The relationship between chronic health conditions and cognitive deficits in children, adolescents, and young adults with down syndrome: A systematic review.

BACKGROUND: Individuals with Down syndrome are predisposed to a number of chronic health conditions, but the relationship between these conditions and cognitive ability is not clear. The primary objective of this systematic review is to assess this relationship by evaluating studies that measure cognitive performance in the context of Down syndrome-associated chronic health conditions.
METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Studies included in this review (1) included children, adolescent, and young adult participants with Down syndrome and one or more co-occurring health conditions; (2) were quantitative; and (3) reported outcomes related to both chronic health conditions and cognitive performance. A set of predetermined chronic health conditions that are common in Down syndrome (e.g. sleep disorders, congenital heart disease, thyroid disease, seizure disorders, and pulmonary hypertension) were selected based on prevalence rates in Down syndrome.
RESULTS: Fifteen studies met inclusion criteria. The majority these of studies assessed cognitive performance in association with sleep disorders (47%) and congenital heart disease (47%). Fewer studies reported on the effect of thyroid disease (7%) and seizure disorders (7%) on cognitive ability. None of the studies reported cognitive outcomes related to pulmonary hypertension. Of the chronic health conditions evaluated, associations between sleep disorders and cognitive dysfunction were most common among individuals with Down syndrome.
CONCLUSIONS: Individuals with Down syndrome exhibit deficits in cognitive ability, particularly related to attention, executive function and verbal processing. These deficits may be further exacerbated by the presence of chronic health conditions, particularly sleep disorders. Individuals with Down syndrome and co-occurring sleep disorders may benefit from early interventions to mitigate their risk for adverse cognitive outcomes.

Introduction

Individuals with Down syndrome (DS) exhibit impairments in cognitive ability, and are at increased risk for a wide range of chronic health conditions. Common comorbidities observed in DS include hearing or vision loss (60–75%), sleep disordered breathing such as obstructive sleep apnea (OSA) (70%), congenital heart defects (50%), thyroid disorders (4–18%), seizure disorders (1–13%), and persistent pulmonary hypertension (5%) [1-3]. In the general pediatric population, these conditions impact cognitive ability to varying degrees, contributing to deficits in attention, memory, executive function, visual-motor integration, and associated with lower intelligence quotient (IQ) [4-16]. While the above-described health conditions are common in DS, to date, only neurosensory deficits have been assessed for a relationship with cognitive ability [17, 18]. The objective of this systematic review is to address this gap in knowledge by determining from available evidence the impact of non-neurosensory chronic health conditions on cognitive functioning in DS.

Individuals with DS have a mild to moderate intellectual disability. The cognitive phenotype characteristic of DS is variable but includes deficits in attention, executive function (i.e., a broad range of higher-order skills that are necessary for goal directed behavior, including inhibition, working memory, cognitive flexibility, set-shifting, planning, and behavior regulation), expressive language, verbal processing, and explicit long-term memory, whereas certain aspects of visuospatial ability, associative learning, and implicit long-term memory may be relatively preserved [19]. Although cognitive deficits characteristic of DS often occur in the presence of multiple co-occurring health conditions [20], the extent to which specific conditions influence cognitive ability has not been systematically investigated. The objective of this systematic review is to evaluate and summarize evidence for a relationship between chronic health conditions commonly observed in DS and cognitive disability. Comparisons of cognitive ability (i.e. outcome data) were made between individuals with DS and diagnosed with a prespecified health condition (i.e. sleep disorders, cardiovascular disorders, thyroid disorder, seizure disorder, pulmonary disorder) and individuals with DS and without these health conditions.

Materials and methods

A systematic review was conducted in collaboration with an academic medical librarian, and in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) guidelines [21] (S1 Table), rather than from an existing protocol specific to this investigation. Using the MEDLINE (PubMed, PsycINFO) and EMBASE databases, a search was performed for all English-language articles published between 1948 and October, 2019 using the following Medical Subject Heading (MESH) terms ‘down syndrome’, ‘trisomy 21’, ‘mongolism’ AND ‘chronic health conditions’, ‘chronic diseases’, ‘comorbid*’, ‘multimorbid*’, ‘congenital heart disease’, ‘congenital heart malformation’, ‘heart defect’, ‘cardiovascular disorder’, ‘hypertension,’ ‘hyperthyroid’, ‘hypothyroid’, ‘thyroid disorder’, ‘thyroid disease’, ‘sleep apnea’, ‘sleep disturbances’, ‘sleep disorder*’, ‘sleep interrupt*’, ‘epilepsy’, ‘infantile spasms’, ‘seizures’, ‘cardiopulmonary’, ‘pulmonary disease’, ‘pulmonary disorder’, ‘pulmonary defect’ AND ‘memory’, ‘memories’, ‘attention’, ‘executive function’, ‘intelligence quotient’, ‘IQ’, ‘quotient*’, ‘intelligen*’, ‘cognitive’, ‘neurocognitive’, ‘neurodevelop*’, ‘cognition’, ‘visual-spatial’, ‘visual-integrat*’, ‘visual motor’, ‘motor skill’, ‘reaction*’, ‘latenc*’, and ‘processing speed’ (completed: October 9, 2019). All studies yielded by this search strategy were then extracted to a database by the academic medical librarian.

All articles underwent two rounds of screening by two independent reviewers (KG, HC), in accordance with the Cochrane guidelines for the reporting of systematic reviews [22]. In the initial round, titles and abstracts were reviewed to determine whether articles met designated inclusion criteria: 1) study conducted in children, adolescents, and/or young adults with DS who were diagnosed with at least one co-occurring health condition (limited to sleep disordered breathing, cardiovascular disorder, thyroid disorder, seizure disorder, pulmonary disorder), 2) study reported outcomes for cognitive performance in the context of chronic health conditions, employing standardized metrics for assessing neurocognitive outcomes, i.e. formal assessments of attention, memory, and executive function. The definition of executive function employed for this review is a broad construct of higher-order processes that can be measured through performance-based cognitive testing or proxy-reported standardized ratings from the perspective of a caregiver, parent or teacher. Therefore, studies that employed informal observations or non-standardized metrics of cognition were excluded. Given that the focus of this review was on children, adolescents and young adults with DS, studies that included older participants with a comorbid diagnosis of Alzheimer’s disease and/or dementia were also excluded. Case reports, review articles, validity/reliability studies, conference abstracts, editorials, and animal studies were excluded at this stage.

