2018 - Review EP en S.Down

Systematic Review
Periodontal disease in patients with Down

syndrome
A systematic review
Flávia Almeida Ribeiro Scalioni, MS; Camila Faria Carrada, MS; Carolina Castro Martins, PhD;
Rosangela Almeida Ribeiro, PhD; Saul Martins Paiva, PostDoc
ABSTRACT
Background. The authors systematically reviewed the scientific evidence of an association be-
tween periodontal disease and Down syndrome (DS).
Types of Studies Reviewed. In this systematic review, the authors included observational studies
in which the investigators assessed the prevalence, incidence, or experience of periodontal disease
in patients with DS compared with that in healthy patients. The authors used the Population,
Exposure, Comparison, Outcome structure. The population was patients of any age, the exposure
was the presence of DS, the comparison was the absence of DS, and the outcome was the presence
of periodontal disease. The authors conducted an electronic search in 5 databases through March
2017. Two independent reviewers assessed the risk of bias by using the Fowkes and Fulton scale.
The authors performed a meta-analysis to compare periodontal disease among patients with DS
and those without DS. The authors calculated a summary effect measuredstandard mean
differencedwhen evaluating the means of the oral hygiene index. The authors assessed the strength
of evidence from the selected studies by using a modified Grading of Recommendations Assessment,
Development and Evaluation system.
Results. The authors included 23 case-control studies in the systematic review and submitted 3
to meta-analysis. In the qualitative analysis, results from most studies showed that the prevalence
of some periodontal parameters was higher among patients with DS than among those without
DS. Evaluations of the Fowkes and Fulton scale point to many methodological problems in the
studies evaluated. Results of the meta-analysis revealed no differences between groups with re-
gard to the oral hygiene index (standard mean difference, 0.05; 95% confidence interval, 0.55
to 0.65; I2 ¼ 0.0%).
Conclusions and Practical Implications. Further research is required, in particular well-designed
studies that avoid the deficiencies identified in the studies in this review.
Key Words. Down syndrome; oral health; periodontal diseases.
JADA 2018:149(7):628-639
https://doi.org/10.1016/j.adaj.2018.03.010
P
eriodontal disease is a multifactorial condition, and investigators have suggested a specific
microbiological profile.1 This condition can manifest in the gingival tissues or affect the
supporting tissues of the teeth (periodontal ligament, cementum, and alveolar bone).2
Smoking, diabetes, and genetically transmitted characteristics are risk factors for the develop-
ment of periodontal disease.3
Down syndrome (DS) is a genetic disorder resulting from an error in chromosome distribution
during cell division and is one of the most common genetic abnormalities among humans.4-6 People
with DS have specific orofacial characteristics, and study investigators have suggested that there is a
higher prevalence rate of periodontal disease in this population.7 In addition to immunodeficiency,
other factors, such as tooth morphology, mouth breathing, malocclusion, and early microbial
Copyright ª 2018
colonization by periodontal pathogens, may explain the high prevalence and increased severity of
American Dental
Association. All rights periodontal disease in people with DS.8-10 Although investigators have reported a higher prevalence
reserved. rate of periodontal disease in people with DS than in people of the same age without DS or with
628 JADA 149(7) n http://jada.ada.org n July 2018

