Pediatrics 2011 Sleep Disordered Breathing

Confidential - Not for Circulation
Sleep Disordered Breathing in a Population-Based Cohort: Behavioral Effects at 4 and 7 Years
Journal: Manuscript ID: Article Type:
Pediatrics 2011-1402 Regular Article 10-May-2011
Date Submitted by the Author: Complete List of Authors:
Keyword/Category:
The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007
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Bonuck, Karen; Albert Einstein College of Medicine, Family and Social Medicine Chervin, Ronald; University of Michigan, Neurology Freeman, Katherine; Albert Einstein College of Medicine, Department of Epidemiology and Population Health Xu, Linzhi; Albert Einstein College of Medicine, Family and Social Medicine Behavior disorders/problems, Sleep-disordered breathing, Sleep Apnea
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Sleep Disordered Breathing in a Population-Based Cohort: Behavioral Effects at 4 and 7 Years Karen Bonuck, PhD (corresponding author) Professor, Department of Family Medicine Albert Einstein College of Medicine 1300 Morris Park Avenue Bronx, NY 10461 Karen.bonuck@einstein.yu.edu phone 718 430 4085
Katherine Freeman, Dr.P.H. Professor, Department of Epidemiology and Population Health Montefiore Medical Center/Albert Einstein College of Medicine 111East 210th Street Bronx, NY 10467 kfreeman@montefiore.org phone: 718 920 5223
Ronald D. Chervin, MD, MS Professor, Department of Neurology and Director, Sleep Disorders Center University of Michigan C728 Med Inn Bldg 1500 E. Medical Center Dr. Ann Arbor, MI 48109-5845 chervin@umich.edu phone 734-647-9064 Linzhi Xu, PhD Research Associate, Department of Family and Social Medicine Albert Einstein College of Medicine 1300 Morris Park Avenue Bronx, NY 10461 Linzhi.Xu@einstein.yu.edu
KeyWords: sleep-disordered breathing, behavior, longitudinal This study was supported by grants from the National Heart Lung & Blood Institute- R21HL091241 and R21HL091241-01A1. Conflict of Interest: The authors have no conflicts of interest relevant to this article to disclose
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Contributors Statement Page All authors meet the criteria for authorship. Dr. Bonuck conceptualized and designed the study, drafted the initial manuscript, reviewed and modified the analyses in collaboration with Drs. Freeman and Xu, and incorporated co-author feedback into the final manuscript. Dr. Freeman worked to develop the methods, carried out initial analyses, supervised final analyses of Dr. Xu, and reviewed and revised the final manuscript. Dr. Chervin advised on study design and analyses, and carefully reviewed and revised multiple versions of the manuscript. Dr. Xu collaborated on statistical design issues, completed final analyses, and reviewed and revised the final version of the paper.
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Objectives: Examine statistical effects of sleep-disordered breathing (SDB) symptom trajectories from 6 months to 7 years on subsequent behavior. Patients and Methods: Parents in the Avon Longitudinal Study of Parents and Children (ALSPAC) reported on childrens snoring, mouth breathing, and witnessed apnea at >2 surveys at 6, 18, 30, 42, 57, and 69 months, and completed the Strengths and Difficulties Questionnaire (SDQ) at 4 (n=9,206) and 7 (n=8,342) years. Cluster analysis produced 5 Early (6-42 months) and Late (6-69 months) symptom trajectories (clusters). Adverse behavioral outcomes were defined by top 10th percentiles on SDQ total and subscales, at 4 and 7 years, in multivariable logistic regression models. Results: The SDB clusters predicted 20%-90% increased odds of subsequent problematic behavior, controlling for 16 potential confounders. Early clusters predicted problematic behavior at 7 years equally well as at 4 years. The Worst Case cluster, with peak symptoms at 2.5 years that subsequently resolved, nonetheless at 7 years predicted hyperactivity (OR=1.96, 95% CI [1.52 to 2.53]), conduct (1.61, [1.39 to 2.19]), and peer difficulties (1.69, [1.39 to 2.06]), whereas a Later Symptom cluster predicted emotional difficulties (1.69, [1.39 to 2.06]). In two clusters, all SDB symptoms peaked before 1.5 years and abated by 2.5 years, but still predicted 40%-50% increased odds of behavior problems at 7 years. Conclusions: In this large, population-based, longitudinal study, early-life SDB symptoms had strong, persistent statistical effects on subsequent behavior in childhood. Findings suggest that SDB symptoms may require attention as early as the first year of life.
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What is Known on This Subject Sleep disordered breathing (SDB) is associated with neurobehavioral morbidity in children. Prior related research has generally been cross-sectional or short (i.e. 1-2 years) follow-up studies of a single symptom (i.e. snoring, obstructive sleep apnea, mouth-breathing), with limited control for confounders. What This Study Adds SDB was assessed as a trajectory of combined symptoms from 6 months to 6.75 years, in over 11,000 children. SDB was associated with 40% and 60% more behavioral difficulties at 4 and 7 years, respectively.
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Introduction Neurobehavioral morbidity is common in childhood sleep disordered breathing (SDB) that can range from snoring to obstructive sleep apnea (OSA). Mouth-breathing is another frequent clinical finding. 1 2 SDB causes abnormal gas exchange, interferes with normal restoration during sleep, and disrupts cellular and chemical homeostasis. 3 The supposed resultant dysfunction of the prefrontal cortex impairs attention, executive functioning, behavioral inhibition, self-regulation of affect and arousal, and other socio-emotional behaviors. 