by using the Cochrane Risk Of Bias Assessment Tool for Non-Randomized Studies of
Interventions (ACROBAT-NRSI). This tool has seven different categories for which the individual studies were evaluated, i.e., bias due to confounding; bias in the selection of participants for the study; bias in the measurement of interventions; bias due to departures from intended interventions; bias due to missing data; bias in the measurement of outcomes; and bias in the selection of the reported result. Per study, each category and an overall judgement about risk of bias was labeled as either being at a low, moderate, serious, or critical risk of bias. As stated in the guideline of the tool, it is rare if a non-randomized study is judged with a low risk of bias due to confounding and, therefore, most studies in this meta-analysis have been judged as having at least a moderate risk. More information on the ACROBAT-NRSI can be found on www.riskofbias.info. A sensitivity analysis was conducted by excluding low quality studies (i.e., those with a high risk of bias: serious or critical as rated by the ACROBAT-NRSI).
Additionally, an overall meta-analysis was performed of all of the atopic diseases combined to illustrate the effect of the general atopic state on the development of ADHD.
RESULTS
Study inclusion
The study selection for the systematic review is presented in a flow diagram (Figure 1). From the 100 studies included for the full text review, 28 studies were included for the qualitative synthesis, which are presented in Table 1 and Table 2. In total, 72 full review articles were excluded for further analysis. The majority of the articles were excluded because: (1) the study was not published as a peer reviewed article (n = 22), (2) the study used cross-sectional data already included in the review of Schmitt et al. (n = 19), (3) there was no quantitative data available in the study for one of the three major atopic diseases (n = 18), or (4) the study population was not focused on children (<18 years of age) (n = 4).
Figure 1. PRISMA Flow diagram of the systematic review
102
Figure 1. PRISMA Flow diagram of the systematic review
Tabl
e 1.
Incl
uded studies published after the re
vie
w of Schmi
tt et al.
loo
king in
to the co-occurrence of ADH
D and differen t a topic diseases. St ud y o ut co m e ( 95 % C I) N umb er of pa rt ic ipa n ts Ag e M et h o d a ss es sm en t at o py Me th od ass ess m en t A D H D C or re ct ion for con fou nd ing A st hm a Bl ac km an 2 01 3 O R 1 .7 (1 .7 -2 .1) 60 ,33 8 6-17 y ea rs Par en tal qu es tio nna ire Par en tal qu es tio nn air e Ye s Ch an g 2 013 N o s ig ni fic an t d iff er en ce i n A D H D s co re b et w ee n a to pi c and no n-at op ic g ro up 55 9 3-7 y ea rs Par en tal qu es tio nna ire Par en tal qu es tio nn air e No Ch en 2 014 O R 3. 15 (2 .6 7-3. 72 )* 9, 44 9 10 -15 y ea rs Ph ys ic ia n d ia gn os is Ph ys ic ia n d ia gn os is No Cho u 2 01 3 OR 1 .54 (1 .13-2. 10 )* 22 1, 06 8 0-17 y ea rs Ph ys ic ia n d ia gn os is Ph ys ic ia n d ia gn os is No G ar g 2 014 O R 3 .3 6 ( 1. 64 -6 .8 7) 27, 55 6 2-5 y ea rs Pa re nt al r ep or t o f ph ys ic ia n d ia gn os is Pa re nt al r ep or t o f ph ys ic ia n d ia gn osi s Ye s H ol m be rg 2 01 5 O R 1 .3 5 ( 0. 97 -1 .8 9) 16 ,4 63 9-12 y ea rs Ph ys ic ia n d ia gn os is Ph ys ic ia n d ia gn os is Ye s Ja m es 2 013 O R 3 .3 9 ( 2. 04 -5 .6 4) 18 ,999 4-6 y ea rs Par en tal qu es tio nna ire Par en tal qu es tio nn air e Ye s Kw on 2 014 O R 1 .6 0 ( 1. 30 -1 .9 6) 4, 11 3 M ea n ( SD ): 7 .7 8 (1 .17 ) Par en tal qu es tio nna ire Ps yc hi at ris t d iag no si s Ye s Li n 2 014 O R 1 .8 1 ( 1. 70 -1 .9 3) 26 ,93 0 0-17 y ea rs Ph ys ic ia n d ia gn os is Ph ys ic ia n d ia gn os is Ye s Sa ric ob an 2 01 1 O R 1 .4 1 ( 0. 