In the second round of review, both reviewers then conducted a full text screening of the refined list to determine the final number of included studies, ensuring that each paper met the designated inclusion criteria. Discrepancies between reviewers that were related to article eligibility were presented to the study team and a consensus was reached through discussion. To identify additional publications not discovered using traditional indexing resources, all articles referenced by the included studies also underwent full text review. The risk of bias was assessed for each included article using the Cochrane Risk of Bias in Systematic Reviews (ROBIS) tool (S2 Table) [23]. Risk of bias was assessed across four different domains related to 1) study eligibility criteria, 2) identification and selection of studies, 3) data collection and study appraisal, and 4) synthesis and findings. The risk of bias for each of the domains, as well as for the overall risk of bias for in the review, were rated as unclear, low, or high. Only studies with a low risk of bias were included in the systematic review.

Results

We identified 7,990 articles, of which 34 met criteria for full text review and 15 were determined eligible for inclusion in this review (Fig 1). All of the studies included individuals with DS between the ages of 0 to 18 years, and in three studies extended to young adults up to 31 years. The included articles comprised 7 prospective cohort studies, 4 cross-sectional studies, and 4 case-control studies that were predominantly conducted in the U.S. and U.K., as well as in Israel, Greece, Thailand, and Taiwan. Sample sizes varied from 12 to 226 (mean 64, median 38). Included articles are summarized in Table 1, categorized by type of chronic health condition assessed. Risk of biases is shown in S2 Table (see Supporting information).

Fig 1

Table 1

Summary of studies examining the associations between chronic health conditions and cognitive performance in individuals with DS.