4 Behavioral manifestations include both externalizing (e.g., hyperactivity, aggression, impulsivity) and internalizing (e.g., somatic complaints, social withdrawal) behaviors.5 SDB reportedly peaks from 2-6 years of age,6 but also occurs in younger children.7 It is unclear which of the core biological processes associated with SDB best predict neurobehavioral morbidity; genetic, individual, and environmental variables likely play a role in how this morbidity is expressed.4 Regardless of etiology, SDBs neurological effects may be irreversible,8 highlighting the saliency of under-detection. Despite the breadth of studies on SDBs neurobehavioral effects in children, methodological limitations persist. Meta-analyses found existing work rife with poor sampling, insufficient consideration of confounders, and imprecise use of statistical tools.9 10 Nearly all studies have been cross-sectional, and most longitudinal studies have focused on pre/post-adenotonsillectomy (T&A) assessments or have included no more than 2 years of follow-up. A meta-analysis of SDB differences associated with attention-deficit/hyperactivity disorder (ADHD) 11 relied upon just 2 small studies 12, 13 and excluded children with anxiety or depressive disorders. This study describes the combined trajectory of 3 hallmark SDB symptomssnoring, mouth-breathing, and witnessed apneaand their longitudinal statistical effects on behavior. Our research questions were: 1) What effect do early SDB patterns (i.e., clusters) from 6 through 42 months of life have upon socialemotional behavior at 4 and 7 years?; and 2) What effect do SDB patterns from 6 months through nearly 6 years have on behavior at 7 years of age? Data were collected over 7 time points during the critical period in SDB development, from 6 months through nearly 7 years of age in a prospective, population-based cohort.
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Patients and Methods Population The Avon Longitudinal Study of Parents and Children (ALSPAC), a geographically based cohort study of children, enrolled pregnant women residing in a defined part of the former county of Avon in southwest England with an expected date of delivery between April 1991 and December 1992. A total of 14,541 pregnant women were enrolled. The cohort , described in detail elsewhere,14 is broadly representative of the UK population in terms of socioeconomic status (SES), although with a slight under-representation of ethnic minority families, and overrepresentation of wealthier families. Our analyses excluded: triplet and quadruplet births, children who did not survive to 1 year and children with conditions such as major congenital disorders that are likely to affect SDB or behavioral assessment. The resulting base sample, used to derive SDB clusters and behavioral outcomes, was 13,810 infants.
ALSPACs internal law and ethics committee reviews all proposals for secondary analyses and approves policies for data handling and analysis. Ethical approval for this study was obtained from the ALSPAC Law and Ethics Committee and the Local Research Ethics Committee. All participants provided informed consent.
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SDB Assessment
In ALSPACs mailed questionnaires, parents reported on their childs snoring, apnea and mouthbreathing when s/he was 6, 18, 30, 42, 57, 69 or 81 months of age. These items were: 1) Mouth-breathing: Does she breathe through her mouth rather than her nose?. At 57 months and older, parents were asked to report separately for mouth-breathing when awake vs. asleep, though only the latter was used in analyses; 2) Snoring: Does she snore for more than a few minutes at a time?; and 3) Apnea: When asleep, does she seem to stop breathing or hold breath for several seconds at a time?. Responses were categorized along ordinal scales of 3, 4, or 5 levels. Given this inconsistency in response categories, we extrapolated the values to a common scale (0-100) with the Always responses
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anchored at one end and the Never or Rarely/Never responses anchored at the other, and proportionate spacing in-between (i.e. 4 category scale was recoded as 0, 33, 66, 100). Variables were then transformed to zscores, with higher scores indicating greater symptom burden. The ALSPAC parent-reported SDB measures are similar or identical to question-items previously validated against polysomnographic (PSG) data from sleep laboratories. Some validated questionnaires have included parent report of all three SDB symptoms,15-19 -- whereas others have included only snoring and apnea.20, 21
Behavior Assessment The Strengths & Difficulties Questionnaire (SDQ), 22 a widely used behavioral screen, was completed by mothers when children were 4 and 7 years old. The 25 item SDQ has 5 scales: inattention/hyperactivity; emotional symptoms (anxiety and depression); peer problems; conduct problems (aggressiveness and rulebreaking); and a prosocial scale (sharing, helpfulness, etc.). A total difficulties (range= 0-40) score is generated by summing all but the latter scale because the absence of prosocial behavior is conceptually different from the presence of psychological difficulties. Higher scores denote more problems. Missing data were prorated according to SDQ instructions.23 The SDQ scores were dichotomized at the upper 10% based on psychometric
testing,24 ALSPAC,25, 26 and other UK cohort studies.27
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Covariate Assessment Initial covariate selection was guided by prior ALSPAC studies of SDQ outcomes 26, 28-34, and nonALSPAC studies of sleep problem effects upon SDQ outcomes. 35, 36 Based upon this literature review, and exploratory analyses, 16 potential confounders were incorporated into analyses. Socioeconomic status was measured by paternal employment (manual vs. professional), maternal education (higher vs. lower), and housing inadequacy (if either > 1 person/room or homeless). Family adversity was measured by an 18 item index of stressors (e.g., maternal psychopathology, crime, financial insecurity) used in other ALSPAC analyses;37 higher values signify more adversity. Intrauterine exposures of maternal
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smoking or alcohol use in the first trimester (yes/no), and fish intake at 32 weeks gestation (servings/week) were assessed, as was whether the child was ever breast-fed, and mothers age at delivery. Household variables included family size (0, 1, or >2 children in household at 6 months interview) and the HOME Inventory38 to assess the quality of parenting and home environment. Child demographics included race (white vs. other) and gender, low birth weight (<2500 grams) and prematurity (< 37 weeks). BMI contributes to increased levels of SDB, which, given causal mechanisms,39 is more likely to affect neuro-behavioral outcomes than BMI. Therefore, to decrease risk of over-adjustment in multivariate models, BMI was not included as a covariate.
