Methods
Given the recent NICE systematic review of the evidence for intervention in OME and the recognition that studies of OME in Down syndrome were very limited and of poor quality, this review was not designed to be a systematic review of all the evidence. Rather, the primary aim of this targeted review was to identify and assess the current state of literature regarding OME in children with Down syndrome to provide an informed background to the study and to contribute to the VOI analyses.
This review summarises the published research into glue ear in children with Down syndrome including the efficacy of interventions, cost-effectiveness and the barriers to recruitment and participation in health research, specifically in terms of studies incorporating RCT methodology.
Search strategy
The search strategy involved an electronic search of the following 15 electronic databases from inception through to June 2012:
The Cochrane Library
EconLit
Tufts Cost-Effectiveness Analysis (CEA) Registry
MEDLINE
PubMed
PsycINFO
EMBASE
Applied Social Sciences Index and Abstracts (ASSIA)
Maternity and Infant Care
PsycARTICLES
Web of Science
Web of Knowledge (WoK)
British Psychological Society (BPS)
American Psychological Society (APS)
Centre for Reviews and Dissemination (CRD).
The search terms used included ‘children’, ‘Down* syndrome’, ‘otitis media with effusion’, ‘OME’, ‘glue ear’, ‘infant’, ‘research’. The terms were used in multiple combinations. Criteria for inclusion were (1) studies that were published in English; (2) studies that were published in peer-reviewed journals or government policy documentation; (3) studies that focused on children with Down syndrome who were experiencing OME; (4) studies that demonstrated the efficacy of treatments for OME (including surgical procedures such as grommets, adenoidectomy, HAs, antibiotics and any other appropriate treatments); and (5) RCTs that involved children with Down syndrome.
Criteria for exclusion were (1) studies that were focused on other forms of otitis media (unless specifically relevant) or other hearing problems (e.g. sensorineural hearing loss); (2) studies that were focused on Down syndrome in the general population, not affected by otitis media (e.g. studies of motor development); (3) studies of otitis media not in the Down syndrome population or other relevant populations (e.g. general population); (4) studies that were published in the grey literature or letters; and (5) studies that were focused on adults and not children.
Inclusion
Publications identified from the electronic search strategy were scrutinised by title and abstract to determine inclusion. Those reporting evidence that met the inclusion criteria were retrieved, and read by one reviewer for final decision on whether or not the data would contribute. The reference lists of included publications were searched to identify any further relevant studies.
Data extraction
A narrative synthesis was adopted. It was expected that included studies would be heterogeneous owing to the broad nature of the review. Relevant articles were reviewed to identify the topic of the article, the results and the methods used.
Results
The literature review confirmed the findings of the NICE report,17 in that there is a paucity of research/literature concerning the treatment options and effectiveness of such treatments for OME in children who have Down syndrome. No systematic reviews specifically concerning the efficacy of OME interventions in children with Down syndrome were identified. For example, Browning et al.21 in their evaluation of RCTs on the efficacy of grommets (or ventilation tubes) for hearing loss associated with OME acknowledged the exclusion of Down syndrome from clinical trials, referring to participants with Down syndrome to note only how RCTs excluded them as a group.
Prevalence
Prevalence rates of glue ear at various ages have been reported as 59%,11 54.9%,12 77%,13 68%2 and 93%,2 as detailed below.
Schwartz and Schwartz11 investigated 39 non-institutionalised infants and children (mean age 3.1 years) with Down syndrome in the USA during the summer period and found that 59% showed evidence of ‘at least unilateral middle-ear effusion’.
In a survey using parent questionnaires and interviews in Australia to explore health problems and checks in 204 children with Down syndrome, Selikowitz12 reported that a glue ear diagnosis had been made in 112 children (54.9%).
Tomasevic13 reported a total population of 93 children, aged 18 months to 18 years, with Down syndrome, in Oxford, UK. Glue ear was diagnosed in 54 children (77%) and grommets were inserted in 29 children (54% of 54).