Author(s), Year; CHC Category	Study Type (location)	Age range (years): n Population	Neurocognitive measure(s)	Neurocognitive Scoring/Domains	Neurocognitive Results
Andreou et al., 2002 Sleep disorder	Prospective cohort (Greece)	17–25: 12 DS+SDB	Raven Progressive Matrices (RPM)	Raw: Visual-Spatial, Reasoning 1) Sum of correct items	SDB negatively correlated with visual-spatial scores, particularly in adults with DS+ untreated SDB.
Chen et al., 2013 Sleep disorder	Prospective cohort (U.S.)	14–31: 29 DS+parent- rated OSA	1) Choice Reaction Time test2) Verbal Fluency test3) Knock-Tap Test	Raw: Executive Function 1) mean reaction time 2) sum of words generated 3) sum of correct responses	The severity of parent-rated OSA in DS moderately correlated with executive function performance. More severe symptoms predicted poorer performance.
Breslin et al., 2014 Sleep disorder	Prospective cohort (U.S.)	7–12: 38 DS±OSA	Cambridge Neuropsych. Test Automated Battery (CANTAB):1) Intra-Extra Dimensional Set Shifting2) Paired-Associative Learning Task3) Simple Reaction Time TaskKaufman Brief Intelligence Test (KBIT-II)	Raw: Executive Function 1) Stages completed 2) Mean errors 3) Median reaction timeSS: Full, Verbal, Non-verbal IQ	DS+OSA completed fewer stages for the set shifting task of cognitive flexibility. Reaction time and mean errors did not differ between groups.DS+OSA had lower verbal IQ. No differences in full-scale or non-verbal IQ.
Brooks et al., 2015 Sleep disorder	Prospective cohort (U.S.)	6–14: 25 DS±OSA	Stanford-Binet Intelligence Scales, 4th Edition (SB-4)Beery-Buktenica Developmental Test of Visual-Motor Integration (Berry VMI)Conners Hyperactivity Index *Parent rept	SS: Full IQ, Bead Memory, Vocabulary, Quantitative Pattern Analysis, Memory for Sentences, ComprehensionSS: Visual, Motor, and Visual-Motor IntegrationSS: Attention	No differences in cognitive performance between DS children with and without OSA. Total sleep time and latency contributed to cognitive performance.Of 10 DS+OSA, the 5 treated with adenotonsillectomy and/or CPAP showed improvements in parent-reported attention.
Joyce et al., 2017 Sleep disorder	Case control (U.K.)	2–5: 44 DS+SDB: 22 TD+SDB: 22	Mullen Scales of Early Learning (MSEL)	Sc: Gross motor, fine motor, visual reception, receptive language, expressive languageRaw: sum of total score	SDB in preschoolers with DS not associated with cognitive outcomes involving motor skills and language.
Joyce et al., 2019 Sleep disorder	Prospective cohort (U.K.)	3–6: 80 DS±OSA	Behavior Rating Inventory of Executive Function–Preschool Version (BRIEF-P) *Parent rept	T score: Inhibit, shift, emotional control, working memory, inhibitory self-control index, flexibility index, emergent metacognition index, global executive composite, plan/organize	OSA associated with poorer working memory, emotional control, and shifting (aspects of executive function).
Lee et al., 2019 Sleep disorder	Prospective cohort(Taiwan)	6–18: 30 DS±OSA	Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R)Wechsler Intelligence Scale for Children (WISC-IV)Wechsler Adult Intelligence Scale (WAIS-III)Developmental Neuropsychological Assessment (NEPSY) visuomotor precision	Sc: Vocabulary (this was the only subtest reported in the results)SS: FSIQSc: Fine motor skills	After adjustment for age and FSIQ, DS+OSA not associated with deficits in vocabulary or visuomotor precision.In a subgroup of ages 6–12 years, OSA associated with lower WPPSI-R vocabulary. No associations with visuomotor precision.
Rihtman et al., 2010 Cardiovascular disorder	Cross-sectional (Israel)	6–17: 60 DS±other congenital anomalies (36 CHD)	Stanford-Binet Intelligence Scales (SB-4)Beery-Buktenica Developmental Test of Visual-Motor Integration (Berry VMI)	SS: Full IQ, Verbal, Abstract/Visual, Qualitative Reasoning, Short-Term MemorySS: Visual, Motor, and Visual-Motor Integration	Presence or severity of congenital anomaly (i.e. CHD) not associated with cognitive performance.
Visootsak et al., 2011 Cardiovascular disorder	Case control (U.S.)	0.5–2: 29 DS+CHD: 12 DS-CHD: 17	Bayley Scales of Infant and Toddler Development (Bayley-III)	SS: Cognitive, Language, and Motor.	Infants with DS+CHD had lower motor composite scores, but no differences in cognitive or language composite scores.
Visootsak et al., 2013 Cardiovascular disorder	Case control (U.S.)	2–3.5: 29 DS+CHD: 12 DS-CHD: 17	Mullen Scales of Early Learning (MSEL)	Sc: Expressive Language, Receptive Language, Visual Reception, Fine Motor	No differences in expressive, receptive language, or visual and fine motor.
Alsaied et al., 2016 Cardiovascular disorder	Cross-sectional (U.S.)	0–2: 36 DS+CHD: 12 DS-CHD: 243–5: 38DS+CHD: 7 DS-CHD: 316–18: 104DS+CHD: 26 DS-CHD: 78	Bayley Scales of Infant and Toddler Development (Bayley-III)Peabody Developmental Motor Scales (PDMS-II)Brief Rating Inventory of Executive Function (BRIEF) *Parent reptDifferential Ability Scales (DAS-II)Stanford-Binet Intelligence Scales (SB-5)	SS: Language, MotorSc:" Receptive Language, Expressive Language, Fine Motor, Gross MotorRaw: Visual Motor, GraspingSS: Fine MotorT score: Executive function, Initiate, Global executive composite, Behav. Regulation, Emotional control, Inhibit, Plan/Organize, Monitor, Working memory, Composite organization of materialsSS: Nonverbal IQSS: Full IQ, Knowledge, Qualitative Reasoning, Visual Spatial	Infants with DS+CHD had lower receptive, expressive, and language scores. No differences in fine/gross motor scores.Preschoolers with DS+CHD did not differ in auditory or expressive language, visual motor, grasping, or fine motor scores.Children with DS+CHD did not differ in executive function, nor in performance-based measures of nonverbal IQ, full IQ, knowledge, qualitative reasoning, and visual spatial skills.
Visootsak et al., 2016 Cardiovascular disorder	Case-control (U.S.)	0.5–2: 57 DS+CHD: 20 DS-CHD: 37	Bayley Scales of Infant and Toddler Development (Bayley-III)	Raw Composite: Cognitive, Expressive Language, Receptive Language, Gross Motor, Fine Motor	In adjusted analyses, DS+ASVD had lower gross motor and cognition/ expressive language scores.
Rosser et al., 2018 Cardiovascular disorder (among other CHC)	Cross-sectional (U.S.)	6–25: 226 DS+CHD:122 DS-CHD: 104	Arizona State Cognitive Battery: CANTAB, reaction time, paired-associate learning, spatial span, intra/extradimensional set-shiftingVirtual computer-generated arenaModified dots taskFinger sequencing taskDevelopmental Neuropsychological Assessment (NEPSY) visuomotor precisionKaufman Brief Intelligence Test (KBIT-II)Scales of Independent Behavior-Revised (SIB-R)*Parent reptBehavior Rating Inventory of Executive Function-School Age (BRIEF)* Parent reptNisonger Child Behavior Rating Form (NCBRF) *Parent rept	Z scores: Associative learning, reaction time, memory span, set-shiftingRaw: Spatial learningRaw: Inhibitory control, working memoryRaw: Sensorimotor functionSc: Fine motor skillsSS: Full, Verbal, Non-verbal IQSc: Motor, social and communication, personal living, community living skillsT score: Executive function, Initiate, Global executive composite, Behav. Regulation, Emotional control, Inhibit, Plan/Organize, Monitor, Working memory, Composite organization of materialsSc: Compliant/calm, adaptive social, conduct problems, insecure/anxious, hyperactive, self-injury/stereotypic, self-isolated/ritualistic, overly sensitive	CHD requiring surgery in the first years of life was not associated with poorer cognitive ability for both performance-based and proxy-reported assessments, after adjusting for gender, race/ethnicity, socioeconomic status.
Wasant et al., 2008 Cardiovascular & thyroid disorders (among other CHC)	Cross-sectional (Thailand)	3–6: 100	Capute Scales of Cognitive Adaptive Test/Clinical Linguistic and auditory Milestones Scales (CAT/CLAMS)	SS: Developmental Quotient (DQ)	CHD, but not thyroid disorders, was associated with lower DQ. Family income and age at the first speech-training program were the only independent predictors of DQ.
Tapp et al., 2005 Seizure disorder	Prospective cohort (U.S.)	1–3: 29 DS+IS: 8 DS-seizures: 21	Bayley Scales of Infant and Toddler Development (Bayley-III)	Sc: Receptive Language, Expressive Language, Fine Motor, Gross MotorSS: Cognitive	DS+IS scored lower across all cognition domains. IS treatment delays did not contribute to neurodevelopmental outcomes.

