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Original Research: Sleep Disorders |

Greater Risk of Hospitalization in Children With Down Syndrome and OSA at Higher ElevationDown Syndrome and OSA at Elevation FREE TO VIEW

Kristin M. Jensen, MD; Carter J. Sevick, MS; Laura A. S. Seewald, BA; Ann C. Halbower, MD; Matthew M. Davis, MD, MAPP; Edward R. B. McCabe, MD, PhD; Allison Kempe, MD, MPH; Steven H. Abman, MD
Author and Funding Information

From the Children’s Outcomes Research Program (Drs Jensen and Kempe and Mr Sevick), Breathing Institute (Dr Halbower), Pediatric Heart Lung Center (Dr Abman), Department of Pediatrics (Drs Jensen and Halbower), Department of Internal Medicine (Dr Jensen), and Linda Crnic Institute for Down Syndrome (Ms Seewald), University of Colorado School of Medicine, Aurora, CO; Child Health Evaluation and Research Unit (Dr Davis), University of Michigan Health System, Ann Arbor, MI; Institute for Healthcare Policy and Innovation and Gerald R. Ford School of Public Policy (Dr Davis), University of Michigan, Ann Arbor, MI; and the Department of Medical Affairs, Office of Medicine and Health Promotion (Dr McCabe), March of Dimes Foundation, White Plains, NY.

CORRESPONDENCE TO: Kristin M. Jensen, MD, Departments of Pediatrics and Internal Medicine, University of Colorado School of Medicine, 13199 E Montview Blvd, Ste 300, Mailstop F-443, Aurora, CO 80045; e-mail: kristin.jensen@ucdenver.edu


Preliminary data from this analysis were presented by Dr Jensen at the Pediatric Academic Societies Meeting, April 28-May 1, 2012, Boston, MA.

FUNDING/SUPPORT: This study was funded in part by the Robert Wood Johnson Foundation Clinical Scholars Program and in part through gift funds provided by the Anna and John J. Sie Foundation and the Global Down Syndrome Foundation to the Linda Crnic Institute for Down Syndrome.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(5):1344-1351. doi:10.1378/chest.14-1883
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BACKGROUND:  Children with Down syndrome (DS) are at high risk for OSA. Increasing elevation is known to exacerbate underlying respiratory disorders and worsen sleep quality in people without DS, but whether altitude modulates the severity of OSA in DS is uncertain. In this study, we evaluate the impact of elevation (≤ 1,500 m vs > 1,500 m) on the proportion of hospitalizations involving OSA in children with and without DS.

METHODS:  Merging the 2009 Kids’ Inpatient Database with zip-code linked elevation data, we analyzed differences in the proportion of pediatric hospitalizations (ages 2-20 years) involving OSA, pneumonia, and congenital heart disease (CHD), with and without DS. We used multivariable logistic regression to evaluate the association of elevation with hospitalizations involving OSA and DS, adjusting for key comorbidities.

RESULTS:  Proportionately more DS encounters involved OSA, CHD, and pneumonia within each elevation category than non-DS encounters. However, the risk difference for hospitalizations involving OSA and DS increased disproportionately at higher elevations (DS: 16.2% [95% CI, 9.2%-23.2%]; non-DS: 0.1% [95% CI, −0.4% to 0.7%]). Multivariable estimates of relative risk indicate increased risk for hospitalization involving OSA at higher elevations for people with DS and in children aged 2 to 4 years or with two or more chronic conditions.

CONCLUSIONS:  At elevations > 1,500 m, children with DS and OSA have a disproportionately higher risk for hospitalization than children with OSA without DS. This finding has not been described previously. With further validation, this finding suggests the need for greater awareness and earlier screening for OSA and its complications in patients with DS living at higher elevations.

Figures in this Article

Occurring in one in 1,000 live births worldwide, Down syndrome (DS) is the most common identifiable cause of intellectual disability; the estimated prevalence in the United States is 250,000 people.1,2 OSA is among the most common comorbidities associated with DS, with some prevalence estimates reaching > 90%.37 This increased risk results from anatomic and physiologic differences in people with DS, such as small upper airways, poor upper airway tone, laryngomalacia, pulmonary hypoplasia, and lingual tonsils.313 The American Academy of Pediatrics (AAP) recommends that all children with DS undergo a sleep study by age 4 years with screening for symptoms of OSA at all well-child examinations.14,15 However, parental assessments of OSA symptoms correlate poorly with disease status,10,16 such that many people with DS do not undergo appropriate testing. This is especially concerning given that the consequences of untreated OSA range from behavioral disturbances and learning difficulties to neuronal changes in the brain, pulmonary hypertension, and right-sided heart failure.4,17