39 -5. 15) * 56 6 6-17 y ea rs Pa tie nt w as f ol lo w ed -u p fo r a sth m a i n a ller gy cl ini c Par en tal qu es tio nn air e No Sc hi ev e 2 01 2 O R 1 .9 (1 .7 -2 .2 ) 38 ,6 76 3-17 y ea rs Pa re nt al r ep or t o f ph ys ic ia n d ia gn os is Pa re nt al r ep or t o f ph ys ic ia n d ia gn osi s Ye s Sh yu 20 12 O R 1 .3 8 ( 1. 02 -1 .8 6) 22 6, 55 0 0-17 y ea rs Ph ys ic ia n d ia gn os is Ps yc hi at ris t d iag no si s Ye s Su w an 2 011 O R 1 .3 7 ( 0.3 5-5.3 3) 80 5-15 y ea rs H is to ry a nd p hy si ca l ex ami na tio n Pe dia tr ic ia n di ag nos ed Ye s Ts ai 2 01 4 O R 1 .4 3 ( 1. 05 -1 .9 5) 22 1, 06 8 0-17 y ea rs Ph ys ic ia n d ia gn os is Ph ys ic ia n d ia gn os is Ye s Ec ze m a C amff er m an 2 01 0 O R 1 .8 5 ( 0. 38 -9 .12 )* 10 7 6-1 6 y ea rs A tt en di ng a ller gy a nd der m at ol og y cl ini cs Par en tal qu es tio nn air e No Ch an g 2 013 N o s ig ni fic an t d iff er en ce i n A D H D s co re b et w ee n a to pi c and no n-at op ic g ro up 55 7 3-7 y ea rs Par en tal qu es tio nna ire Par en tal qu es tio nn air e No
Cho u 2 01 3 O R 0 .9 6 (0 .6 2-1. 49 )* 22 1, 06 8 0-17 y ea rs Ph ys ic ia n d ia gn os is Ph ys ic ia n d ia gn os is No G ar g 2 014 O R 3 .8 5 ( 1. 94 -7 .6 4) 27, 56 6 2-5 y ea rs Pa re nt al r ep or t o f ph ys ic ia n d ia gn osi s Pa re nt al r ep or t o f ph ys ic ia n d ia gn os is Ye s Sc hi ev e 2 01 2 O R 1 .7 (1 .5 -1 .9 ) 38 ,6 76 3-17 y ea rs Pa re nt al r ep or t o f ph ys ic ia n d ia gn osi s Pa re nt al r ep or t o f ph ys ic ia n d ia gn os is Ye s Sh yu 20 12 O R 0. 73 (0. 48 -1 .0 9) 22 6, 55 0 0-17 y ea rs Ph ys ic ia n d ia gn os is Ps yc hi at ris t d iag no si s Ye s Su w an 2 011 O R 1 .18 ( 0. 27 -5 .0 3) 80 5-15 y ea rs H is to ry a nd p hy si ca l ex ami na tio n Pe dia tr ic ia n di ag nos ed Ye s Ya ghm ai e 2 01 3 O R m ild 1 .6 6 ( 1. 28 -2 .15 ), m od er at e 1 .7 6 ( 1. 30 -2 .3 8) , sev er e 4 .3 5 ( 2. 73 -6 .9 3) 79 ,6 67 0-17 y ea rs Pa re nt al r ep or t o f ph ys ic ia n d ia gn osi s Pa re nt al r ep or t o f ph ys ic ia n d ia gn os is Ye s R hi ni ti s Ch an g 2 013 N o s ig ni fic an t d iff er en ce i n A D H D s co re b et w ee n a to pi c and no n-at op ic g ro up 55 7 3-7 y ea rs Par en tal qu es tio nna ire Par en tal qu es tio nn air e No Cho u 2 01 3 O R 1 .8 3 ( 1. 48-2.2 7) 22 1, 06 8 0-17 y ea rs Ph ys ic ia n d ia gn os is Ph ys ic ia n d ia gn os is Ye s G ar g 2 014 O R 2 .7 6 ( 1. 24 -6 .16 ) 27, 56 6 2-5 y ea rs Pa re nt al r ep or t o f ph ysi ci an d ia gn osi s Pa re nt al r ep or t o f ph ys ic ia n d ia gn os is Ye s Kw on 2 014 O R 1 .3 8 ( 1.1 2-1. 68 ) 4, 11 3 M ea n ( SD ) 7 .7 8 (1 .17 ) Par en tal qu es tio nna ire Ps yc hi at ris t d iag no si s Ye s Le e 2 014 O R 2 .8 1 ( 1.1 2-7.1 0) * 16 0 6-13 y ea rs D ia gn os is b y a p ed ia tr ic al le rg is t (P ar en tal ) I nt er vi ew No Sh yu 20 12 O R 1 .7 1 ( 1. 48 -1 .9 8) 22 6, 55 0 0-17 y ea rs Ph ys ic ia n d ia gn os is Ps yc hi at ris t d iag no si s Ye s Su w an 2 011 O R 3 .8 ( 1. 41 -1 0. 26 80 5-15 y ea rs H is to ry a nd p hy si ca l ex ami na tio n Pe dia tr ic ia n di ag nos ed Ye s Ts ai 2 011 O R 2. 07 (1 .8 3-2. 34 )* 22 6, 55 0 0-17 y ea rs Ph ys ic ia n d ia gn os is Ph ys ic ia n d ia gn os is No Ya ng 2 014 A D H D s ym pt om s s co re w as si gn ifi ca nt h ig her i n a lle rg ic rh in iti s g ro up 14 4 6-1 4 y ea rs Par en tal qu es tio nna ire IgE -m ea sur em en t No * C al cu la te d f ro m t he a va ila bl e i nf or m at io n i n t he a rt ic le . A bbr ev ia tion s: A D H D , A tt en tion -D efi ci t/ Hy pe ra ct iv ity D is or de r; OR , O dd s Ra tio ; S D , S ta nd ar d D ev ia tion .