DS = Down syndrome, TD = typically developing without Down syndrome, SDB = sleep disordered breathing, WS = William’s syndrome, ID = Intellectual disability, CHC = Chronic health condition, CHD = Congenital heart disease, ASVD = Atrioventricular septal defect, ASD = Atrial septal defect, OSA = Obstructive sleep apnea, IS = infantile spasms, SQ = sleep quality, IQ = intelligence quotient, DQ = developmental quotient, MA = mental age, SS = standard composite score, SD = 15. Sc = Scaled scores based on age-normed T scores.

Sleep disordered breathing and obstructive sleep apnea

Seven of fifteen articles (47%) reported on the spectrum of respiratory sleep disorders observed in association with cognitive performance in DS [24-31]. In six out of seven articles, presence of a respiratory sleep disorder was determined by polysomnography or an equivalent measure (domiciliary cardio-respiratory polygraphy, employed by Joyce, et al., [28] and [29]), and in one article, OSA was determined by parent report (Sleep Questionnaire, Chen, et al.). Two articles reported on sleep disordered breathing (SDB) and five on obstructive sleep apnea (OSA). SDB was defined by the number of apnea events per hour, heart rate, and oxygen saturation, whereas OSA determined by polysomnography was defined by stricter criteria, specifically the number of apnea and hypopnea events per hour of sleep. The studies that examined effects of OSA on cognition used thresholds commonly employed in pediatric populations and ranging from ≥1 - ≥1.5 events/hour, although one study used an adult-defined cutoff of ≥5 events/hour (Brooks, et al.) All seven studies employed a diverse set of performance-based cognitive assessments, noted for each study to measure aspects of executive function, visual-spatial skills, reasoning, attention, memory, motor skills, verbal fluency, cognitive flexibility and intelligence quotients (IQ).

Two articles reported on sleep disordered breathing (SDB) and seven on obstructive sleep apnea (OSA). In five of these studies, presence of OSA or SDB was associated with impaired visuospatial abilities, as well as deficits in aspects of executive function including slower reaction times, decreased verbal fluency, decreased cognitive flexibility as measured by set shifting ability, poorer emotional control, poorer working memory, poorer language function, and significantly lower verbal IQ [24, 26, 27, 29, 30]. One study reported on a potential age-effect of sleep disorders, showing that younger children with DS and OSA (ages 6–12 years) were more likely to have impaired expressive vocabulary as measured by a subtest of the Wechsler Preschool and Primary Scale of Intelligence, when compared with adolescents and young adults with DS between the ages of 12–25 years [30]. Frequency of sleep apnea per hour was also negatively correlated with visual-perceptual ability, as measured by the Raven’s Progressive Matrices [32] in adolescents and young adults with DS, with increased apneic frequency associated with worse performance [24].

Three studies supplemented polysomnography with parent-reported sleep behaviors [26, 27, 31]. Breslin et al. found no difference in daytime sleepiness or total sleep time between DS children with and without OSA, noting poor correlation between parent-reported outcomes and polysomnography. Brooks et al. noted a relationship between sleep latency (time to sleep onset) and intelligence assessed by the Stanford-Binet. Chen et al. noted that difficulties with initiating and maintaining sleep was negatively correlated with verbal fluency performance. Two studies found no associations with sleep disorders and cognitive function [28, 31]; however, both employed non-standard definitions of OSA and SBD (see Discussion). In sum, the majority of studies that examined the effect of OSA and SBD in DS observed an increased risk for cognitive impairment in younger children and adolescents with DS and co-occurring sleep disorders.

Cardiovascular disorders

Seven out of fifteen articles (47%) reported on cardiovascular disorders in association with cognitive performance, all of which focused on congenital heart disease (CHD) [33-39]. Again, a wide range of performance-based cognitive assessments were used to measure IQ, developmental quotients (DQ), visual-motor abilities, gross/fine motor skills, language, behavior, cognition, learning and memory, and aspects of executive function including set-shifting, behavioral and emotional control, working memory, and planning/organizing skills.

The most commonly reported disorder was congenital atrioventricular septal defect (AVSD), a moderately complex CHD often corrected within the first year of life. Among infants and toddlers between the ages of 6–36 months, there were no clear associations between CHD and cognitive ability, with mixed reports regarding composite scores of cognition, motor, and language revealing a significant association in some reports and no association in other reports [33–36, 38]. Studies that detected cognitive impairment assessed younger children with DS within three years of a surgical repair that had been performed during the first year of life [33-35]. In contrast, studies conducted in older children and young adults observed no impact of CHD on IQ, motor skills, language ability, spatial learning, sensorimotor function, and performance-based and parent-reported aspects of executive function [33, 37, 39]. In the largest of these cohorts (n = 234), there was no association between CHD and either performance-based or parental ratings of cognitive performance in children ages 6–25 years [39], suggesting that corrected CHD does not have a significant impact on long-term cognitive development. Although lower DQ was reported in one study that included children three to six years old [38], cognitive deficits were not noted among children with DS and CHD age ≥3 years, albeit these conclusions are limited by the cross-sectional nature of these studies.

Thyroid disorders

One out of fifteen articles (7%) reported on thyroid disorders in association with cognitive performance in DS, together with multiple other co-occurring chronic health conditions. The study employed a performance-based cognitive assessment (Capute Scales of Cognitive Adaptive Test/Clinical Linguistic and auditory Milestones Scales) to measure DQ in children ages 3–6 years [40], and did not observe an association between DQ and early thyroid dysfunction, specifically, congenital hypothyroidism that was treated within the first 2 months of life [38].

Seizure disorders

One out of fifteen articles (7%) reported on infantile spasms, a severe, refractory type of seizure disorder, in association with cognitive performance in DS [41]. The study employed a performance-based measure of IQ (Bayley Scales of Infant Development), which includes composite scores of cognition, language, and motor ability [42]. In comparison with age-matched children with DS and without a history of infantile spasms (1 to 3 years), children with DS and infantile spasms demonstrated significantly lower scores in domains of cognition, receptive language, expressive language, fine motor, and gross motor skills (i.e., 1.5 standard deviations lower across all domains) [41].