Barr et al.,2 reporting findings from a prospective database set up since 2004 to capture the ear, nose and throat (ENT) health status of every preschool child with Down syndrome (aged 9 months to 6 years) in Greater Glasgow, accessing the community-based surveillance clinic, note that the prevalence of ENT problems is high in children with Down syndrome and that surgical treatment is frequently required. Between September 2004 and September 2008, data were available for 79 (91%) of the children. The prevalence of glue ear was 93% at 1 year old, although not all were symptomatic, dropping to 68% by 5 years old. During the time frame of the study, 37% of children were listed for surgery at some point, either adenotonsillectomy for obstructive symptoms or grommet insertion for OME. Barr et al.2 recommend an active approach of regular ENT and audiology observation followed by early intervention, aimed at maximising long-term health and educational attainment.
Outcomes
The hearing loss associated with glue ear in children who do not have Down syndrome mediates the emergence of difficulties in other areas. It may affect other developmental abilities in the long term and, for example, may hinder a child’s speech and language development, such that their understanding and production of language (fluency, grammar and syntax) are compromised.24 Other cognitive and social abilities that may be negatively affected as a secondary consequence of glue ear are attention skills,25 behaviour,26,27 and learning and educational progress, particularly literacy and social interaction,28 with a consequent impact on quality of life.29
Analyses of several unpublished large databases (OM8-30, Q-16, Eurotitis 2) provide valuable information regarding parental concerns for children with glue ear but without Down syndrome (M Haggard, University of Cambridge, February 2013, personal communication). The Q-16 database indicates that the concerns mentioned most frequently by parents and carers for children without the learning difficulties and medical problems associated with Down syndrome were hearing (20.8%) and school progress (20.1%) and five other categories each accounted for > 5%. However, it is not clear to what extent these findings would be altered for particular populations of children, such as those with Down syndrome.
For children without Down syndrome there may be differences between the views of parents/carers, teachers and ENT surgeons concerning the relative importance of the impact of glue ear on different domains of development. A questionnaire study28 surveyed the perception of the impact of glue ear over four areas involving language and education, hearing, behaviour and balance between three groups involving parents, teachers and ENT consultants. The results indicated that teachers weighed language and education more highly than parents and ENT consultants, but that parents weighed hearing more highly than any other group. ENT professionals were least likely to weigh hearing as important. Differences attributed to the importance of different outcomes by stakeholders may influence the path that treatment takes.
Management of glue ear
There are a number of potential treatments for glue ear noted in the wider literature, but the evidence base is equivocal and only surgery and HAs are recommended by NICE guidelines.17
Many reviews are available regarding the effectiveness of intervention for glue ear in children who do not have Down syndrome. These include a clinical evidence review of all interventions,30 and systematic reviews on the effectiveness of treatment of OME in the general population of grommet insertion,21,31 adenoidectomy,32 autoinflation,33 antibiotics,34 antihistamines and decongestants,35 oral and topical intranasal steroids36 and zinc supplements.37 Most refer to participants with Down syndrome only to note that they were excluded from RCTs. Few studies16,18,19 and no reviews report the effectiveness of interventions for children with Down syndrome who have OME.
Surgical intervention
Grommets/ventilation tubes
Grommets [also known as ventilation tubes, pressure equalisation (PE) tubes and T-tubes] are tiny tubes that are inserted into the eardrum. They allow air to pass through the eardrum, between the outer and middle ear, which keeps the air pressure on either side equal. The surgeon makes a tiny hole in the eardrum and inserts the grommet or ventilation tube into the hole. It usually stays in place for 6–12 months and then falls out. This is typical and not considered to affect a child.
There are conflicting reports in the literature of grommet insertion being successful as an intervention,16 and not successful,18 for children with Down syndrome who have glue ear.
Rovers et al.20 conducted an individual patient data (IPD) meta-analysis of grommets used for glue ear in order to identify subgroups of children who might benefit more than others from having ventilation tubes inserted. Rovers et al.20 noted the following:
Subgroups that might benefit more from treatment with ventilation tubes include those with speech or language delays, behaviour and learning problems, Down’s syndrome, or children with cleft palate. These could not be studied in this IPD meta-analysis as these subgroups were excluded in individual trials. The experience of many clinicians that these subgroups of children benefit more from treatment with ventilation tubes has not yet been evidenced in RCTs. As the question whether to treat these children with ventilation tubes is very relevant for clinical practice, future trials studying these subgroups are justified.