Derivation of SDB Clusters To predict behavior at 4 years, Early clusters were derived from n=11,309 participants in the base sample with >2 of the first 4 SDB measures. To predict 7 year behavioral outcomes, we derived Later clusters from n=11,510 participants in the base sample with >2 of the first 6 SDB measures. SDB Z scores (see above) were partitioned into clusters using SAS FASTCLUS version 9.1 (Cary, NC) with k-means cluster solutions for 5, 6, 7 and 8 unique sets of clusters; within each solution, differences across time points were compared among clusters to demonstrate their uniqueness. We validated the clusters clinical significance and uniqueness against measures of a) wheezing and b) tonsils and/or adenoid removal. Wheezing history in ALSPAC is predictive of physician-diagnosed asthma, 40 a known risk factor for SDB, 41, 42 while adenotonsillectomy is the first line treatment for SDB.7 Our methodology for selecting final cluster solutions was informed by prior analytic work,43-45, This process produced exposure variables that included n=5 conceptually and statistically distinct Early clusters (6-42 months), and n=5 comparable Later clusters (6-69 months) that were extensions of Early clusters. Briefly, these are: 1)symptoms Peak @ 6 and then return to normal, 2) symptoms Peak @ 18 months and then return to normal, 3) symptoms peak at 30 months and then persist (Worst case), 4) symptoms emerge at 42 months and then persist (Late Symptom) and 5) Normals who are asymptomatic throughout.
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Statistical Analysis
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For SDQ scores at 4 and 7 years, we calculated the mean (sd), and proportions above and below the 10% cut-off for the base sample, and their associations with putative covariates. We describe the association between SDQ mean (sd) total scores at 4 and 7 years and the Early and Later clusters, by analysis of variance (ANOVA), Only participants with non-missing SDQ data are included in analyses of behavioral outcomes. Multivariate logistic regression analyses examined adjusted and unadjusted relationships between clusters and SDQ total and subscales at 4 and 7 years. Initial models included all putative covariates. Only those variables that were significant (p<=0.05) variables were retained in multivariate models. Odds ratios (OR) and 95% confidence intervals (95%CIs) represent the odds of being in the top 10% vs. the remaining 90% of SDQ scores. To address multi-collinearity, variance inflation factors (VIF) were derived to assess the effects of individual independent variables upon variance. A conservative VIF threshold of 10 was employed in model testing. 46 Analyses were conducted using SAS v9.1.47
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Results: Data completion and attrition.
SDB longitudinal data were relatively complete (not shown): Early cluster analyses (4 year SDQ outcomes), based upon 9,206 participants, included n=7,701 (84%), n=1,107 (12%) and=398 (4%) with SDB data for 4/4, 3/4, and 2/4 timepoints, respectively. Early cluster analyses of the n=8,167 participants with 81 month SDQ outcomes included n=7,875 (96%) with SDB data for >3/4 timepoints. Later cluster analyses (81 month SDQ data) for n=8,243 participants, included n=7,528 (91%) with SDB data for >5/6 timepoints. Missing SDQ or SDB data were significantly associated with: non-white race, pre-maturity, low birth weight, manual (vs. professional) paternal employment, lower (vs. higher) maternal educational status, housing inadequacy, not being breastfed, and higher levels of wheezing (not shown).
Sample Characteristics and Association with Top 10% of SDQ Total Scores
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Characteristics of the base sample and associations with behavioral outcomes are shown in Table 1.Children in the upper 10% of SDQ scores had significantly more adverse characteristics (e.g.,higher maternal smoking, lower maternal education, higher Family Adversity Index scores, and lower HOME scores) than the remaining 90%, at 4 and 7 years, but no differences by race, maternal alcohol intake during pregnancy, or adenoid removal.
Cluster Description and Association with Sample Characteristics Five early clusters representing n=11,309 children are illustrated in Figures 1a-1e; their descriptive characteristics are shown in Table 2. Four are symptomatic (55% of sample) and one (Normals, 45% of sample) is asymptomatic. Worst Case has the greatest symptom burden, and most adverse risk profile, followed by Late Symptom. The three symptoms patterns are essentially parallel in the other clusters, but in these two, snoring levels are nearly double those of apnea or mouth-breathing. Peak@ 18 and Peak @ 6 have moderate symptom levels which abate prior to 30 months. Whether assessed as a continuous or dichotomous (10% v. 90%) variable, SDQ total scores differed significantly across the four symptomatic clusters, and in combined symptomatic clusters vs. Normals.
Five comparable later clusters representing n=8,243 children are illustrated in Figures 2a-e (descriptive characteristics not shown). Patterns are similar to the Early clusters, except that in this Late Symptom cluster snoring and mouth-breathing peak together at lower levels at 57 months with no marked apnea, and; the Peak @ 6 apnea levels are nearly double those of the Early clusters.
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SDQ Total Score The SDB clusters significantly predict SDQ total scores at 4 and 7 years (Table 3). Unadjusted Early cluster effects of 40%-140% attenuate to 20%-90% in multivariate analyses. The strongest and most persistent Early cluster effects are for Worst Case, with outcomes essentially unchanged between 4 (OR=1.66, 95% CI=1.29-2.13) and 7 years (OR=1.67, 95% CI= 1.27-2.18). Later clusters unadjusted effect sizes of 65%140% attenuate to 40%-90% in multivariate analyses. In these Later cluster models there is a 40% effect for
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Peak@6 and 50% effect for Peak@18.Membership in any symptomatic cluster is associated with being in the upper 10% of total SDQ scores (v. Normals), an effect that increases slightly from 4 (OR=1.40, 95% CI=1.21 to 1.61) to 7 years (OR=1.57, 95% CI=1.34 to 1.84: Later clusters). SDB effects were stronger than those of maternal smoking, alcohol use in pregnancy, maternal education and paternal employment in multivariate analyses (Table 3). Neither race, pre-maturity, low- birthweight, maternal fish intake, nor maternal age, were significant in any multivariate analysestotal or subscale (not shown). Only male gender and not being the second or later-born child had greater adverse effects. Greater family adversity was associated with poorer behavioral outcomes, while higher home environment scores were associated with improved outcomes. Gender-cluster interactions were not significant for any total or sub-score
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analyses.