Pulmonary disorders

None of the studies reported on pulmonary disorders and cognitive performance in DS, possibly reflecting a relatively low prevalence of pulmonary hypertension in children with DS.

Discussion

In sum, evidence obtained in this systematic review suggests that respiratory sleep disorders, specifically SBD and OSA, are associated with poorer cognitive function in children and young adults with DS, particularly in the domains of verbal IQ, visual-perceptual skills and aspects of executive function including set shifting ability, emotional control, verbal fluency and working memory. OSA has been defined in pediatric populations as at least 1 apnea or hypopnea event per hour of sleep [43, 44]. The three studies that found an association between OSA and cognitive function adhered to this definition, whereas the two that found no association did not: one employed adult age-based thresholds for defining OSA (≥5 events per hour of sleep) and the other used median cutoffs for defining high or low apnea hypopnea index in the study population, which may explain the lack of associations observed. When defined by polysomnography and using the above threshold, the incidence of OSA in DS participants for the included studies ranged from 51–80%, consistent with recent reports [3]. CHD was also associated with cognitive performance, but the results were less consistent and the effect limited to younger children with recent history of surgical repair, suggesting short-term rather than permanent impact on cognitive ability. Of note, although both CHD and SDB/OSA are common in DS, none of the included studies considered the contributions of these conditions, if co-occurring, on cognitive function. Additional studies are needed to address this deficit in our understanding of the impact of DS-associated chronic health conditions on cognitive function.

There was only one report of association between infantile spasms and cognitive performance, but the results were consistent with the higher rates of cognitive disability observed in conjunction in non-DS children diagnosed with this seizure disorder [45]. Lastly, although chronic, uncontrolled hypothyroidism is known to adversely impact cognitive ability [46], if corrected early there was no discernable impact on cognitive ability in children with DS. Chronic uncorrected hypothyroidism is rare, so that there are limited opportunities to assess the impact of untreated hypothyroidism on cognitive ability in DS.

In our review, poor quality sleep had the strongest and most consistent association with an adverse impact on cognitive development in children with DS, particularly in the areas of verbal IQ and aspects of executive function. The American Academy of Pediatrics guidelines for health supervision in children with DS include recommendations for obtaining a pediatric sleep study or polysomnogram prior to the age of four [1]. Early diagnosis and intervention may mitigate the detrimental effects of poor sleep quality during early brain development, a critical period of growth and high neuroplasticity, so that individuals with DS may reach their full cognitive potential.

Interventions that improve sleep quality are available, and can lead to subsequent improvements in cognitive ability. Early intervention should be considered to mitigate the negative effects of recurrent, long-term apnea events. Tonsillectomy and/or adenoidectomy (TA) is one of the more commonly used and successful surgical options available for treating childhood apnea [47]. In children with DS, TA improves sleep quality and reduces symptoms of OSA and reduces symptoms of OSA [48-51], suggesting potential benefit for mitigating the negative impact of OSA on cognitive ability. In severe cases, alternate and complementary surgical approaches may be employed [52, 53]. However, there is evidence for somewhat reduced efficacy of TA in mitigating OSA in children with DS, who often experience persistent moderate to severe residual OSA [49, 50]. Also of note, while early TA intervention improves nonverbal reasoning, fine motor skills, and selective attention in non-DS children [54], the impact of TA on cognitive outcomes in DS has not yet been investigated.

In cases where surgical intervention is not successful, continuous positive airway pressure (CPAP) device may also alleviate OSA symptoms. However, compliance with these devices is often poor, especially among individuals with DS [55]. While no DS-specific studies have been conducted to improve CPAP adherence through systematic desensitization or exposure techniques, such techniques have been successfully employed in DS to treat phobias [56, 57], and may also serve useful for increasing CPAP compliance. Use of devices designed for pediatric populations that feature brightly-colored fabric patterns and cushioned shapes may also reduce discomfort and encourage use.

Limitations to this review include a search strategy that was restricted to two databases and only English language articles. Only a small number of published studies were found that evaluated both cognitive performance and chronic health conditions in DS. In addition, the inconsistent methods employed for assessing cognitive ability precluded conducting a meta-analysis of the studies reviewed, necessitating a systematic review that was largely qualitative. Although there were associations noted between the above described chronic health conditions and cognitive performance in DS, it is important to note that the sample sizes for many these studies were relatively small, ranging from 12 to 69 participants for the majority of the studies (80%), and therefore may have lacked sufficient power to draw strong conclusions. Moreover, the lack of association between chronic health conditions and cognitive ability that we observed among older DS individuals may be related to a widening gap in cognitive ability between chronologically age-similar DS and non-DS children as they age, which can strengthen the floor effect over time. Although we included only those studies with a low risk of global bias (based on the Cochrane ROBIS guidelines), we identified independent potential biases to our review, such as studies with insufficient power to detect large effects due to a small sample size and a lack of reported sensitivity analyses (S2 Table), findings that were expected given the scarcity of literature on cognition related to health conditions in DS.

In sum, the impact of chronic health conditions on cognitive ability in DS is understudied. This systematic review is the first to assess the potential burden of chronic health conditions on cognitive performance in a neurodevelopmentally vulnerable population. Our findings suggest a need for more comprehensive characterization of the burden of chronic health conditions experienced by DS populations, and how these conditions relate to social, physical and cognitive ability. Further, the observed impact of respiratory sleep disorders on cognition warrants further study of sustainable, early interventions for children with DS that may mitigate the impact of this condition on cognitive potential.