High elevation is a known risk factor for exacerbating respiratory disorders and worsening sleep quality, due to central apnea and hypoxemia.18,19 Although higher elevation increases the risk for central apnea and repeated intermittent oxygen desaturations in all people, young children are especially vulnerable to altitude-related disorders due to smaller airways, fewer alveoli, and increased airway reactivity.20 These elevation-related differences can be further exacerbated in children with underlying respiratory conditions, including the airway anomalies often associated with DS.11,18

Despite known anatomic and physiologic risks, to our knowledge no studies have addressed whether elevation is associated with clinically significant differences in OSA in people with DS. Therefore, we sought to characterize the association of increasing elevation on the proportion of hospitalizations with a diagnosis of OSA in children with DS vs those without DS.

Data Sources
2009 Kids’ Inpatient Database:

Patient-encounter data were obtained using the 2009 Kids’ Inpatient Database (KID) from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality.21 The KID is a nationally representative sample of all-payer inpatient care for children ≤ 20 years old in the United States, containing data from nearly 4 million hospital-sampled discharges for children from 44 states. Among these 44 states, 25 included hospital zip code data that were used for this analysis.21 This study was determined exempt by the Colorado Combined Institutional Review Board because the KID is a deidentified, publicly available dataset (study #12-0958).

Determination of Elevation:

Elevation data were provided by the Altitude Research Center at the University of Colorado.22 The geographic unit for this study was the 2000 US Census five-digit zip code tabulation area, which approximates US Postal Service zip code boundaries. Zip code elevations were estimated using elevations for the centroids of a grid composed of squares with 30-m sides, using data from a US Geological Survey digital elevation model.23,24 To minimize the effect of mountains on mean elevation within zip code tabulation areas, the model assumes that there were no residences above 3,200 m and excluded elevations above this level.25 We then matched elevations for zip codes to hospital zip codes from the 2009 KID. Of the > 3.4 million hospital zip codes in the 2009 KID, elevation data were not available for 70 using the previously described method. We calculated elevation data for these 70 zip codes from latitude and longitude coordinates that corresponded to a given zip code provided freely by SAS Analytics (SAS Institute Inc), using the US Geological Survey “getElevation” method.26,27 For subcategorization, we used elevation categories of ≤ 1,500 m vs > 1,500 m, based on the global distribution of the human population28 and generally accepted definitions of low altitude (≤ 1,500 m) and moderate to high altitude (> 1,500 m).18 For the reader’s edification, 1,500 m is equivalent to 4,921 feet.

Cohort Identification

The 2009 KID included 6,393,803 encounters after applying survey weights. We identified our cohort from the 57% of all encounters that listed a corresponding hospital zip code (weighted n = 3,674,514). We then excluded all patients < 2 years old (weighted n = 2,109,918) to prevent misclassification of our outcomes of interest with neonatal causes of apnea and pneumonia. This led to our final cohort of 1,564,596 hospital encounters (weighted number).

Variable Definitions

We identified our diagnoses of interest by the presence of appropriate International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes within any of the 25 diagnostic fields available for each encounter.29 DS was defined by ICD-9-CM code 758.0.29,30 We defined congenital heart disease (CHD) by the presence of ICD-9-CM codes 745-745.9, 746-746.9, and 747-747.49; and hypothyroidism by ICD-9-CM codes 243, 244.3, 244.8, and 244.9.29 OSA was defined by ICD-9-CM codes 327.20, 327.23, 327.29, 780.51, 780.53, and 780.57; overweight/obese was defined as ICD-9-CM codes 278.0-278.02; and pneumonia was defined as ICD-9-CM codes 480.0-486.9.29

Age, sex, number of procedures, length of stay (LOS), and number of chronic conditions were predetermined by Healthcare Cost and Utilization Project. We defined “excess chronic conditions” as the number of chronic conditions in excess of DS and OSA. We stratified age by 2 to 4 years vs 5 to 20 years to evaluate differences in risk for patients younger than the AAP guidelines for OSA evaluation in children with DS.14 We defined “risk difference” as the proportion of patients hospitalized at elevations > 1,500 m with the condition of interest minus the proportion of those hospitalized at elevations ≤ 1,500 m with that condition.