SDQ Subscores
Unadjusted effects of Early and Later cluster models are shown in Table 4. For the Hyperactivity, Emotional, Conduct, and Peer subscales, all but one cluster-subscale association was significant, with effects of 30%-130%. For the Pro-Social subscale, Peak@6 was the only cluster to have consistent significant adverse effects. In adjusted analyses, nearly every cluster-subscale association remained significant (Table 5), with effects of 20%-100%.
Prosocial- Peak@6 was associated with approximately 30% greater odds of being in the lowest decile across outcomes at 4 and 7 years. All but one of the remaining associations was not significant. Hyperactivity-with two exceptions, all effects were significant, and increased from 4 to 7 years. Furthermore, Early cluster effects at 4 years for Worst Case (OR=1.55, 95% CI=1.23 to 1.96) and Late Symptom (OR=1.51, 95% CI=1.21 to 1.88) clusters equaled or increased, respectively, at 7 years [(OR=1.95, 95% CI=1.51 to 2.52) and (OR=1.59, 95% CI=1.23 to 2.04)]. Emotional- with one exception at 4 years, all effects were significant (range 20%-70%), and most increased from 4 to 7 years. Late Symptom had the strongest effect at 4 (OR=1.49, 95% CI=1.18 to 1.89) and 7 years
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(OR=1.63, 95% CI=1.29 to 2.06) based upon Early cluster models, with effects persisting to 7 years (OR=1.69, 95% CI= 1.39 to 2.06) in Later cluster models. Conduct- with two exceptions, all effects were significant (range20%-70%). Both Worst Case and Peak@18 effects increased from 4 to 7 years, while Late Symptom and Peak @6 effects attenuated over that time. Peer- While 8 of 12 cluster-subscale associations were significant, SDB effects were more modest (range20%40%) and stable over time, compared to the other subscales. Effects were strongest for Worst Case in the Later cluster models (OR=1.40, 95% CI=1.09 to 1.78).
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Discussion
We examined the effects of snoring, apnea, and mouth-breathing patterns (clusters) upon behavior, from infancy through 7 years in over 11,000 children. By 4 years, children in any symptomatic cluster were 40% more likely to exhibit behavioral difficulties consistent with a clinical diagnosis; by 7 years, they were nearly 60% more likely. These effects, in a population-based cohort that controlled for 16 putative confounders, exceeded those of any measured pre-natal (i.e., maternal age, smoking or alcohol use), gestational age, birthweight, breast-feeding, SES, family adversity, or home environment exposure. Furthermore, symptom clusters observed through 3.5 years were as predictive of behavioral difficulties at 7 years, as they were at 4 years, for nearly every SDQ total and subscale outcome. Regarding specific clusters, Worst Case had the greatest overall effects-- 90% increased likelihood of behavioral problems based upon symptoms observed through 3.5 yearsfollowed by the Late Symptoms cluster. In two clusters, all SDB symptoms peaked before 1.5 years and abated by 2.5 years, but still predicted 40%-50% increased odds of behavior problems at 7 years. Regarding specific behaviors, Hyperactivity, Emotional, Conduct, and Peer difficulties were significantly higher for symptomatic children, with nearly every cluster-subscale association significant. As expected from prior literature, effects were strongest for Hyperactivity, especially for Worst Case-- nearly 60% at 4 years, and
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nearly 100% at 7 years. Peer relations, though generally linked to earlier SDB symptoms, appear to have suffered the least among the behavior subscales. Compared to prior parent-reported effects of SDB upon later behavior, our findings are conservative. In a study of 1,000 third graders, snoring at baseline was associated with 2-10 fold increases in SDQ-assessed hyperactivity, emotional, conduct and peer difficulties at one year follow-up in age- and gender-adjusted analyses.48 A pediatric clinic sample of 229 2-13 year olds found that baseline SDB symptoms predicted 4-fold increases in hyperactive behaviors at 4 year follow-up, after adjustment for age, gender, and baseline hyperactivity.49 These studies differed from ours, with smaller, less representative samples, lack of data from the earliest years, use of other (non-SDQ) behavioral measures, and limited control for confounders. Alternatively, several cross-sectional studies that employed different operational definitions of SDB and SDQ outcomes found no effects. One, a large nationally representative cross-sectional sample of 5000 Australian 45 year olds, found that neither SDQ total, nor the Hyperactivity, Peer, or Emotional scale (actual) scores were greater among children with snoring and/or breathing difficulties during sleep > 4 times per week.35 Likewise, among n=635 6-8 year olds, snoring >1 time week in the past 6 months was not associated with high (upper 10th%ile) SDQ scores.36
This is the first study to assess SDB as a trajectory of combined symptoms, across a key period of development from 6 months to 6.75 years, in a large sample. Previous studies had smaller samples that were often cross-sectional, or longitudinal 2 years or less of follow-up. Many were not population-based, involved school-age children only, or did not adjust for as wide a range of counfounders.8, 50 The potential impact of confounders is evidenced by the fact that aside from the SDB clusters, 10 of 16 putative covariates were not significant in any multivariate analyses, and most unadjusted effects of SDB attenuated in controlled analyses. The current study has several limitations. First, SDB data were derived from parent report, rather than objective testing. However, the symptom-items used reflect widely accepted and well-validated SDB risk factors. Further, use of objective measures such as polysomnography in large epidemiological studies is infeasible, and may be less effective given their limited ability to predict SDB morbidity or response to treatment.16 Second, missing SDB and SDQ data were associated with identified SDB risk factors, e.g., maternal smoking, lower