Reproduced from [Archives of Disease in Childhood. Grommets in otitis media with effusion: an individual patient data meta-analysis. Rovers M, Black N, Browning G, Maw R, Zielhuis G, Haggard M. 90: 480–5, 2005.] with permission from BMJ Publishing Group Ltd. p. 48420
Davies38 reports an early study of hearing and middle ear dysfunction in 100 children with Down syndrome and the findings are contrasted with those of previous studies. Normal hearing was indicated in only 16% of the study sample. Decongestants and antibiotics were established to be of limited use, with surgery frequently carried out. Davis reports a number of problems with surgery including (1) the anaesthetic risks posed by children because of respiratory problems or congenital heart disease; (2) the difficulty of surgery caused by stenosis of the ear canal; (3) the ineffectiveness of the results in the long term; and (4) a heightened risk of post-surgery middle ear infection. Davis reports that 32 children had to have grommets inserted on up to three occasions, with only two children showing continued improvement after 2 years.
Selikowitz18 examined the short-term efficacy of T-tubes or grommets for secretory otitis media (SOM) in 24 children with Down syndrome, aged 6–14 years. Children were tested with audiometry at 6–9 weeks after having T-tubes inserted for bilateral SOM. There was no hearing improvement in 40% of ears compared with only 9% of 21 age-matched control children who also presented with bilateral SOM. The paper concluded that T-tubes for SOM in children with Down syndrome have a pronounced short- and long-term failure rate and recommended that this should be clarified with the parents prior to insertion. It was suggested that management should involve making sure that adequate intervention was provided to allow patients to hear as much as possible. Continuing hearing loss may necessitate the use of HAs.
Iino et al.19 recommend a conservative approach, suggesting that the use of ventilation tubes should be reserved for cases in which hearing loss, secondary to middle ear secretion, is severe or when there are physical changes to the tympanic membrane (e.g. atelectasis). This was one of the studies reviewed by the NICE report,17 and was a longitudinal observational study following 28 children with Down syndrome, up to at least 7 years of age, and 28 age-matched control children who had T-tubes inserted for > 2 years (n = 50 ears in each group).19 Children were assessed every month for 6 months post surgery and then thereafter every 2 months. At the time of the last visit, 11 out of 50 ears in the Down syndrome group and 39 out of 50 ears in the control group had normal or retracted eardrums. The authors define this as cured. Complications such as atelectasis, permanent perforation and cholesteatoma were found in 15 of the children with Down syndrome and six of the control children. Improvements in hearing levels to < 25 dB at the last visit were recorded for 10 out of 50 ears in the children with Down syndrome and 40 out of 50 ears in the control children. Iino et al.19 concluded that the insertion of T-tubes was much less effective in children with Down syndrome than in control children. They made the following recommendation:
For the treatment of OME in children with Down syndrome, we propose that conservative management should be the approach of first choice and that indications for the insertion of tympanostomy tubes should be limited only when hearing loss due to middle ear effusion is in a severe degree and when pathological changes of the eardrum, such as adhesion and deep retraction pocket formation, are going to occur.
Reproduced from [International Journal of Pediatric Otorhindaryngology. 49(2). Lino Y, Imamura Y, Harigai S, Tanaka Y. Efficacy of tympanostomy tube insertion for otitis media with effusion in children with Down Syndrome. 143–9 Copyright Elsevier Science Ireland Ltd (1999)]. with permission from Elsevier. p. 14819
In the more positive study reviewed in the NICE guidelines17 conducted in Cincinnati, USA, Shott et al.16 advocate, prior to the age of 2 years, an early and aggressive medical and surgical treatment of OME, which can involve grommet insertion.16 This 5-year longitudinal study followed 48 children with Down syndrome every 6 months. Forty of the children (83%) required insertion of PE tubes because of chronic otitis media, with 55% requiring between two and four sets of PE tubes. After treatment (PE tubes and/or antibiotics) 97.7% of the children had normal to borderline hearing levels (undefined).
In a retrospective review of 29 children with Down syndrome aged 1–10 years referred for common ENT problems to a paediatric otolaryngology clinic in New Mexico, 13 children had PE tubes inserted bilaterally and 7 out of 26 procedures led to a complication.39
Complications of grommet insertion are more common in children with Down syndrome. Tomasevic,13 in a series of 93 children in Oxford, reported that insertion and retention of grommets was an issue, with a repeat insertion rate of 59%. Otitis externa was noted in 28% and residual tympanic membrane perforation in 10%.