Data Analysis

Data analysis was performed taking into account the complex sampling and weighting scheme of the 2009 KID using the PROC SURVEY functions in SAS 9.3 (SAS Institute Inc). We applied sampling weights to all analyses based on documentation for the 2009 KID, with the corresponding survey-weighted results reported here.31 Univariable comparisons were conducted using the SURVEYFREQ procedure within SAS. Using a multivariable relative risk (RR) model, we assessed the strength of associations between elevation and OSA in hospitalized patients with and without DS. The final model for RR of hospitalization involving OSA included DS, age, sex, chronic conditions in excess of DS and OSA, and elevation category. We did not include CHD or obesity in this model, due to multicollinearity with key variables of interest and poor fidelity of the associated diagnostic codes, respectively.32

Study Cohort

We identified 1,564,596 discharges of patients 2 to 20 years old with available hospital zip codes, of which 6,869 encounters (0.4% of the study cohort) involved patients with DS. On average, hospitalizations for people with DS occurred at younger ages, had longer lengths of stay, and involved a greater number of chronic conditions than hospitalizations for people without DS (age 2-4 years at hospitalization: DS 39%, non-DS 14%, P < .001; LOS ≥ 2 days: DS 78%, non-DS 59%, P < .001; two or more chronic conditions in excess of DS and OSA: DS: 61%, non-DS 33%, P < .001). A higher proportion of hospitalizations for people with DS involved CHD, hypothyroidism, OSA, and overweight/obesity (Table 1).

Table Graphic Jump Location
TABLE 1 ]  Demographics and Characteristics of Hospitalizations by Down Syndrome Status: High Elevation vs Low Elevation

Data given as No. (%) unless otherwise indicated.

a 

P values were significant at P < .05 for all comparisons between the cohort with Down Syndrome and the cohort without Down Syndrome within each elevation category (≤ 1,500 m or > 1,500 m).

Differences in Cardiopulmonary Diagnoses by DS and Elevation

We conducted subgroup analyses comparing patients hospitalized at elevations ≤ 1,500 m vs > 1,500 m within DS and non-DS encounters. These comparisons revealed similar proportions of sex, age, LOS, and number of chronic conditions within each diagnostic category (DS and non-DS). Proportions of the common DS-related comorbidities of CHD, hypothyroidism, and overweight/obesity were also similar across elevation categories for patients with and without DS (Table 1). P values were significant at P < .05 for all comparisons between DS and non-DS cohorts within each elevation category (≤ 1,500 m or > 1,500 m). The point estimates for these comparisons are identical to those in Table 1 for comparisons within DS and non-DS.

OSA:

Within each elevation category, proportionally more DS encounters involved a diagnosis of OSA than did non-DS encounters (Table 1). However, the risk difference (ie, the difference in proportions between encounters at elevations > 1,500 m vs ≤ 1,500 m) was substantially greater for patients with DS and OSA than those without DS. As demonstrated in Figure 1, the risk difference for a hospitalization at elevations > 1,500 m to involve DS and OSA was 16.2%, whereas the risk difference in people with OSA but without DS was 0.1%.

Figure Jump LinkFigure 1 –  Risk differences (proportions of diagnosis among encounters at elevations > 1,500 m minus proportions at elevations ≤ 1,500 m) of hospitalizations involving OSA.Grahic Jump Location

Subgroup analysis of hospitalizations for children with OSA showed increased LOS with higher elevation within both the DS and non-DS cohorts (DS with OSA: n = 1,005; LOS ≥ 2 days: ≤ 1,500 m: 68.7%, > 1,500 m: 77.4%, P = .07. Non-DS with OSA: total n = 13,674; LOS ≥ 2 days: ≤ 1,500 m: 62.4%, > 1,500 m: 77%; P = .0043.)

Pneumonia:

Similar to OSA, more DS encounters involved a diagnosis of pneumonia than non-DS encounters within each elevation category (Table 1). We also observed increased pneumonia hospitalizations at higher elevations in both the DS and non-DS populations. In contrast to OSA, the risk difference in hospitalizations involving pneumonia at elevations > 1,500 m vs ≤ 1,500 m showed substantial overlap in the CIs between elevation categories (DS: 10.6% [95% CI, −1.9% to 23.1%]; non-DS: 1.4% [95% CI, 0.5%-2.3%]), such that we cannot demonstrate a definitive association between elevation and pneumonia in the DS population (Fig 1).