6
Tabl
e 2.
Studies examining the inc
idence of ADH
D and differen
t a
topic diseases used in the meta-an
al ysis. Ty p e o f st u d y N umb er of pa rt ic ipa n ts Ag e Me th od ass ess m en t at o py Me th od ass ess m en t A D H D C o nf o u n d er s ad ju ste d O ve ra ll r is k o f b ia s O u tco m e O dd s R at io A st hm a Ch en 2 013 Co hor t 11 ,4 70 0-1 4 y ea rs Ph ys ic ia n d ia gn os is Ps yc hi at ris t di ag nos is A ge , s ex , u rb an iz ati on , co mo rb id a lle rg ic d ise ase s Se rio us H R: 1. 31 (1 .0 7-1. 59 ) Go od w in 2 01 3 Co hor t 217 9 0-17 y ea rs Pa re nt al re po rt of p hy si ci an di ag nos is Par en tal qu es tio nn air e M at er na l a ge , m at er na l ed uc ati on , m at er na l sm ok in g i n p re gn an cy , m at er na l s m ok in g a t a ge 5 , m at er na l h is to ry o f m en ta l he al th p ro bl em s a t a ge 8 an d f ami ly fun ct io ni ng a t ag e 5 y ea rs . Se rio us 1. 84 (1 .11 -3 .0 2) Hak 2 01 3 C as e-co nt ro l 442 0 0-1 4 y ea rs Re cor de d di ag no si s f or as thm a Re cor de d d iag no si s fo r A D H D a nd pr esc rip tio n f or m et hy lp hen ida te A ge , l ow b irth a nd /o r pr et er m d el iv er y, c om or bi d al ler gi c d is ea se s, p ra cti ce M od er ate 1. 4 ( 1. 2-1. 7) M og en sen 20 11 Co hor t 18 12 8-1 4 y ea rs Par en tal qu es tio nn air e Par en tal qu es tio nn air e Se x, s oc io ec on om ic s ta tu s, bi rth w ei gh t, p rev io us sy m pt om s o f A D H D , co m or bi d e cz em a Cr iti ca l H I: 1 .8 8 ( 1.1 4-3. 09) IN : 0. 88 (0. 54 -1. 43 ) O ver al l A D H D : O R 1 .2 8 ( 0. 61 -2. 70 ) Ts ai 2 013 C as e-co nt ro l 22 ,8 45 0-17 y ea rs Ph ys ic ia n d ia gn os is Ps yc hi at ris t di ag nos is A ge , s ex , i nd ex y ea r a nd in de x m on th , u rb an iz ati on , co mo rb id a lle rg ic d ise ase s M od er ate 1.1 5 ( 0. 95 -1 .3 8) Va n d er S ch an s 20 16 C as e-co nt ro l 21, 28 5 0-12 y ea rs M ed ic ati on p ro xy M ed ic ati on p ro xy A ge , s ex , u rb an iz ati on , pr es en ce o f d iab et es m el lit us t yp e 1 , ep ileps y, or de pr es si on , c om or bi d al le rgi c di se as es M od er ate 1. 4 ( 1. 2-1. 5) Ec ze m a G en un ei t 2 01 4 Co hor t 770 0-13 y ea rs Pa re nt al re po rt of p hy si ci an di ag nos is Pa re nt al r ep or t o f ph ys ic ia n d ia gn os is Se x, m at er na l a ge , na tio nal ity , s ch oo l ed uc ati on , p ar en ta l a to pi c di se ase , c omo rb id rh in iti s Se rio us 1. 27 (0 .7 1-2. 28 )
Hak 2 01 3 C as e-co nt ro l 442 0 0-1 4 y ea rs Re cor de d di ag no si s f or at op ic d er m ati tis Re cor de d d iag no sis fo r A D H D a nd pr esc rip tio n f or m et hy lp hen ida te A ge , l ow b irth a nd /o r pr et er m d el iv er y, p ra cti ce M od er ate 1. 3 ( 0. 9-1. 7) Sc hmi tt 2 01 0 Co hor t 29 16 0-1 0 y ea rs Pa re nt al re po rt of p hy si ci an di ag nos is Par en tal qu es tio nn air e A ge , s ex , s oc io ec ono m ic st at us , p ar en ta l e du ca tio n, br ea st -fe ed in g, s in gl e par en t, c om or bi d al le rgi c di se ase s Se rio us 1.1 9 ( 0. 88 -1 .6 1) Sc hmi tt 2 01 1 Co hor t 1, 57 8 0-1 0 y ea rs Pa re nt al re po rt of p hy si ci an di ag nos is Par en tal qu es tio nn air e Se x, l oc ati on , h ou se ho ld inc om e, br ea st -f ee di ng , si ng le p ar en t, e ar ly p et ex po su re , d ay c ar e w ith in inf an cy , p ar en tal h is to ry fo r e cz em a, p re gn an cy unp lan ne d/ un in te nd ed, co mo rb id a lle rg ic d ise ase s Se rio us 1. 78 (1 .0 2-3. 09 ) Ts ai 2 013 C as e-co nt ro l 22 ,8 45 0-17 y ea rs Ph ys ic ia n d ia gn os is Ps yc hi at ris t di ag nos is A ge , s ex , i nd ex y ea r a nd in de x m on th , u rb an iz ati on , co mo rb id a lle rg ic d ise ase s M od er ate 1. 40 (1 .2 2-1. 