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26 Jun 2020

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The Relationship between Chronic Health Conditions and Cognitive Deficits in Children, Adolescents, and Young Adults with Down Syndrome: A Systematic Review

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Reviewer #1: This systematic review found 15 studies which investigated the relationship between chronic health conditions and cognition in children with Down syndrome (DS). The study used the gold standard of PRISMA for selecting the papers included in the systematic review. Almost half of the studies focused on sleep disorders which are very common in DS but a large number also focused on cardiovascular disorders particularly congenital heart disease which is also very common in the DS population. The summary of the studies appears in the supplementary Table S1 and I would urge the authors to include this table in the main body of the manuscript. The manuscript summarises important information regarding cognitive outcomes in children with DS and how these might be improved by treating other common chronic health conditions. However there are a number of limitations in the format in which the review is currently presented.

Major comments:

As sleep disorders and congenital heart disease are both extremely common in DS it is not surprising that most of the studies have related these disorders to cognitive function. What the review does not make clear is how these conditions were treated when they presented in the same child. Children with DS also are much more likely to be affected by sleep problems associated with the initiation and maintenance of sleep – and these are not mentioned see Rosen D, Lombardo A, Skotko B, Davidson EJ. Parental perceptions of sleep disturbances and sleep-disordered breathing in children with Down syndrome. Clin Pediatr (Phila). 2011;50:121-5; Hoffmire CA, Magyar CI, Connolly HV, Fernandez ID, van Wijngaarden E. High prevalence of sleep disorders and associated comorbidities in a community sample of children with Down syndrome. J Clin Sleep Med. 2014;10:411-9; Churchill SS, Kieckhefer GM, Bjornson KF, Herting JR. Relationship between sleep disturbance and functional outcomes in daily life habits of children with Down syndrome. Sleep. 2015;38:61-71. Up to 97% of children with DS also have obstructive sleep apnoea depending on the patient selection criteria, definitions and methodology used (Walter et al., Insights into the effects of sleep disordered breathing on the brain in infants and children: imaging and cerebral oxygenation measurements. Sleep Medicine Reviews. 2019 Dec 16;50:101251. doi: 10.1016/j.smrv.2019.101251). The review needs to discuss how sleep disorders in general and congenital heart disease may interact and it the papers identified if subjects had both sleep disorders and congenital heart disease.

Sleep disordered breathing (SDB) is the global term generally used to cover both central and obstructive breathing patterns during sleep. Obstructive SDB describes a spectrum of severity of disorders which ranges from primary snoring which is not associated with sleep disruption or gas exchange abnormalities to obstructive sleep apnoea (OSA). In children, OSA is usually defined as an obstructive apnoea hypopnoea index of > 1 event per hour of sleep. The authors need to rewrite the section of discussion which does not make it plain if the papers are talking about polysomnographically defined OSA or parental reports of SDB.

The section on treatment of OSA also needs to be rewritten as adenotonsillectomy is the first line of treatment for OSA in both typically developing children and children with DS. Adenotonsillectomy is less effective in children with DS as the authors report, and CPAP is frequently used when OSA is not completely resolved with adenotonsillectomy. Other forms of surgery are also common in children with DS include tracheostomy, mandibular distraction osteogenesis for children with significant retrognathia, genioglossus advancement, rapid maxillary advancement, lingual tonsillectomy, tongue reduction, tongue hyoid advancement or suspension, uvulopalatopharyngoplasty, tonsillar pillar plication, and laryngotracheoplasty (Rosen D. Management of obstructive sleep apnea associated with Down syndrome and other craniofacial dysmorphologies. Current Opinion in Pulmonary Medicine. 2011;17:431-6) and recently hypoglossal nerve stimulation (Diercks GR, Wentland C, Keamy D, Kinane TB, Skotko B, de Guzman V, et al. Hypoglossal Nerve Stimulation in Adolescents With Down Syndrome and Obstructive Sleep Apnea. JAMA Otolaryngol Head Neck Surg. 2017).

The co-occurrence of sleep disorders and congenital heart disease should also be discussed regarding thyroid and seizure disorders.

Reviewer #2: Thank you for giving me the opportunity to read this interesting systematic review on the relationship between cognitive deficits and chronic health conditions in people with Down Syndrome. The manuscript requires significant changes:

1.It is not clear why certain chronic health conditions were selected, e.g. why was hearing impairment (a common health condition) not included?

2. Was Mosaic Down syndrome included as it is not described as a search term.

3. Was hand searching and reference lists for articles carried out? if not, why was this not included as part of the methodology as it is standard practice. Please also state the date range within which articles were searched.

4. What tool was used to assess the risk of bias? please provide a reference.

5.How was data extracted? was this done by one or more raters?

6. No information is given on how the data was analysed. Given that quantitative outcomes were included, there should be an explicit statement of why a meta-analysis was not performed. There appears to be a narrative synthesis of data but there is no attempt to provide statistics for any of the relationships discussed.

7. In the results section, it would be helpful to provide a summary of how many studies were of each type, the variation in terms of sample sizes and where the studies were conducted (this information should be included in the tables)

8. In the discussion section, please provide a discussion of the limitations of the study (e.g. only three electronic databases searched, only English language articles etc...).

**********

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Reviewer #1: No

Reviewer #2: No

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5 Aug 2020

Review Comments to the Author

Reviewer 1

Reviewer 1 requested that we include Table S1, a summary of the studies reviewed, in the main body of the manuscript. This has been done, and is now shown as Table 1.

1. As sleep disorders and congenital heart disease are both extremely common in DS it is not surprising that most of the studies have related these disorders to cognitive function. What the review does not make clear is how these conditions were treated when they presented in the same child. Children with DS also are much more likely to be affected by sleep problems associated with the initiation and maintenance of sleep – and these are not mentioned.

see Rosen D, Lombardo A, Skotko B, Davidson EJ. Parental perceptions of sleep disturbances and sleep-disordered breathing in children with Down syndrome. Clin Pediatr (Phila). 2011;50:121-5; Hoffmire CA, Magyar CI, Connolly HV, Fernandez ID, van Wijngaarden E. High prevalence of sleep disorders and associated comorbidities in a community sample of children with Down syndrome. J Clin Sleep Med. 2014;10:411-9; Churchill SS, Kieckhefer GM, Bjornson KF, Herting JR. Relationship between sleep disturbance and functional outcomes in daily life habits of children with Down syndrome. Sleep. 2015;38:61-71.