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SES. Although biases that involve selective drop-out may alter prevalence estimates, other ALSPAC analyses found only marginal effects on regression models predicting behavioral outcomes.51 This is likely the case in our study, in which such biases would render our findings more conservative. These robust findings, from the largest ever cohort study of SDB exposure and future neurobehavioral morbidity, provide importance evidence that early childhood SDB affects the developing brain to produce phenotypes that may only become apparent years later. The most significant long-term effects occurred in children who experienced the worst symptoms by 2.5 years of age. Furthermore, children whose symptoms peaked by 1.5 years but then abated by 30 months continued to experience significant adverse behavioral outcomes at 7 years. SDB is relatively common in childhood. In prior analyses of this cohort the prevalence of habitual snoring ranged from 10%- 21% from 6 months to 6.75 years.52 The potential clinical implications are significant: in a large national survey of childrens health, those with ADHD in comparison to their peers had increased adjusted risks of co-morbid learning disability (8-fold), anxiety (8-fold), and low social competence
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(3-fold).53
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Conclusion
If ultimately confirmed by randomized controlled treatment trials, findings presented here could have substantial implications for public health approaches to screening and treatment. A 2009 consensus statement by U.K. pediatricians and pediatric specialists noted that the natural history of SDB, where a child changes from normality to abnormality, and where the risks of developing complications of the condition outweigh the risks of the surgical intervention, has not been established.54 Although data from multicenter, randomized controlled trials, such as the current NIH-funded Childhood Adenotonsillectomy (CHAT) study, will ultimately be required to prove cause-and-effect relationships, the new data presented here provide important epidemiologic evidence to support attention to SDB symptoms beginning as early as the first year of life.
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Acknowledgements: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. In addition, the authors wish to thank the following members of the studys advisory group: Dr. Raanan Arens (Montefiore Medical Center/Albert Einstein College of Medicine), Dr. John Bent (Montefiore Medical Center/Albert Einstein College of Medicine), Dr. Peter Blair (University of Bristol), Dr. Pauline Emmett (University of Bristol), Dr. Peter Fleming (University of Bristol), Dr. Jon Heron (University of Bristol), Dr. Carole Marcus (Childrens Hospital of Philadelphia), Dr. Kenneth Ong (Cambridge University), Dr. Sanjay Parikh (Montefiore Medical Center/Albert Einstein College of Medicine), and Dr. Susan Redline (Case Western Reserve University).
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Table 1: Sample: Demographics for total sample and by SDQ Scores at 4 and 7 Years
SDQ total Score, 4 years Total Sample* N=13,810 Maternal Smoked during pregnancy, any Alcohol during pregnancy, any Fish intake during pregnancy, mean (sd) Age at delivery, mean years (sd) Breastfed this child, ever Child Gender, male Race, white Premature, <37 weeks 25.1% 54.5% 1.88(1.75) 27.99(4.96) 75.3% 30.6% 55.7% 1.94 (1.80) 27.52 (4.78) 72.6% 20.0% 55.4% 1.87 (1.73) 28.87 (4.64) 78.51% 30.9% 58.4% 1.80 (1.53) 28.12 (4.74) 76.8% 18.7% 55.6% 1.89 (1.75) 29.03 (4.56) 79.2% Top 10% N=1,250 Lower 90% N=8,102 SDQ Total Score, 7 Years Top10% N=908 Lower 90% N=7,208
Low birthweight, <2500 grams Adenoids removed, ever Tonsils removed, ever Socioeconomic and Family Maternal Education, Lower (%) Paternal Employment, Manual (%) Housing, Inadequate, (%) Family Adversity Index, Mean (range, 0-18) HOME Score, mean (range: 0-8) Parity, >=1
*These n=13,810 constitute the base sample used to derive the clusters and SDQ outcomes. p<.01 for difference between top 10% vs. lower 90% p<.05 for difference between top 10% vs. lower 90% Lower defined as O level education or less (equivalent to school leaving certificate at 16 in the UK), from 5 original groupings.
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51.6% 97.4% 5.9% 5.2% 7.6% 4.6% 64.6% 44.0% 12.4% 1.78(1.98) 5.75(1.66) 55.4%
55.2% 98.2% 6.2% 5.7% ---------
51.2% 98.3% 5.2% 4.5% ---------
60.0% 98.2% 6.5% 5.6% 4.9% 9.2%
50.6% 98.3% 4.9% 4.2% 3.9% 6.3%
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70.9% 51.9% 18.7% 2.63 (2.26) 5.61 (1.76) 52.0%
59.0%
60.7% 363 (47.5%) 18.4% 2.85 (2.38) 5.48 (1.75) 50.7%
57.8% 39.1% 11.1% 1.71 (1.85) 5.84 (1.61) 54.5%
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2,328 (39.3%) 11.8%
1.74 (1.88) 5.81 (1.62) 54.5%
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Table 2: Association Between Early Clusters (n= 11,309) and Potential Confounders and SDQ outcome
Peak @ 6 n=2270 (21.1%) (1) Maternal Characteristics Smoked during pregnancy, any Alcohol during pregnancy, any Fish intake during pregnancy, mean Age at delivery, mean (years) Breastfed this child, Ever Child Characteristics Gender, male Race, white Premature, <37 weeks Low birth weight, <2500 grams Socioeconomic and Family Characteristics Maternal Education, Lower (%) Paternal Employment, Manual (%) Housing, Inadequate (%) Family Adversity Index mean (range, 0-18) HOME Score, mean (range: 0-8) Parity, >=1 Outcome SDQ SDQ top10% @ 4 year SDQ top10% @ 7 year SDQ continuous @4 year SDQ continuous @7 year 24.9% 53.8% 1.85 28.32 74.9% 25.4% 53.8% 1.86 28.01 75.2% 29.2% 55.0% 1.95 27.78 69.3% 28.3% 53.9% 1.93 27.90 74.5% 18.3% 56.5% 1.87 28.93 78.5% <0..001 0.119 0.673 <0.001 <0.001 Peak @ 18 n=2009 (17.8%) (2) Worst Case n=862 (7.6%) (3) Late Symptom n=1063 (9.4%) (4) Normals n=5105 (45.1%) (5) P
*
54.1% 98.1% 5.4% 4.3%
52.8% 96.8% 5.5% 5.7%
55.7% 97.9% 7.7% 5.8%
52.0% 97.6% 7.1% 5.8%
49.3% 98.2% 5.0% 4.3%
<0.001 0.008 0.005 0.013
65.5% 43.1% 15.1% 2.14 5.72 55.1% 13.5% 11.8% 14.58 8.12
15.1% 18.6% 12.9% 16.7% 14.65 15.32 7.90 8.74 Combined Symptomatic (1,2,3,&4) SDQ top10% @4 year 15.77% SDQ top10% @7 year 13.28% SDQ continuous @4 year 14.83 SDQ continuous @7 year 8.16 * P values are calculated from chi-square test or analysis of variance.
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66.4% 46.5% 15.0% 2.14 5.73 53.3%
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67.7%
67.1% 43.7% 12.9% 2.12 5.71 53.8%
58.4% 39.5% 10.1% 1.62 5.81 55.7% 10.1% 8.6% 13.90 6.77 10.14% 8.61% 13.90 6.78
<0.001 <0.001 <0.001 <0.001 0.081 0.437 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
47.4% 17.3% 2.48
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5.72 55.1%
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20.1% 14.6% 15.36 8.27
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Table 3: Cluster Effects Upon SDQ Total Scores at 4 and 7 Years