Congenital Heart Disease:

We evaluated the differences in hospitalization patterns for the common DS-related comorbidity of CHD, the severity of which is adversely affected by hypoxia. Similar to both OSA and pneumonia, proportionately more DS encounters involved CHD than non-DS encounters (Table 1). Unlike OSA but similar to pneumonia, the risk difference between hospitalizations involving CHD demonstrated substantial overlap in CIs between DS categories (DS: 4.7% [95% CI, −7.2% to 16.6%]; non-DS: 0.3% [95% CI, −0.6% to 1.3%]), indicating that elevation is not definitively associated with CHD hospitalizations in the DS population (Fig 1).

OSA and DS: RR Model

We evaluated the association of elevation with hospitalizations involving both DS and OSA with a multivariable RR model controlling for DS, age category, the number of chronic conditions in excess of DS and OSA, and elevation category (Fig 2). With this model, we observed a RR of 2.49 for hospitalizations involving OSA in people with DS at elevations > 1,500 m (95% CI, 1.68-3.69) compared with a nonsignificant RR of 1.11 in people without DS. We also found increased risk for hospitalization involving OSA in patients who were 2 to 4 years old (RR, 4.36; 95% CI, 3.99-4.78), male (RR, 1.65; 95% CI, 1.55-1.75), and those with two or more chronic conditions in excess of DS and OSA (two to three excess chronic conditions: RR, 4.08 [95% CI, 3.76-4.43]; four or more excess chronic conditions: RR, 9.77 [95% CI, 8.78-10.86]).

Figure Jump LinkFigure 2 –  Adjusted relative risk of hospitalizations involving OSA. The relative risk for each domain in this model is distinct from the other predictors in this model.Grahic Jump Location

In this sample of pediatric hospitalizations across the United States, we found that elevations > 1,500 m were associated with increased risk for hospitalizations involving OSA in children with DS compared with those without DS. While OSA is a known comorbidity of DS, a pronounced, increased risk associated with higher elevations has not been previously described. Previous work by Tarasiuk et al33 shows that children and adults with OSA demonstrate more health-care use compared with aged-matched patients without OSA, even at lower altitudes. AAP guidelines suggest formal sleep studies in children with DS by 4 years old14; however, our data indicate that children with DS ages 2 to 4 years had additional risk for hospitalization in the presence of OSA (RR, 2.49).

Our findings are consistent with prior work by other investigators. In 2010, Swiss researchers reported exacerbations of sleep apnea at elevations > 1,500 m in untreated, normally developed adults with OSA.34 DS is a documented risk factor for high-altitude pulmonary edema (HAPE),18,3537 with a 2008 French case report36 suggesting increased risk for HAPE at elevations from 1,500 to 2,500 m in people with DS when they suffer from OSA. The International Mountaineering and Climbing Federation lists DS as a predisposing factor for HAPE in its Consensus Statement on the management of children at altitude.38

Multiple factors contribute to high risk for OSA in people with DS, including small upper airways, poor upper airway tone, laryngomalacia, tracheomalacia, and lingual tonsils.35,710 Individuals with DS have been shown to have persistence of a double-capillary network and pulmonary hypoplasia with decreased alveolarization, as well as elevated endostatin levels that may contribute to abnormal vascular growth in DS.13,16,3942 We speculate that interactions between intermittent hypoxia with OSA in the setting of abnormal upper airways and abnormal distal lung structure may contribute to our findings of increased risk for hospitalizations involving OSA in children with DS at higher elevations. That is, we postulate that elevation exacerbates the underlying physiologic abnormalities present in DS, such that intermittent hypoxia intensifies the underlying DS phenotype; consequently, children with DS and OSA become more symptomatic at higher elevations than children with OSA without DS.

Our study has significant clinical implications for the management of people with DS at higher elevations. Prevalence estimates for OSA in children with DS reach 90%,35,7,10 yet the presence of OSA in people with DS correlates poorly with parental assessment.10,16 Consequently, many children with DS do not undergo evaluation for OSA. The consequences of unrecognized OSA include behavioral disturbances, cognitive impairment, pulmonary hypertension, right-sided heart failure, and cardiovascular disease.4,7,10,16,17,43,44 As mentioned, the presence of OSA alone has been shown to increase health-care use.33 It has also been suggested that OSA contributes to the increased prevalence of pulmonary hypertension seen in children with DS.4 Our data demonstrate increased hospitalizations in children with OSA and DS living at higher elevations, suggesting a synergistic deleterious effect between DS and OSA at higher elevation. We also observed an additional risk for hospitalization in children with DS and OSA ages 2 to 4 years. This indicates that earlier diagnosis and management of OSA may be warranted in children with DS. Given the alignment between our findings and the medical literature reviewed here, we speculate that unrecognized or undertreated OSA contributes to the severity of respiratory illness in children with DS, which is a leading cause of their mortality, second only to CHD.45,46