Up to 97% of children with DS also have obstructive sleep apnea depending on the patient selection criteria, definitions and methodology used (Walter et al., Insights into the effects of sleep disordered breathing on the brain in infants and children: imaging and cerebral oxygenation measurements. Sleep Medicine Reviews. 2019 Dec 16;50:101251. doi: 10.1016/j.smrv.2019.101251). The review needs to discuss how sleep disorders in general and congenital heart disease may interact and in the papers identified if subjects had both sleep disorders and congenital heart disease.

No studies assessed the interaction between CHD and sleep disorders and their combined impact on cognitive function. This is clearly an area of unmet need, and our discussion has been revised to note this deficit in the literature (page 9, lines 171-175). We have also included the incidence of OSA across all included studies, when defined according to pediatric thresholds, in our discussion (page 9, lines 166-168) and have included reference to a recent meta-analysis determining the incidence of OSA in DS (70%).

Thank you for the suggestion to include sleep behaviors. We have added a paragraph describing associations observed in these studies between cognition and the initiation/maintenance of sleep (page 7, lines 107-112).

2. Sleep disordered breathing (SDB) is the global term generally used to cover both central and obstructive breathing patterns during sleep. Obstructive SDB describes a spectrum of severity of disorders which ranges from primary snoring which is not associated with sleep disruption or gas exchange abnormalities to obstructive sleep apnoea (OSA). In children, OSA is usually defined as an obstructive apnoea hypopnoea index of > 1 event per hour of sleep. The authors need to rewrite the section of discussion which does not make it plain if the papers are talking about polysomnographically defined OSA or parental reports of SDB.

We sincerely appreciate this comment and note that SDB and OSA were not clearly defined in our review. We have clarified how the studies evaluated and defined SDB and OSA in the body of the text (page 6, lines 83-92), modified Table 1 accordingly, and also included a discussion of the standard definition employed in the pediatric setting and how adherence to this standard may have impacted the results of our review (page 9, 161-168).

3. The section on treatment of OSA also needs to be rewritten as adenotonsillectomy is the first line of treatment for OSA in both typically developing children and children with DS. Adenotonsillectomy is less effective in children with DS as the authors report, and CPAP is frequently used when OSA is not completely resolved with adenotonsillectomy. Other forms of surgery are also common in children with DS include tracheostomy, mandibular distraction osteogenesis for children with significant retrognathia, genioglossus advancement, rapid maxillary advancement, lingual tonsillectomy, tongue reduction, tongue hyoid advancement or suspension, uvulopalatopharyngoplasty, tonsillar pillar plication, and laryngotracheoplasty (Rosen D. [Rosen, 2011 #2752]. Current Opinion in Pulmonary Medicine. 2011;17:431-6) and recently hypoglossal nerve stimulation (Diercks GR, Wentland C, Keamy D, Kinane TB, Skotko B, de Guzman V, et al. Hypoglossal Nerve Stimulation in Adolescents With Down Syndrome and Obstructive Sleep Apnea. JAMA Otolaryngol Head Neck Surg. 2017).

The co-occurrence of sleep disorders and congenital heart disease should also be discussed regarding thyroid and seizure disorders.

The discussion has been re-written and re-organized to summarize current recommendations regarding the management of sleep disorders in DS. We have added the reference regarding surgical options as suggested. Older references have been removed, and primary intervention is now noted as adenotonsillectomy (page 10, lines 188-198). Regarding co-occurrence of conditions, please see our response to comment #1.

Reviewer 2

1.It is not clear why certain chronic health conditions were selected, e.g. why was hearing impairment (a common health condition) not included?

Thank you for this question. We selected the five most common chronic health conditions that occur in Down syndrome, and excluded neurosensory conditions as there is already data that presence of these comorbidities impact cognitive ability. We have clarified this in our introduction as follows, on page 3, lines 9-12).

o ‘While the above-described health conditions are common in DS, to date, only neurosensory deficits have been assessed for a relationship with cognitive ability (17, 18). The objective of this systematic review is to address this gap in knowledge by determining from available evidence the impact of non-neurosensory chronic health conditions on cognitive functioning in DS.’

2. Was Mosaic Down syndrome included as it is not described as a search term.

Mosaic Down syndrome was not included as a search term, as it is often an exclusion criteria for studies evaluating outcomes in DS. Of the included studies, Breslin et al. and Rosser et al. specifically mention excluding subjects with mosaicism.

3. Was hand searching and reference lists for articles carried out? if not, why was this not included as part of the methodology as it is standard practice. Please also state the date range within which articles were searched.

We relied on a medical librarian to conduct a complex search of the electronic database, and then supplemented this search with manual reference list scans. Specifically, articles referenced by the included studies underwent full text review to identify any additional publications not discovered using traditional indexing resources. A statement clarifying this aspect of our approach has been added to the Methods (page 5, line 63-65). The date range of studies searched has now been included in the Methods, page 4, lines 32-33.

4. What tool was used to assess the risk of bias? please provide a reference.

Thank you for this question. We used the Cochrane Risk of Bias in Systematic Reviews (ROBIS) tool to assess bias, and have now described this approach more completely in the Methods (page 5, lines 65-70) and in the Discussion (page 11, lines 217-220). The relevant reference has also been added.

5.How was data extracted? was this done by one or more raters?

All potentially eligible articles were initially extracted by a medical librarian into a database. Both raters then independently reviewed the title and abstracts to determine initial eligibility (1st round), and then in the second round read the full articles to determine final eligibility. After each round, any conflicts were resolved by an independent third party. In the Methods, the review strategy has been revised to clarify how the articles were selected.