Early Cluster Models Top 10% v. Lower 90% OR (95% CI) Unadjusted, SDB Peak @ 6(1) Peak @ 18 Mos.(2) Worst Case (3) Late Symptom(4)
Symptomatic(1,2,3,4) v. Normals (5) 4 Years
1
Later Cluster Models

1.2
7 years
7 years
1,2
1.38(1.17,1.63) 1.57(1.33,1.86) 2.02(1.62,2.51) 2.23(1.83,2.72)
<0.001 <0.001 <0.001 <0.001
1.43(1.18,1.72) 1.57(1.29,1.91) 2.12(1.66,2.72) 1.82(1.43,2.31)
<0.001 <0.001 <0.001 <0.001
1.65(1.34,2.04) 1.69(1.39,2.05) 2.42(1.90,3.09) 2.03(1.66,2.48)
<0.001 <0.001 <0.001 <0.001
1.66(1.46,1.88)
<0.001
1.63(1.41,1.88)
<0.001
1.86(1.61,2.16)
<0.001
Adjusted , SDB Peak @ 6(1) Peak @ 18 Mos.(2) Worst Case (3) Late Symptom(4)
Clusters1,2,3 & 4 v. Normals (5) Covariates
3
1.20(1.00,1.45) 1.36(1.13,1.65) 1.66(1.29,2.13) 1.84(1.46,2.30)
1.40(1.21,1.61)
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0.051 <0.001 <0.001 <0.001
1.20(0.98,1.47) 1.29(1.05,1.60) 1.67(1.27,2.18) 1.50(1.16,1.94)
0.082 0.017 <0.001 0.002
1.39 (1.11,1.74) 1.49 (1.29,1.84) 1.89(1.45,2.47) 1.69 (1.35,2.10)
0.004 <0.001 <0.001 <0.001
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<0.001 N.S. 0.004 <0.001 0.001 <.001 N.S. 0.088 <0.001
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1.34(1.15,1.36)
<0.001
1.57(1.34,1.84)
<0.001
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Smoking during pregnancy Gender, male Maternal education, lower Paternal employment, manual Family Adversity Index Home Score Parity 1 v. 0 2 v. 0
---------1.22 (1.07,1.40) 1.38 (1.18,1.61) 1.33 (1.15,1.54) 1.21 (1.17,1.25) ---------0.91 (0.78,1.05) 0.63 (0.52,0.78)
1.24 (1.04,1.49)
<0.017 <0.001 0.002 N.S.
1.24 (1.04,1.48) 1.55 (1.33,1.81) 1.29 (1.10,1.52) ---------1.24 (1.20,1.28) 0.91 (0.87,0.95) 0.73 (0.62,0.87) 0.59 (0.47,0.73)
0.019 <0.001 0.002 N.S. <0.001 <0.001 0.600 <0.001
1.54 (1.32,1.80) 1.29 (1.10,1.52) -----------
1.24 (1.20,1.29) 0.91 (0.87,0.95) 0.73 (0.61,0.86) 0.58 (0.46,0.72)
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<0.001 <0.001 0.618 0.001
Adjusted for fish intake, FAI, Mother and home score, smoke during pregnancy, alcohol during pregnancy, race, breast feeding ever, housing inadequency, parity, gestation age, paternal social, maternal education, birth weight, maternal age, gender. 2 Additional adjusted for Tonsils or adenoids removed. 3 Covariates shown are only those that were significant (p<.05) in reduced models with each of the four symptomatic models incorporated as a separate variable (vs. combined clusters 1,2,3, & 4).
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Table 4 Unadjusted Cluster Effects Upon SDQ Subscales at 4 and 7 Years