Limitations

Our study has several limitations common to studies using data obtained from hospital encounters. First, the KID includes encounter-level data, so we were unable to determine if multiple encounters in the dataset resulted from the same patient. Each discharge is listed as a discrete encounter for a given hospital, such that transfers between institutions are listed as separate encounters. While this raises concerns regarding frequently hospitalized patients, previous studies indicate that the majority of adults with DS are hospitalized less than once yearly.47 While pediatric patients with DS may display different patterns of inpatient care than adults, we do not anticipate these differences would impact our study outcomes.

Second, the identification of our cohort and study outcomes is reliant upon billing codes, which are subject to errors of omission and commission. From previous work among members of the study team, we believe that such errors will not result in a systematic bias that would significantly impact the outcome of this study.30,47,48

Third, 45% of states (representing 42% of available discharges in the KID) opted to exclude zip code and county-level designations when they provided their data to the Agency for Healthcare Research and Quality. Therefore, our analyses represent patterns of hospital care in the states that reported zip codes in the 2009 KID (Arizona, California, Colorado, Florida, Iowa, Illinois, Kentucky, Massachusetts, Maryland, Minnesota, Montana, North Carolina, New Hampshire, New Jersey, Nevada, New York, Oregon, Pennsylvania, Rhode Island, Utah, Virginia, Washington, Wisconsin, West Virginia). We conducted a sensitivity analysis of our findings by attributing elevation category to states without hospital zip codes, based on the median elevation within those states, and found no differences in the trends identified in this study. For this reason, we excluded the states without a documented zip code and conducted our analysis using elevation data determined by the methods described.

Fourth, the elevation categories were assigned by location of hospitalization, not patient residence, which may inaccurately assign elevation categories in some circumstances. To affect our findings in material ways, individuals would have to reside in a different elevation category than the hospital to which they were admitted. The frequency with which this occurs is not available from the dataset, nor is it known more generally.

Finally, insights into the mechanisms underlying these findings are limited by the lack of availability of medical records that would allow us to investigate the evaluation of patients with OSA and their related complications, interventions, and long-term outcomes. These limitations notwithstanding, we believe that the presence of such prominent differences as those observed in our study represent a significant association of elevation with OSA for individuals with DS.

Children with DS and OSA have a disproportionately higher risk for hospitalization at elevations > 1,500 m than children without DS who have OSA, with additional risks noted in children < 4 years old or with two or more chronic conditions. Current AAP guidelines suggest formal sleep studies in children with DS by age 4 years14; however, our data indicate that younger children with DS had increased risk for hospitalization in the presence of OSA. To validate our results, we are evaluating longitudinal data in both inpatient and outpatient settings. Further study will help define the need to adopt earlier screening policies, increase inpatient monitoring, and improve provider education for children with DS living at higher elevations.

Author contributions: K. M. J. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. K. M. J. wrote the first draft of the manuscript; C. J. S., L. A. S. S., A. C. H., M. M. D., E. R. B. M., A. K., and S. H. A. contributed to the study design, data analysis and interpretation, and the writing of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Halbower is on the editorial board of CHEST. The other authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The funding sources for this study had no influence on the study design, collection, analysis, or interpretation of the data, the writing of this report, or the decision to submit this report for publication.

Other contributions: The authors wish to thank Achamyeleh Gebremariam, MS, of the Child Health Evaluation and Research Unit at the University of Michigan, for supplying the 2009 Kid’s Inpatient Database; Deborah Thomas, PhD, for sharing the elevation data from the Altitude Research Center at the University of Colorado; and Doron Shmueli, MS, of the University of Colorado, for his work on the preliminary analysis of this study. We thank Wolfgang C. Winkelmayer, MD, ScD, MPH, and Michael Hurley, MS, of Stanford University, and Dustin A. Hoppe, BS, and Deidre Kile, MS, of the University of Colorado for their assistance with zip code elevation calculations. We also thank Brenda Beaty, MPH, of the University of Colorado, for her careful review of the statistical analyses used in this study.