Adenoidectomy
Adenoidectomy is surgical removal of the adenoid, which is a focus of lymphoid tissue located in the space at the back of the nose above the soft palate. Adenoid removal has been shown to increase the benefit from grommet insertion in certain groups of children without Down syndrome.40 Adenoidectomy, often in combination with tonsillectomy, may be performed in children with Down syndrome to relieve upper airway obstruction. This surgery is not without complications, in particular bleeding, and often specialist postoperative care is required, depending on the size and age of the child and on the severity of their airway obstruction.
Casselbrant et al.,41 in a study of children without Down syndrome, concluded that adenoidectomy with or without tube insertion, provided no advantage to children aged 2–4 years with chronic OME compared with tube insertion alone, and was not recommended as first-line surgical treatment. In the UK TARGET trial (Trial of Alternative Regimens for Glue Ear Treatment),40 adjuvant adenoidectomy was reported to double the benefit from short-stay grommets in children without Down syndrome, aged 3–6 years, with persistent glue ear.
A retrospective review of the outcomes of adenoidectomy operations compared 27 children with Down syndrome (age 1–15 years) with 53 age- and sex-matched control children in the USA.42 Long-term follow-up data were collected by telephone interview. Children with Down syndrome had less improvement than control children in middle ear effusion (23.1% vs. 68.0%) and also in symptoms related to nasal obstruction. Children with Down syndrome were 7.7 times more likely than control children to suffer chronic ear drainage.
Device intervention
Behind-the-ear hearing aids
Air conduction aids comprise an ear mould (to hold the aid in place and deliver the amplified sound into the ear canal) and a behind-the-ear digital aid. They can be used for any type of hearing loss. It is necessary to have accurate hearing thresholds measured to ensure the amplification is set appropriately. For some children with Down syndrome the shape of their outer ear can make it difficult to get good-fitting, secure ear moulds, which makes it difficult to keep the HAs in place. Wearing ear moulds can also exacerbate ear infections in some children, which can mean they are unable to wear their HAs until the infection has cleared.
No studies were identified that specifically explored the use of conventional behind-the-ear HAs in children with Down syndrome.
Bone-anchored hearing aid technology, including soft band
Bone-anchored hearing aids are bone conduction aids that utilise a permanent titanium implant to route sounds directly through the skull to the inner ear. They are suitable for patients with any type of hearing loss and who have problems wearing air conduction HAs. For children who are too young for a permanent implant owing to the lack of sufficient thickness of skull bone to hold the device or whose conductive loss is likely to be temporary, the BAHA can be worn on a softband that holds the aid firmly against the child’s head. Skull thickness in very young children and the quality of the bone (it is too soft) means that surgical placement of a permanent fixture is usually delayed until the child is at least 4 years old. Although the softband is easy to wear and put on, some children dislike wearing anything around their heads and do not tolerate the sensation of the band well. Mostly this can be overcome by a slow, structured introduction to wearing the band but, in some cases, the child does not accept it and an alternative has to be found.
Ramakrishnan et al.43 report a retrospective, anonymised, cross-sectional survey in the UK using two assessment measures: the Glasgow Benefit Inventory and the Listening Situations Questionnaire (parent version) which were completed at least 3 months after the device was fitted. Of the 109 patients (age 6 months to 26 years), 22 were children with syndromes (or ‘syndromic’ children), nine of whom were young people with Down syndrome. Of these nine, six were fitted with a softband BAHA and three had implanted devices. Improvements were seen in both outcome measures. Ramakrishnan et al.43 conclude that using BAHAs and softband BAHAs leads to appreciable improvements in quality of life for hearing-impaired children and young people, including those with Down syndrome, and suggest that there is major underutilisation of BAHAs in children with ‘skull and congenital abnormalities’ (e.g. Down syndrome).
Kunst et al.44 report a series from the Netherlands of 22 patients (7–73 years) with moderate ‘mental retardation’, 12 of who had Down syndrome, fitted with implanted BAHAs. They also demonstrated improvements in domains assessed by the Glasgow Children’s Benefit Inventory (GCBI) and in learning and listening assessed by the Listening Inventory for Education.
McDermott et al.45 report a study of 15 children with Down syndrome (aged 2–15 years) who were implanted with a BAHA over a 15-year period. All were long-term users, and benefits were also demonstrated in scores on the GCBI.