61 ) Va n d er S ch an s 20 16 C as e-co nt ro l 21, 28 5 0-12 y ea rs M ed ic ati on p ro xy M ed ic ati on p ro xy A ge , s ex , u rb an iz ati on , pr es en ce o f d iab et es m el lit us t yp e 1 , ep ileps y, or de pr es si on , c om or bi d al le rgi c di se as es M od er ate 1. 2 ( 1. 0-1. 4) R hi ni ti s Hak 2 01 3 C as e-co nt ro l 442 0 0-1 4 y ea rs Re cor de d di ag no si s f or al ler gi c r hi ni tis Re cor de d d iag no si s fo r A D H D a nd pr esc rip tio n f or m et hy lp hen ida te A ge , l ow b irth a nd /o r pr et er m d el iv er y, p ra cti ce M od er ate 1.1 (0 .9 -1 .4 ) Ts ai 2 013 C as e-co nt ro l 22 ,8 45 0-17 y ea rs Ph ys ic ia n d ia gn os is Ps yc hi at ris t di ag nos is A ge , s ex , i nd ex y ea r a nd in de x m on th , u rb an iz ati on , co mo rb id a lle rg ic d ise ase s M od er ate 1. 59 (1 .4 9-1. 71 ) Va n d er S ch an s 20 16 C as e-co nt ro l 21, 28 5 0-12 y ea rs M ed ic ati on p ro xy M ed ic ati on p ro xy A ge , s ex , u rb an iz ati on , pr es en ce o f d iab et es m el lit us t yp e 1 , ep ileps y, or de pr es si on , c om or bi d al le rgi c di se as es M od er ate 1. 2 ( 0. 9-1. 5) A bb rev ia tio ns : A D HD , A tt en tio n-D efi ci t/ H yp er ac tiv ity D is or der ; HR , Ha za rd R at io ; H I, H yp er ac tiv ity /I mp ul si vi ty ; I N, In at ten tio n
6
Qualitative systematic review
A total of 19 studies examining the co-occurrence of asthma, eczema, and/or rhinitis with
ADHD published after the review of Schmitt et al.9, are presented in Table 1. The majority of
the studies assessed the diseases with a parental questionnaire (45%) or a physician diagnosis (45%) with regard to both the exposure of atopy and the outcome of ADHD. The majority of the physician diagnoses were assessed through patient registries without a specification of the method of diagnosis. In addition, some studies specified the method of diagnosis ranging from following the GINA-guidelines, physical examination, to skin prick tests in an atopy assessment and a combination of structured interviews and different diagnostic questionnaires in the assessment of ADHD. Adjustment for common confounding factors was applied in most studies (n = 20/31 studies). In the vast majority of studies focusing on both asthma and rhinitis with ADHD, a statistically significant higher co-occurrence of both diseases compared to the reference group was evident (asthma: n = 10/14; rhinitis: n = 7/9). In studies that examined the co-occurrence of eczema and ADHD, only three out of the eight studies exhibited a statistically significant higher prevalence of both atopic diseases. Furthermore, though not significant, five out of the eight studies showed odds ratios above 1, indicating a higher co-occurrence of both diseases.
Quantitative review and meta-analysis of longitudinal studies
Nine studies focused on the comparison of one or more atopic diseases in (early) childhood, children without an atopic disease in (early) childhood, and the development of ADHD later in life. These studies were performed in either a retrospective case-control study setting or in a prospective or retrospective cohort study setting.
Asthma and ADHD
When combined over the six included studies, the overall odds ratio of children having asthma compared to children without asthma and the odds of ADHD onset was 1.34 (95% CI 1.24-1.44).
Combining the different studies resulted in low heterogeneity (I2: 0%, p =0.46) of the studies
(Figure 2a).The funnel plot to assess publication bias (Figure 2b) demonstrates that small sample sized studies of lower odds of developing ADHD when having asthma are possibly omitted from the included studies due to publication bias. For inclusion of the study of Chen et al. in the meta-analysis and comparison with the other studies, the hazard ratio was assumed to be similar with an odds ratio. Comparing the calculated crude odds ratio (1.56 [95% CI 1.30-1.87]) of Chen et al. with the adjusted hazard ratio (1.31 [95% CI 1.07-1.59]) yielded similar results.