AAP

American Academy of Pediatrics

CHD

congenital heart disease

DS

Down syndrome

HAPE

high-altitude pulmonary edema

ICD-9-CM

International Classification of Diseases, Ninth Revision, Clinical Modification

KID

Kids’ Inpatient Database

LOS

length of stay

RR

relative risk

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Chi TPL, Krovetz J. The pulmonary vascular bed in children with Down syndrome. J Pediatr. 1975;86(4):533-538. [CrossRef] [PubMed]
 
Zorick TS, Mustacchi Z, Bando SY, et al. High serum endostatin levels in Down syndrome: implications for improved treatment and prevention of solid tumours. Eur J Hum Genet. 2001;9(11):811-814. [CrossRef] [PubMed]
 
Ryeom S, Folkman J. Role of endogenous angiogenesis inhibitors in Down syndrome. J Craniofac Surg. 2009;20(suppl 1):595-596. [CrossRef] [PubMed]
 
Stenmark KR, Abman SH. Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia. Annu Rev Physiol. 2005;67:623-661. [CrossRef] [PubMed]
 
Marcus CL, Brooks LJ, Draper KA, et al; American Academy of Pediatrics. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012;130(3):e714-e755. [CrossRef] [PubMed]
 
Halbower AC, Mahone EM. Neuropsychological morbidity linked to childhood sleep-disordered breathing. Sleep Med Rev. 2006;10(2):97-107. [CrossRef] [PubMed]
 
Englund A, Jonsson B, Zander CS, Gustafsson J, Annerén G. Changes in mortality and causes of death in the Swedish Down syndrome population. Am J Med Genet A. 2013;161A(4):642-649. [CrossRef] [PubMed]
 
Miodrag N, Silverberg SE, Urbano RC, Hodapp RM. Deaths among children, adolescents, and young adults with Down syndrome. J Appl Res Intellect Disabil. 2013;26(3):207-214. [CrossRef] [PubMed]
 
Jensen KM, Davis MM. Health care in adults with Down syndrome: a longitudinal cohort study. J Intellect Disabil Res. 2013;57(10):947-958. [CrossRef] [PubMed]
 
Jensen KM, Taylor LC, Davis MM. Primary care for adults with Down syndrome: adherence to preventive healthcare recommendations. J Intellect Disabil Res. 2013;57(5):409-421. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Risk differences (proportions of diagnosis among encounters at elevations > 1,500 m minus proportions at elevations ≤ 1,500 m) of hospitalizations involving OSA.Grahic Jump Location
Figure Jump LinkFigure 2 –  Adjusted relative risk of hospitalizations involving OSA. The relative risk for each domain in this model is distinct from the other predictors in this model.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Demographics and Characteristics of Hospitalizations by Down Syndrome Status: High Elevation vs Low Elevation

Data given as No. (%) unless otherwise indicated.

a 

P values were significant at P < .05 for all comparisons between the cohort with Down Syndrome and the cohort without Down Syndrome within each elevation category (≤ 1,500 m or > 1,500 m).

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Zorick TS, Mustacchi Z, Bando SY, et al. High serum endostatin levels in Down syndrome: implications for improved treatment and prevention of solid tumours. Eur J Hum Genet. 2001;9(11):811-814. [CrossRef] [PubMed]
 
Ryeom S, Folkman J. Role of endogenous angiogenesis inhibitors in Down syndrome. J Craniofac Surg. 2009;20(suppl 1):595-596. [CrossRef] [PubMed]
 
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Marcus CL, Brooks LJ, Draper KA, et al; American Academy of Pediatrics. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012;130(3):e714-e755. [CrossRef] [PubMed]
 
Halbower AC, Mahone EM. Neuropsychological morbidity linked to childhood sleep-disordered breathing. Sleep Med Rev. 2006;10(2):97-107. [CrossRef] [PubMed]
 
Englund A, Jonsson B, Zander CS, Gustafsson J, Annerén G. Changes in mortality and causes of death in the Swedish Down syndrome population. Am J Med Genet A. 2013;161A(4):642-649. [CrossRef] [PubMed]
 
Miodrag N, Silverberg SE, Urbano RC, Hodapp RM. Deaths among children, adolescents, and young adults with Down syndrome. J Appl Res Intellect Disabil. 2013;26(3):207-214. [CrossRef] [PubMed]
 
Jensen KM, Davis MM. Health care in adults with Down syndrome: a longitudinal cohort study. J Intellect Disabil Res. 2013;57(10):947-958. [CrossRef] [PubMed]
 
Jensen KM, Taylor LC, Davis MM. Primary care for adults with Down syndrome: adherence to preventive healthcare recommendations. J Intellect Disabil Res. 2013;57(5):409-421. [CrossRef] [PubMed]
 
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