Early Cluster Models Top 10% v. Lower 90% OR (95% CI) Pro-Social Peak @ 6 Peak @ 18 Mos. Worst Case Late Symptom Hyperactivity Peak @ 6 Peak @ 18 Mos. Worst Case Late Symptom Emotional Peak @ 6 Peak @ 18 Mos. Worst Case Late Symptom Conduct Peak @ 6 Peak @ 18 Mos. Worst Case Late Symptom Peer Peak @ 6 Peak @ 18 Mos. Worst Case Late Symptom 4 Years p 7 years p Later Cluster Models 7 years p
1.35(1.13,1.63) 1.17(0.96,1.43) 1.29(0.98,1.69) 1.01(0.77,1.33) 1.34(1.15,1.57) 1.31(1.11,1.55) 1.89(1.53,2.33) 1.72(1.41,2.10) 1.27(1.06,1.52) 1.32(1.10,1.60) 1.58(1.23,2.02) 1.54(1.23,1.95) 1.60(1.36,1.88) 1.45(1.22,1.72) 1.71(1.37,2.15) 1.95(1.59,2.39) 1.29(1.07,1.54) 1.29(1.07,1.56) 1.43(1.11,1.83) 1.25(0.98,1.59)
0.001 0.121 0.068 0.928 <0.001 0.001 <0.001 <0.001 0.011 0.003 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.006 0.008 0.006 0.077
1.41(1.16,1.70) 1.33(1.08,1.63) 1.37(1.03,1.82) 0.95(0.71,1.27) 1.56(1.30,1.88) 1.53(1.26,1.87) 2.23(1.74,2.85) 1.74(1.36,2.22) 1.47(1.23,1.75) 1.43(1.19,1.71) 1.63(1.27,2.09) 1.66(1.32,2.08) 1.51(1.25,1.82) 1.55(1.27,1.88) 1.95(1.51,2.52) 1.46(1.13,1.89)
<0.001 0.006 0.030 0.731 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.004 0.002 <0.001 <0.001 0.006
1.37(1.11,1.68) 1.22(0.99,1.49) 1.11(0.83,1.48) 0.88(0.69,1.11) 1.69(1.37,2.08) 1.58(1.29,1.92) 2.25(1.76,2.88) 1.94(1.58,2.37) 1.65(1.36,2.00) 1.53(1.28,1.84) 1.76(1.38,2.24) 1.90(1.58,2.29) 1.43(1.16,1.77) 1.61(1.33,1.96) 1.98(1.54,2.55) 1.55(1.26,1.91) 1.37(1.14,1.66) 1.42(1.19,1.70) 1.64(1.30,2.08) 1.40(1.16,1.69)
0.003 0.055 0.481 0.275 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.001 <0.001 <0.001 <0.001 0.001 <0.001 <0.001 <0.001
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1.31(1.11,1.56) 1.41(1.18,1.68) 1.65(1.30,2.09) 1.38(1.10,1.74)
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Table 5 Adjusted Clusters Effects Upon SDQ Subscales at 4 and 7 Years