Figure 2.
a) Forest plot of meta-analysis of asthma in childhood and the development of ADHD. b) Funnel plot of meta-analysis of asthma in childhood and the development of ADHD a
b
Abbreviations: ADHD, Attention-Deficit/Hyperactivity Disorder; SE, Standard Error; OR, Odds Ratio; CI, Confidence Interval.
a
b
Eczema and ADHD
Combining the included studies that focused on eczema in childhood and the development of ADHD resulted in an overall odds ratio of 1.32 (95% CI 1.20-1.45) compared to children without
eczema (Figure 3a). The heterogeneity of the six studies combined was low (I2: 0%, p = 0.64),
and the funnel plot indicated no signs of publication bias (Figure 3b).
Figure 3.
a) Forest plot of meta-analysis of eczema in childhood and the development of ADHD. b) Funnel plot of meta-analysis of eczema in childhood and the development of ADHD.
Abbreviations: ADHD, Attention-Deficit/Hyperactivity Disorder; SE, Standard Error; OR, Odds Ratio; CI, Confidence Interval.
a
b
Rhinitis and ADHD
The three studies that focused on rhinitis in childhood and the development of ADHD showed an overall higher odds ratio of 1.52 (95% CI 1.43-1.63) compared to children without
rhinitis but with a substantial higher heterogeneity (I2: 82%, p = 0.004), which is categorized as
considerable (Figure 4a). Although the sample size of the included studies was low (n=3), the funnel plot indicates an underrepresentation of higher odds of developing ADHD when having rhinitis in the smaller sample sized studies, which could indicate publication bias (Figure 4b).
Figure 4.
a) Forest plot of meta-analysis of rhinitis in childhood and the development of ADHD. b) Funnel plot of meta-analysis of rhinitis in childhood and the development of ADHD.
Abbreviations: ADHD, Attention-Deficit/Hyperactivity Disorder; SE, Standard Error; OR, Odds Ratio; CI, Confidence Interval.
Sensitivity analysis
The results of the assessment of bias are presented in the last column of Table 2. The complete risk of bias assessment can be found in Appendix III in Supplementary material. Differences in the risk of bias assessment between studies were primarily based on differences in the bias due to confounding and bias in the selection of participants for the study categories. Most studies adjusted for possible confounding factors such as age, gender, and other comorbid atopic diseases.
Only including the studies in the meta-analysis that were rated as moderate or low risk of bias resulted in a different overall outcome for both the effect of asthma and eczema on the development of ADHD. In both groups, three studies were rated as having a moderate risk of bias. In the asthma group, this resulted in an overall odds ratio of 1.33 (95% CI 1.22-1.45) of children having asthma in childhood and developing ADHD compared to children without
asthma with a moderate heterogeneity (I2: 34%). The overall outcome of the scenario analysis
was comparable with the basic analysis of the six studies, however, heterogeneity (I2) was
higher. In the eczema group, the scenario analysis resulted in an overall odds ratio of 1.32 (95% CI 1.19-1.46) of having eczema in childhood and developing ADHD later in life compared to
children without eczema. The heterogeneity was still low (I2: 0%).
Combining all of the outcomes from the nine studies resulted in an overall odds ratio of 1.41 (95% CI 1.35-1.48) of having an atopic disease in childhood and developing ADHD later in
life compared to children having no atopy. Heterogeneity was rated as substantial (I2: 51%).
DISCUSSION
Both the qualitative systematic review among cross-sectional studies and the quantitative meta-analysis revealed higher risks for ADHD among children who have an atopic disease than those who do not have an atopic constitution. The majority of the studies investigating the co-occurrence of one of the atopic disorders, i.e., asthma, eczema, or rhinitis with ADHD showed a higher co-occurrence compared to the control group, indicating a higher risk of asthma, eczema, and rhinitis when having ADHD and vice versa. In the meta-analysis, an overall odds ratio of 1.35 (95% CI 1.23-1.54) was ascertained for asthma, 1.32 (95% CI 1.20-1.45) for eczema, and 1.52 (95% CI 1.43-1.63) for rhinitis in childhood and the development of ADHD later in life compared to children not having an atopic disease. These associations were independent of the other atopic disorders and common confounding factors.
Schmitt et al.9 concluded in their systematic review that eczema, and not atopy in general,
was associated with ADHD. They assumed an approximate 1.5-fold increased risk for ADHD that could be attributed to eczema. The increased risk of the co-occurrence of eczema and ADHD corresponds with the results found in this analysis, however, an independent association between the other two atopic diseases, asthma and rhinitis with the co-occurrence of ADHD were also detected. The difference between Schmitt et al. and this analysis could be ascribed
to the relatively lower study quality and lack of adjustment for confounding factors in the studies included in the systematic review of Schmitt et al. Also, a difference in assessment of both the atopic diseases and ADHD in the included studies could have influenced the association between the two diseases. Importantly, the small sample size of the included studies may have affected the study’s ability to determine independent associations of asthma and rhinitis with ADHD.