6. No information is given on how the data was analysed. Given that quantitative outcomes were included, there should be an explicit statement of why a meta-analysis was not performed. There appears to be a narrative synthesis of data but there is no attempt to provide statistics for any of the relationships discussed.

Thank you for making this point. We have now included an explicit statement for why a meta-analysis was not performed, specifically, 1) because the studies included represent a wide range of chronic health conditions and employed inconsistent methods for assessment of cognitive ability, and 2) because we felt our question was sufficiently answered with qualitative data (page 11, lines 208-210).

7. In the results section, it would be helpful to provide a summary of how many studies were of each type, the variation in terms of sample sizes and where the studies were conducted (this information should be included in the tables)

We agree, and have revised Table 1 to include this information, in addition to correcting a few errors we noted in the table. We have also provided information regarding the types of studies included in Table 1, as well as in the text (page 5, lines 74-77):

o ‘The included articles comprised 7 prospective cohort studies, 4 cross-sectional studies, and 4 case-control studies that were predominantly conducted in the U.S. and U.K., as well as in Israel, Greece, Thailand, and Taiwan. Sample sizes varied from 12 to 226 (mean 64, median 38).’

8. In the discussion section, please provide a discussion of the limitations of the study (e.g. only three electronic databases searched, only English language articles etc...).

In response to this request, we have expanded our discussion of study limitations to include the search strategy that was employed (page 9, lines 206-207):

o ‘Limitations to this review include a search strategy that was restricted to two databases and only English language articles.’

26 Aug 2020

PONE-D-20-14548R1

The Relationship between Chronic Health Conditions and Cognitive Deficits in Children, Adolescents, and Young Adults with Down Syndrome: A Systematic Review

PLOS ONE

Dear Dr. Gramatges,

Thank you for resubmitting your work to PLOS ONE. Please make the corrections posed by Reviewer #1 so I can render a decision on this manuscript.

==============================

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

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Reviewer #2: Yes

**********

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Reviewer #1: N/A

Reviewer #2: N/A

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have addressed my comments, however the relationship between sleep disordered breathing and obstructive sleep apnoea is not quite correct. Sleep disordered breathing describes a spectrum of respiratory disorders during sleep which ranges from simple or primary snoring at the mild end which is not associated with sleep disruption or gas exchange abnormalities. Primary snoring is defined when children snore but there is < 1 apnoea or hypopnoea per hour of sleep. Obstructive sleep apnoea is associated with sleep disruption and gas exchange abnormalities and is usually defined when there is > 1 apnoea or hypopnoea per hour of sleep. Page 44 line 161 needs to be corrected apnea or hypopnea rather than and. Page 41 the section on SDB needs to be clarified. Sleep disorder should be changed to respiratory sleep disorder.

Definitions are available in Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: Update of the 2007 AASM manual for the scoring of sleep and associated events. Deliberations of the sleep apnea definitions task force of the american academy of sleep medicine. J Clin Sleep Med 2012;8:597-619.

Reviewer #2: I am satisfied that the authors have addressed my comments and thank the authors for their response.

I have no further comments.

**********

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

==============================

Please submit your revised manuscript by November, 2020. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

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Section Editor

PLOS ONE

27 Aug 2020

August 26, 2020

Editorial Board

PLOS One

Re: PONE-D-20-14548R1, revised manuscript, systematic review

Dear Editorial Board,

Thank you for reviewing our manuscript, entitled ‘The Relationship between Chronic Health Conditions and Cognitive Deficits in Children, Adolescents, and Young Adults with Down Syndrome: A Systematic Review.’ We have revised the manuscript, included with ‘tracked changes,’ and provide a point-by-point response to the reviewer comments detailed below.

Thank you for your consideration of this systematic review for publication in the PLOS One.

Sincerely,

M. Monica Gramatges, MD, PhD

Associate Professor of Pediatrics

ORCID: 0000-0002-0947-104X

Review Comments to the Author

Reviewer 1

The authors have addressed my comments, however the relationship between sleep disordered breathing and obstructive sleep apnoea is not quite correct. Sleep disordered breathing describes a spectrum of respiratory disorders during sleep which ranges from simple or primary snoring at the mild end which is not associated with sleep disruption or gas exchange abnormalities. Primary snoring is defined when children snore but there is < 1 apnoea or hypopnoea per hour of sleep. Obstructive sleep apnoea is associated with sleep disruption and gas exchange abnormalities and is usually defined when there is > 1 apnoea or hypopnoea per hour of sleep. Page 44 line 161 needs to be corrected apnea or hypopnea rather than and. Page 41 the section on SDB needs to be clarified. Sleep disorder should be changed to respiratory sleep disorder.

Definitions are available in Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: Update of the 2007 AASM manual for the scoring of sleep and associated events. Deliberations of the sleep apnea definitions task force of the american academy of sleep medicine. J Clin Sleep Med 2012;8:597-619.

Thank you for this request for clarification.

Line 161 has been corrected to read:

“OSA has been defined in pediatric populations as at least 1 apnea or hypopnea event per hour of sleep.”

The recommended reference (Berry et al.) has been added as a citation here.

Line 81 has been corrected to read:

“Seven of fifteen articles (47%) reported on the spectrum of respiratory sleep disorders observed in association with cognitive performance in DS.”

Similarly, the term ‘respiratory’ has been added as clarification in lines 83, 158, and 228.

31 Aug 2020

The Relationship between Chronic Health Conditions and Cognitive Deficits in Children, Adolescents, and Young Adults with Down Syndrome: A Systematic Review

PONE-D-20-14548R2

Dear Dr. Gramatges,

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Section Editor

PLOS ONE

2 Sep 2020

PONE-D-20-14548R2

The Relationship between Chronic Health Conditions and Cognitive Deficits in Children, Adolescents, and Young Adults with Down Syndrome: A Systematic Review

Dear Dr. Gramatges:

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