A survey46 of the 81 centres performing BAHA surgery in the UK in 2005 reported that 18 had provided BAHAs to patients with Down syndrome. Forty patients aged < 30 years were included and all received implantable devices. There was a high rate of complications (58%) but the authors concluded that BAHA was an effective option in patients with Down syndrome whose HAs or ventilation tubes had been unsuccessful. Softband BAHAs were not assessed in any of these last three studies.44–46
Active observation/watchful waiting
A NHS Quality Improvement Scotland review47 suggested that WW, compared with immediate grommet insertion, does not lead to disruption in the development of language, behaviour or social interaction for children with persistent bilateral glue ear diagnosed before 3 years of age and with no other disabling health conditions. However, the Scotland review47 notes that it is unclear whether or not the ‘safe use of WW’ can be applied to other children who have already presented with language and behavioural difficulties at diagnosis. As children with Down syndrome are characterised as having development that is delayed (at the outset), it might be argued that the use of WW as a management strategy for glue ear in this group might indeed be problematic.
Antibiotics
Although glue ear is defined as being non-infective, in a number of cases bacteria are identifiable in the middle ear fluid. In such cases, antibiotics could be hypothesised to be effective. A Cochrane review34 concluded that the benefits were seen only after long-term administration of antibiotics, and that these benefits did not outweigh the risks of resistance. Studies of children with Down syndrome were specifically excluded.
Other treatments for glue ear
The sections above looked at studies that investigate the effectiveness of treatment options commonly used in health-care settings. There is little research concerning the benefits of these management options in children with Down syndrome. The limited empirical studies there are appear to focus mostly on surgical treatments in this group. However, there are other options that have been used to help manage glue ear in children without Down syndrome. These include autoinflation,33,48 decongestants/antihistamines,38 vaccines,49–51 topical intranasal steroids36,52 and zinc supplements.37
Barriers to research
Of particular interest to this feasibility study are the views and opinions of parents and professionals concerning participation of children with Down syndrome in any future health research, particularly that involving a RCT design.
Most of the literature is concerned with recruitment to RCTs in a general population although one study did consider participation of people with learning disabilities.53
Barriers identified by professionals
In the particular situation explored in this feasibility study, some professional groups (such as ENT surgeons) would be more often responsible for directly recruiting to a trial involving surgical intervention. However, professionals within other disciplines (such as paediatricians, audiologists and SLTs) may also influence the decision of a parent or carer as to whether or not their child should participate in a research trial. Although an individual’s experience of recruitment may vary, research suggests that there are a number of factors that may be important in deciding to recruit to a trial or encouraging a parent to agree to their child taking part.
A systematic review of 78 studies54,55 reported barriers to professionals recruiting to RCTs as lack of time, lack of training, concern about doctor–patient relationships, concern for patients, loss of professional autonomy, difficulties with the consent procedure, lack of reward and recognition, and the research asking a question that was not sufficiently interesting. Spaar et al.,56 in a postal survey of 55 physicians in Switzerland, involved in a trial of rehabilitation options for patients with chronic obstructive airways disease, again highlighted time constraints as the most challenging barrier to recruitment, and the only other factor reported was difficulties with actually including eligible patients because the patient did not want to be randomised to a non-attractive treatment option or saw the process as too complex.
Caldwell et al.,57 exploring the recruitment of children to RCTs with paediatricians in Australia in a qualitative study, conclude that balancing risk and benefit often resulted in clinician non-participation. Many paediatricians saw RCTs as a hindrance rather than a help to the doctor–patient relationship, which they valued highly, because they had to explain the concept of clinical equipoise. Negative elements were again more work, less money and lack of control. Paediatricians recognised that the health status of the child was an important influence for themselves and for parents. If the child has a poor prognosis or the parents are desperate for help, they may be less likely to accept randomisation that involved a placebo or ‘do nothing’ arm. Equally, even if there is genuine clinical equipoise, clinicians are reluctant to lose control of the intervention offered. Poor communication with researchers and lack of detailed information and feedback were seen as barriers to participation.
Barriers identified by parents
Prescott et al.’s review54 identified uncertainty, additional demands, patient preference and concern about information and consent as barriers to patient participation.