Although this is the first meta-analysis assessing the risk of children experiencing different atopic disorders and subsequently developing ADHD, the results of a study such as this must be considered in the context of possible limitations. As the data that is employed in any meta-analysis depends on the methods used by previous authors, heterogeneity between studies is inevitable. This is especially the case in the rhinitis sub-group analysis in which the heterogeneity was rated considerable which was plausibly caused by a small population of
studies (n=3) and different types of assessment of both rhinitis and ADHD. Holmberg et al.23
found similar results of the association between asthma and ADHD despite using multiple types of asthma and ADHD assessments. This indicates that the significant heterogeneity in the association between rhinitis and ADHD is probably because of the small population of studies. Even though the number of studies where rhinitis and ADHD were measured at different time points was small, the overall number of participants in the three studies resulted in a large group of study participants (n = 48,550). Although the heterogeneity was considerable, the association between rhinitis and ADHD remained strong.
Publication bias could have played a role in the asthma sub-group analysis where small sample sized studies with lower odds are missing from the funnel plot. In this case, it is possible that studies with no effect (i.e., where the 95% confidence interval of the odds ratio is including 1 or where the point estimate is close to 1) are less likely to be published and, therefore, are not included in our meta-analysis. However, the publication bias could also be ascribed to the small sample size of studies (n = 6). Taking this into account, it is not believed that negative publication bias is of substantial influence since studies with odds ratio of 1 were found, making it unlikely that a larger study in which no association was determined were missed or not published.
In this study, asthma, eczema, and rhinitis were all classified as being atopic disorders while part of the patients might not have had an atopic disease. In a single study, misclassification could have occurred due to different forms of assessment of the atopic disorder. However, the majority of the studies used in this meta-analysis directly or indirectly reported a physician diagnosis, therefore, it could be assumed that the overall outcome was primarily caused by the atopic form of the disorders.
Much of the current data accords with the Bradford Hill criteria for causation. For example, the criteria state that the association must be biologically plausible and consistent between studies. Furthermore, there should be a sequence in time, and the association should be specific and strong. Currently, there are multiple hypotheses about the biological origin of the association between atopy and ADHD. ADHD could be part of the allergic cascade through
the possible role of hypersensitivity to environmental stimuli in the development of ADHD.24 Another option is the effect of either inflammatory cytokines or the early manifestation of stress, both caused by atopy, and their effect on the development of the brain. A more indirect association between atopy and ADHD could be the involvement of overlapping genetic and/
or environmental risk factors.5 The role of sleeping problems caused by atopy and the effect
on ADHD-like behavior as an effect modifier was a subject of special interest in past studies
of Romanos et al.25 and Yaghmaie et al.26 since sleep is essential for healthy maturation of
the brain. There appeared to be an effect of sleep loss on the association between atopic eczema and ADHD, however, after controlling for sleep loss, the relationship still remained significant. A recent study supported the theory that the association between atopic diseases and ADHD is independent of sleeping problems by demonstrating an independent association
between increased IgE levels and decline in cognitive functioning.27 The ability of inflammatory
cytokines released during an allergic inflammation to cross the blood-brain barrier makes
them likely candidates for playing a role in cognitive and behavioral development.27 However,
it is likely that multiple other factors including genetic, epigenetic, and environmental factors may also be responsible for the interplay that leads to neurodevelopmental disorders like
ADHD.28 Importantly, to examine the subtle relationship between atopic symptoms and ADHD
symptoms more closely, prospective-longitudinal study designs which include multiple or
continuous measurements of these symptoms are needed. For example, Mogensen et al.11
adjusted their prospective cohort study for previous symptoms of ADHD in the development on ADHD symptoms later in life and still determined a positive association between asthma and ADHD development (hyperactive-impulsivity symptoms).
Next to scientific relevance, the association between atopy and ADHD may also have clinical relevance. New insights into the underlying working mechanism could improve both the care for atopic patients as well as patients with ADHD. Currently, a large proportion of atopic patients is undertreated and underdiagnosed due to under recognition and
acknowledgement of the disease as is also discussed by Chivato et al.29. Also, present treatment
of ADHD is focused on addressing ADHD at a symptomatic level while additional insight into the etiology of ADHD could lead to prevention and/or treatment of the underlying pathogenesis of ADHD in children.
CONCLUSION
This study updated and quantified current data on the association between atopic diseases and ADHD. This systematic review and meta-analysis provide strong evidence to support that the three main atopic diseases including asthma, eczema, and allergic rhinitis are independently associated with ADHD in childhood and that individuals have an average of a 30% to 50% greater chance of developing ADHD later in life compared with persons without these diseases.
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APPENDIX I
PRISMA 2009 Checklist
Section/topic # Checklist item on page # Reported TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both. P1
ABSTRACT
Structured summary 2
Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review
registration number.
P2
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. P3 Objectives 4 addressed with reference to participants, interventions, Provide an explicit statement of questions being
comparisons, outcomes, and study design (PICOS). P3
METHODS
Protocol and registration 5 be accessed (e.g., Web address), and, if available, provide Indicate if a review protocol exists, if and where it can registration information including registration number. P5 Eligibility criteria 6
Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as
criteria for eligibility, giving rationale.
P4
Information sources 7
Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last
searched.
P4-5
Search 8 database, including any limits used, such that it could Present full electronic search strategy for at least one be repeated.