Early Cluster Models Top 10% v. Lower 90% OR (95% CI) Pro,Social Peak @ 6 Peak @ 18 Mos. Worst Case Late Symptom Hyperactivity Peak @ 6 Peak @ 18 Mos. Worst Case Late Symptom Emotional Peak @ 6 Peak @ 18 Mos. Worst Case Late Symptom Conduct Peak @ 6 Peak @ 18 Mos. Worst Case Late Symptom Peer Peak @ 6 Peak @ 18 Mos. Worst Case Late Symptom
1
Later Cluster Models 7 years2 p p

1.27(1.03,1.56) 1.16(0.95,1.42) 0.99(0.74,1.33) 0.87(0.68,1.10) 1.50 (1.21,1.86) 1.42(1.16,1.75) 1.96(1.52,2.53) 1.78(1.44,2.20) 1.48(1.21,1.81) 1.47(1.21,1.77) 1.51(1.15,1.97) 1.69(1.39,2.06) 1.21(0.97,1.51) 1.41(1.15,1.72) 1.61(1.39,2.19) 1.36(1.09,1.68) 1.19(0.98,1.45) 1.28(1.07,1.54) 1.40(1.09,1.78) 1.25(1.03,1.52) 0.029 0.150 0.942 0.243 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.003 <0.001 0.085 0.009 <0.001 0.006 0.083 0.008 0.008 0.027
4 Years1 p
1.25(1.03,1.51) 1.16(0.94,1.43) 1.16(0.87,1.54) 0.99(0.74,1.31) 1.13 (0.95,1.34) 1.07 (0.89,1.28) 1.55 (1.23,1.96) 1.51 (1.21,1.88) 1.17(0.97,1.41) 1.23(1.01,1.49) 1.44(1.12,1.86) 1.49(1.18,1.89) 0.025 0.164 0.317 0.936 0.166 0.500 <0.001 <0.001 0.105 0.037 0.005 <0.001 <0.001 0.011 0.005 <0.001 0.033 0.022 0.038 0.267
7 years2
1.32(1.09,1.60) 1.27(1.03,1.56) 1.23(092,1.64) 0.91(0.68,1.23) 1.42 (1.17,1.72) 1.36 (1.11,1.67) 1.95 (1.51,2.52) 1.59 (1.23,2.04) 1.39(1.16,1.67) 1.33(1.09,1.61) 1.37(1.05,1.80) 1.63(1.29,2.06) 1.30(1.07,1.58) 1.34(1.09,1.64) 1.64(1.26,2.13) 1.26(0.97,1.64)
0.005 0.024 0.162 0.538 <0.001 0.004 <0.001 <0.001 <0.001 0.004 0.022 <0.001 0.009 0.005 <0.001 0.088 0.093 0.010 0.014 0.099
1.41(1.20,1.66) 1.26(1.05,1.50) 1.40(1.11,1.77) 1.68(1.36,2.08) 1.22(1.02,1.47) 1.25(1.03,1.52) 1.31(1.02,1.70) 1.15(0.90,1.48)
Adjusted for fish intake, FAI, Mother and home score, smoke during pregnancy, alcohol during pregnancy, race, breast feeding ever, housing inadequacy, parity, gestation age, paternal social, maternal education, birth weight, maternal age, gender. 2 Additional adjusted for Tonsils or adenoids removed ever.
Re
vi
ew
1.16(0.98,1.39) 1.27 (1.06,1.53) 1.36(1.06,1.75) 1.22(0.96,1.55)
Co
py
Page 24 of 33
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1a. Early Cluster
Peak @ 6 Month
3 2 SDB Z Score 1
AP
0 -1 -2 -3 Month 6 18 30 42
SN MB
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1b Early Cluster
Peak @ 18 Month
3 2 SDB Z Score 1 0 -1 -2 -3 Month 6 18 30 42
MB AP SN
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1c. Early Cluster
Worst Case
3 2 SDB Z Score 1
AP
0 -1 -2 -3 Month 6 18 30 42
SN MB
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1d. Early Cluster
Late Symptom
3 2 SDB Z Score 1
AP
0 -1 -2 -3 Month 6 18 30 42
SN MB
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1e. Early Cluster
Normal Case
3 2 SDB Z Score 1
AP
0 -1 -2 -3 Month 6 18 30 42
SN MB
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2a. Later Cluster
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2b. Later Cluster
Re vi ew Co py
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2c. Later Cluster
Re vi ew Co py
Page 32 of 33
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2d. Later Cluster
Re vi ew Co py
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2e. Later Cluster
Re vi ew Co py

Pediatrics 2011 Sleep Disordered Breathing

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Pediatrics 2011 Sleep Disordered Breathing

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Sleep Disordered Breathing in a Population-Based Cohort: Behavioral Effects at 4 and 7 Years

Journal: Manuscript ID: Article Type:

Pediatrics 2011-1402 Regular Article 10-May-2011

Date Submitted by the Author: Complete List of Authors:

Confidential - Not for Circulation

Confidential - Not for Circulation

Confidential - Not for Circulation

Confidential - Not for Circulation

Confidential - Not for Circulation

Confidential - Not for Circulation

Confidential - Not for Circulation

testing,24 ALSPAC,25, 26 and other UK cohort studies.27

Confidential - Not for Circulation

Confidential - Not for Circulation

Results: Data completion and attrition.

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13. 14. 15.

16. 17. 18. 19. 20.

Confidential - Not for Circulation

22. 23. 24. 25. 26.

28. 29. 30.

33. 34. 35. 36.

41. 42. 43.

Confidential - Not for Circulation

Confidential - Not for Circulation

55.2% 98.2% 6.2% 5.7% ---------

51.2% 98.3% 5.2% 4.5% ---------

60.0% 98.2% 6.5% 5.6% 4.9% 9.2%

50.6% 98.3% 4.9% 4.2% 3.9% 6.3%

60.7% 363 (47.5%) 18.4% 2.85 (2.38) 5.48 (1.75) 50.7%

57.8% 39.1% 11.1% 1.71 (1.85) 5.84 (1.61) 54.5%

2,328 (39.3%) 11.8%

1.74 (1.88) 5.81 (1.62) 54.5%

Confidential - Not for Circulation

54.1% 98.1% 5.4% 4.3%

52.8% 96.8% 5.5% 5.7%

55.7% 97.9% 7.7% 5.8%

52.0% 97.6% 7.1% 5.8%

49.3% 98.2% 5.0% 4.3%

<0.001 0.008 0.005 0.013

67.1% 43.7% 12.9% 2.12 5.71 53.8%

47.4% 17.3% 2.48

Confidential - Not for Circulation

Table 3: Cluster Effects Upon SDQ Total Scores at 4 and 7 Years

Later Cluster Models

1.38(1.17,1.63) 1.57(1.33,1.86) 2.02(1.62,2.51) 2.23(1.83,2.72)

<0.001 <0.001 <0.001 <0.001

1.43(1.18,1.72) 1.57(1.29,1.91) 2.12(1.66,2.72) 1.82(1.43,2.31)

<0.001 <0.001 <0.001 <0.001

1.65(1.34,2.04) 1.69(1.39,2.05) 2.42(1.90,3.09) 2.03(1.66,2.48)

<0.001 <0.001 <0.001 <0.001

1.20(1.00,1.45) 1.36(1.13,1.65) 1.66(1.29,2.13) 1.84(1.46,2.30)

0.051 <0.001 <0.001 <0.001

1.20(0.98,1.47) 1.29(1.05,1.60) 1.67(1.27,2.18) 1.50(1.16,1.94)

0.082 0.017 <0.001 0.002

1.39 (1.11,1.74) 1.49 (1.29,1.84) 1.89(1.45,2.47) 1.69 (1.35,2.10)