Caldwell et al.,57 exploring parents’ attitudes to children’s participation in RCTs in Australia, report that the perceived benefits include an offer of hope, the opportunity for better access to new treatments, professionals and information, meeting with parents in a similar situation and helping others. Perceived risks included side effects, being randomised to an ineffective treatment and inconvenience. Agreement to participation would be influenced by factors to do with the parents themselves (knowledge, beliefs and emotional response), with their children (health status, child preference), with the trial (the use of placebos) and with the clinician (recommendation, communication of information). The authors concluded that in order to increase parents’ willingness to agree to participation of their child there is a need to educate parents about trials, improve communication between researchers, clinicians and parents, increase incentives and decrease inconvenience.
The special position of parents as givers of proxy consent for their child is addressed by Shilling and Young.58 This special position results in a dilemma for many parents between wanting to do the best for their child while also protecting them from any potential adverse events.
Nabulsi et al.59 report data from a study of parents in Lebanon, defined as a developing country, exploring differences with the developed world literature. Findings were in fact similar, demonstrating that a parent is a parent regardless of the development status of their country. Facilitators in this study were reported to be direct benefit to the child, trust in the doctor or the institution, financial gain and positive previous experience. Barriers were lack of understanding of randomisation and complex consent forms.
A study by Robotham and Hassiotis53 addressed participation by people with learning disabilities and emphasised the importance of including people who were representative of the study population in the design stage of the research.
Cost-effectiveness
The literature search identified very little health economic literature on the subject. Ackerman et al.60 constructed an economic model to estimate the costs associated with several childhood illnesses in children with Down syndrome. These were respiratory, gastrointestinal and related to the ears (otitis media and sinusitis). The estimated mean cost per episode of otitis media per child with Down syndrome was US$301 (in 1999). The study modelled the impact of a preschool intensive infection control programme. Before the intervention, the estimated cost of illness was US$1235 per child, which was reduced to US$615 per child after the intervention, giving cost savings of around US$620 per child. However, this cost savings estimate is spread over multiple conditions, only one of which is otitis media, therefore the cost savings attributable to a decline in otitis media are potentially less. Hellstrom et al.61 reported that ventilation tubes were cost-effective; however, no details were given as to the economic analysis performed, and no incremental cost-effectiveness ratio (ICER) was reported, giving no justification of this statement. Berman et al.29 investigated a hypothetical case of a 13-month-old boy with bilateral middle ear effusion, using effectiveness data generated by a meta-analysis of clinical trials. The analysis was conducted from a private health insurance perspective, using 1992 Medicaid reimbursement rates to estimate costs. They estimated that the most cost-effective strategy was a corticosteroid plus antibiotic at 6 weeks after diagnosis, further antibiotics for non-responders at 9 weeks, and finally, ventilation tubes for non-responders at 12 weeks. It was estimated that this strategy cost US$600.91, increasing to US$1088.54 with a 6-month follow-up. The estimated difference in national expenditures between the most cost-effective strategy and sequential antibiotics was US$643.6M and the study recommended the implementation of the cost-effective strategy. However, from a UK perspective, this study is not particularly useful, as antibiotics are not a currently accepted method for treating OME, and therefore the results have little application to the UK. The only other model with relevance was the economic model developed for the NICE guidance.17 This model estimated the cost-effectiveness of two surgical interventions – grommets and grommets plus adenoidectomy – against HAs and ‘do nothing’. The model used HAs as the base intervention, with zeroed benefits. The model allowed for repeated surgical interventions, with a child having up to three sets of grommets. However, once receiving a particular treatment, the child would always receive that one treatment – they would not be switched to another. The model estimated that HAs had an expected cost of £752, whereas the ‘do nothing’ cost was £187, the cost of ventilation tubes was £1208, and the cost of ventilation tubes plus adenoidectomy was £1354. HAs were dominated, as they had the same effectiveness as ‘do nothing’; meanwhile, when compared with the ‘do nothing’ intervention, grommets had an ICER of £16,041 per quality-adjusted life-year (QALY). This is below the general NICE threshold value of £20,000 per QALY, but the authors suggested caution when interpreting the results, as the ICERs rose to > £20,000 per QALY in the sensitivity analyses (SAs), in which the HAs were assumed to have some degree of effectiveness, and reported ICERs of approximately £13,500. The economic model developed for the guidance is applicable for only the general population, and the parameters and costs in the model reflect this. Therefore, the results of the economic model must be taken with a degree of caution when applying to the population with Down syndrome.