Appendix II Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if
applicable, included in the meta-analysis). P4-5 Data collection process 10
Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any
processes for obtaining and confirming data from investigators.
P5
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and
simplifications made. P4-5
Risk of bias in individual
studies 12
Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how
this information is to be used in any data synthesis.
P6 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). P5 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of
consistency (e.g., I2) for each meta-analysis. P5
Section/topic # Checklist item Reported on page #
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). 5-6 Additional analyses 16 sensitivity or subgroup analyses, meta-regression), if Describe methods of additional analyses (e.g.,
done, indicating which were pre-specified. P6
RESULTS
Study selection 17 eligibility, and included in the review, with reasons for Give numbers of studies screened, assessed for exclusions at each stage, ideally with a flow diagram. Fig 1 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up
period) and provide the citations. Table 1+2 Risk of bias within studies 19 available, any outcome level assessment (see item 12). Present data on risk of bias of each study and, if Appendix Table 2 +
III Results of individual
studies 20
For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for
each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
Table 1+2, fig 2-4 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. Fig 2-4 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). Table 2, p8 Additional analysis 23 sensitivity or subgroup analyses, meta-regression [see Give results of additional analyses, if done (e.g.,
Item 16]). P8
DISCUSSION
Summary of evidence 24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers,
users, and policy makers).
P8-10 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete
retrieval of identified research, reporting bias). P9-10 Conclusions 26 context of other evidence, and implications for future Provide a general interpretation of the results in the
research. P11
FUNDING
Funding 27 review and other support (e.g., supply of data); role of Describe sources of funding for the systematic funders for the systematic review. P11
From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for
Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal. pmed1000097
APPENDIX II
Search terms
EMBASE: ‘attention deficit disorder’/exp OR ‘attention deficit hyperactivity disorder’:ab,ti OR ‘attention deficit disorder’:ab,ti OR adhd:ab,ti OR ‘hyperkinetic disorder’:ab,ti AND (‘allergic asthma’/exp OR ‘allergic rhinitis’/exp OR ‘atopic dermatitis’/exp OR ‘eczema’/exp OR ‘allergy’/exp OR ‘urticaria’/exp OR ‘immunoglobulin e’/exp OR asthma:ab,ti OR rhinitis:ab,ti OR eczema:ab,ti OR dermatitis:ab,ti OR allerg*:ab,ti OR atopy:ab,ti OR atopic:ab,ti OR urticaria:ab,ti OR
conjuncivitis:ab,ti OR ige:ab,ti OR ‘immunoglobulin e’:ab,ti) Date: September 18, 2015
Number of papers: 789
Pubmed: (((((“Attention Deficit Disorder with Hyperactivity”[Mesh]) OR Attention Deficit Hyperactivity Disorder[tw] OR attention deficit disorder[tw] OR adhd[tw] OR hyperkinetic disorder[tw]) AND ((((((((“Asthma”[Mesh]) OR “Rhinitis”[Mesh]) OR “Eczema”[Mesh]) OR “Dermatitis, Atopic”[Mesh]) OR “Allergy and Immunology”[Mesh]) OR “Urticaria”[Mesh]) OR “Receptors, IgE”[Mesh]) OR (asthma[tw] OR rhinitis[tw] OR eczema[tw] OR dermatitis[tw] OR allerg*[tw] OR atopy[tw] OR atopic[tw] OR urticaria[tw] OR conjunctivitis[tw] OR ige[tw] OR immunoglobulin e[tw])))))
Date: September 18, 2015 Number of papers: 377 Psychinfo:
((DE “Attention Deficit Disorder with Hyperactivity”) OR TI(“Attention Deficit Hyperactivity Disorder” OR “attention deficit disorder” OR “adhd” OR “hyperkinetic disorder”) OR AB(“Attention Deficit Hyperactivity Disorder” OR “attention deficit disorder” OR “adhd” OR “hyperkinetic disorder”)) AND ((DE “Asthma”) OR (DE “Eczema”) OR (DE “Allergic Skin Disorders”) OR AB(“asthma” OR “rhinitis” OR “eczema” OR “dermatitis” OR “allerg*” OR “atopy” OR “atopic” OR “urticaria” OR “conjunctivitis” OR “ige” OR “immunoglobulin e”) OR TI(“asthma” OR “rhinitis” OR “eczema” OR “dermatitis” OR “allerg*” OR “atopy” OR “atopic” OR “urticaria” OR “conjunctivitis” OR “ige” OR “immunoglobulin e”))
Date: September 18, 2015 Number of papers: 171 Total
Date: September 18, 2015
Records after duplicates removed: 945
Risk of Bias assessmen t A CR OB AT -N RSI Q u est io n : C at egor y: 1.1 1. 2 1. 3 1. 4 1. 5 1. 6 R is k o f b ia s 2 .1 2. 2 2. 3 2 .4 R is k o f b ia s 3.1 3. 2 3. 3 R is k o f b ia s 4.1 4. 2 4. 3 R is k o f b ia s A st hm a Ts ai 2 013 PN NA NA Y PY N M od er ate NA NA NA Y Lo w Y Y Y Lo w NA Y Y Lo w Hak 2 01 3 PN NA NA Y PY PY M od er ate NA NA NA Y Lo w Y Y Y Lo w NA Y Y Lo w M og en sen 2 01 1 PN Y NA Y PN PY Se rio us N N N NA Cr iti ca l Y PN Y M od er ate NA Y Y Lo w Ch en 2 013 PN Y NA Y PY PY M od er ate N Y N NA Se rio us Y Y Y Lo w NA Y Y Lo w Go od w in 2 01 3 PN Y NA PN PY PY Se rio us N Y N NA Se rio us Y Y Y Lo w NA PY Y M od er ate v/d S ch an s 2 01 6 PN NA NA Y PY PY M od er ate NA NA NA Y Lo w Y Y Y Lo w NA Y Y Lo w Ec ze m a Sc hmi tt 2 01 1 PN Y NA Y PY PY M od er ate N Y N NA Se rio us Y Y Y Lo w NA Y Y Lo w Sc hmi tt 2 01 0 PN Y NA Y PY PY M od er ate N N N NA Se rio us Y Y Y Lo w NA Y Y Lo w Hak 2 01 3 PN NA NA PN PY PY M od er ate NA NA NA Y Lo w Y Y Y Lo w NA Y Y Lo w G en un ei t 2 01 4 PN Y NA Y PY PY M od er ate N N N NA Se rio us Y Y Y Lo w NA Y Y Lo w Ts ai 2 013 PN NA NA Y PY N M od er ate NA NA NA Y Lo w Y Y Y Lo w NA Y Y Lo w v/d S ch an s 2 01 6 PN NA NA Y PY PY M od er ate NA NA NA Y Lo w Y Y Y Lo w NA Y Y Lo w R hi ni ti s Hak 2 01 3 PN NA NA PN PY PY M od er ate NA NA NA Y Lo w Y Y Y Lo w NA Y Y Lo w Ts ai 2 013 PN NA NA Y PY N M od er ate NA NA NA Y Lo w Y Y Y Lo w NA Y Y Lo w v/d S ch an s 2 01 6 PN NA NA Y PY PY M od er ate NA NA NA Y Lo w Y Y Y Lo w NA Y Y Lo w A bb re via tio ns : Y , Y es ; P Y, P ro ba bl y Y es ; P N , P ro ba bl y N o; N , N o; N I, N o I nf or m at io n; N A , N ot A pp lic ab le
APPENDIX III
Q u est io n : C at egor y: 5.1 5. 2 5. 3 5. 4 5. 5 R is k o f b ia s 6.1 6. 2 6. 3 6. 4 R is k o f b ia s 7. 1 7. 2 7. 3 R is k o f b ia s O ve ra ll r is k o f b ia s A st hm a Ts ai 2 013 PY PY NI NA NA Lo w PY PN NA NA M od er ate PY PY PY M od er ate M od er ate Hak 2 01 3 PY PY NI NA NA Lo w PY PN NA NA M od er ate PY PY PY M od er ate M od er ate M og en sen 2 01 1 PY PY PY NA NA Lo w PN N Y Y Se rio us PY PY PY M od er ate Cr iti ca l Ch en 2 013 PY PY N I/ PY NA NA Lo w PY PN Y Y M od er ate PY PY PY M od er ate Se rio us Go od w in 2 01 3 NI PY PY NA NA M od er ate Y PN Y Y M od er ate PY PY PY M od er ate Se rio us v/d S ch an s 2 01 6 PY PY PY NA NA Lo w Y PN NA NA M od er ate PY PY PY M od er ate M od er ate Ec ze m a Sc hmi tt 2 01 1 Y Y Y NI NA Lo w PY PN Y Y M od er ate PY PY PY M od er ate Se rio us Sc hmi tt 2 01 0 PY PY PY/ N I NA NA Lo w PY PN Y Y M od er ate PY PY PY M od er ate Se rio us Hak 2 01 3 PY PY NI NA NA Lo w PY PN NA NA M od er ate PY PY PY M od er ate M od er ate G en un ei t 2 01 4 PN PY NI NA NI M od er ate PY PN Y Y M od er ate PY PY PY M od er ate Se rio us Ts ai 2 013 PY PY NI NA NA Lo w PY PN NA NA M od er ate PY PY PY M od er ate M od er ate v/d S ch an s 2 01 6 PY PY PY NA NA Lo w Y PN NA NA M od er ate PY PY PY M od er ate M od er ate R hi ni ti s Hak 2 01 3 PY PY NI NA NA Lo w PY PN NA NA M od er ate PY PY PY M od er ate M od er ate Ts ai 2 013 PY PY NI NA NA Lo w PY PN NA NA M od er ate PY PY PY M od er ate M od er ate v/d S ch an s 2 01 6 PY PY PY NA NA Lo w Y PN NA NA M od er ate PY PY PY M od er ate M od er ate A bb re via tio ns : Y , Y es ; P Y, P ro ba bl y Y es ; P N , P ro ba bl y N o; N , N o; N I, N o I nf or m at io n; N A , N ot A pp lic ab le