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other disabilities,11,12 there is no consensus in the literature regarding the prevalence of the disease
in this population or which periodontal parameters may be associated with DS.
DS is increasingly the object of study, not only scientifically but also socially. Thus, knowledge
about the periodontal status of this group of people with special needs is important and can enhance
the effectiveness of preventive and therapeutic measures aimed at minimizing the outcome of
periodontal disease in people with DS. To our knowledge, no previous investigators have conducted
systematic reviews or meta-analyses on this subject. Therefore, our aim was to conduct a systematic
review and meta-analysis to search for scientific evidence of a possible association between DS and
periodontal disease.
METHODS
Search strategy
We published the protocol for this systematic review with the International Prospective Register of
Systematic Reviews under registration CRD42015025490. This report complies with the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses.13
We used the Population, Exposure, Comparison, Outcome structure to define the eligibility
criteria.13 The population was patients of any age, the exposure was the presence of DS, the
comparison was the absence of DS, and the outcome was the presence of periodontal disease.
The inclusion criteria were observational studies (that is, case-control, cross-sectional, cohort
studies) in which the investigators assessed the prevalence, incidence, or experience of periodontal
disease in patients with DS compared with that in healthy patients of any age. We included sys-
tematic reviews and searched the list of references to try to find original studies not retrieved by
means of the electronic search, but we retrieved no systematic reviews. The exclusion criteria were
studies in which the investigators reported periodontal disease in patients with DS without a control
group, experimental studies, case reports, case series, studies written in a language other than En-
glish, studies addressing the prevalence of periodontal disease related to other syndromes, literature
reviews, and studies with an outcome other than periodontal disease. ABBREVIATION KEY
We conducted electronic searches in 5 electronic databases (PubMed, Web of Science, Cochrane
Library, Scopus, and Virtual Health Library) through March 2017. Table 1 lists the databases and ABL: Alveolar bone loss.
AL: Attachment loss.
respective search strategies. We also searched the gray literature in the National Institutes of Health BOP: Bleeding on
website and conducted hand searches. We imposed no restrictions with regard to date of publication. probing.
Two independent reviewers (F.A.R.S., C.F.C.) used the eligibility criteria to analyze the titles C: Control patient.
and abstracts. We first performed a calibration exercise with 20% of the retrieved studies, during CPITN: Community
Periodontal Index
which we found the level of interobserver agreement was substantial (k, 0.756), and we considered of Treatment
Needs.
DS: Down syndrome.
Table 1. Search strategy used for each electronic database.
GB: Gingival bleeding.
ELETRONIC DATABASE SEARCH STRATEGY GI: Gingival index.
GRADE: Grading of
PubMed (http://www.pubmed.gov), ((periodontal bacteria OR periodontal disease [MeSH*] OR periodontal diseases Recommendations
Web of Science (http://www. [MeSH] OR periodontal disease* OR periodontal index [MeSH] OR periodontal Assessment,
isiknowledge.com) indexes [MeSH] OR periodontal pathogens OR periodontitis OR dental plaque
Development and
[MeSH] OR chronic periodontitis [MeSH]) AND (down syndrome [MeSH] OR
trisomy 21 OR mongolism OR trisomy 21 meiotic nondisjunction OR trisomy 21
Evaluation.
mitotic nondisjunction OR partial trisomy 21 OR down syndrome)) MeSH: Medical Subject
Heading.
Cochrane Library ((periodontal bacteria OR periodontal diseases [MeSH] OR periodontal disease* NA: Not applicable.
(http://cochranelibrary-wiley.com/ OR periodontal index [MeSH] OR periodontal index* OR periodontal pathogens NR: Not reported.
cochranelibrary/search/) OR periodontitis OR dental plaque [MeSH] OR chronic periodontitis [MeSH]) AND
OHI: Oral hygiene index.
(down syndrome [MeSH] OR trisomy 21 OR mongolism OR trisomy 21 meiotic
nondisjunction OR trisomy 21 mitotic nondisjunction OR partial trisomy 21 OR
PD: Probing depth.
down syndrome)) PeI: Periodontal index.
PI: Plaque index.
Scopus (https://www.scopus.com) ((periodontal bacteria OR periodontal disease OR periodontal diseases OR PRISMA: Preferred Reporting
periodontal index OR periodontal indexes OR periodontal pathogens OR Items for Systematic
periodontitis OR dental plaque OR chronic periodontitis) AND (down syndrome
Reviews and Meta-
OR trisomy 21 OR partial trisomy 21))
Analyses.
Virtual Health Library (www.bireme.br) (periodontal diseases AND down syndrome) SC: Subgingival
National Institutes of Health (https://www. calculus.
nih.gov/) 0: No problem.
* MeSH: Medical Subject Heading. D: Minor problem.
DD: Major problem.
JADA 149(7) n http://jada.ada.org n July 2018 629

Table 2. Characteristics of the 23 studies included in the systematic review.
PARTICIPANT NO. OF PARTICIPANT PERIODONTAL RESULTS FOR PERIODONTAL DISEASE;

STUDY COUNTRY LOCATION PARTICIPANTS AGE INDEX P VALUE
Kroll and United DS*: public 308 (DS: 149; 5-25 y Abnormal Abnormal tissue loss: 65% DS and 15% C; .01
Colleagues,14 States hospitals; C: 159) tissue loss
1970 C†: public
hospitals
Cutress,15 1971 New DS: specialized 687 (DS: 223; 10-24 y PeI‡; PeI: C had significantly lower mean periodontal scores than
Zealand centers; C: 464) OHI§ did patients with DS at all age levels.
C: home OHI: C had significantly lower scores than did patients with
DS at all age levels.
Orner,16 1975 United DS: specialized 336 (DS: 212; 5-20 y PeI PeI: 0.74 DS and 0.17 C
States centers; C: 124)
C: home
Modéer and Sweden DS: public 78 (DS: 39; C: 39) 10-19 y BOP{; BOP: 26% DS and 0% C; < .001
Colleagues,17 hospitals; PD# > 5 PD > 5 mm: 28% DS and 5% C; < .05
1990 C: public millimeters; SC: 13% DS and 0% C; not significant
hospitals SC**; ABL: 39% DS and 3% C; < .001
ABL††
Stabholz and Israel DS: specialized 62 (DS: 32; C: 30) 8-13 y CPITN‡‡ CPITN: 0.7 DS and 0.5 C; not significant
Colleagues,18 centers;
1991 C: regular
schools
Barr-Agholme Sweden DS: NR§§; 74 (DS: 37; C: 37) 9-21 y GB{{; GB: 19% DS and 0% C; < .05
and Colleagues,19 C: NR PD > 4 mm; PD > 4 mm: 43% DS and 8% C; < .01
1992 ABL; ABL: 32% DS and 3% C; < .01
SC SC: 14% DS and 0% C; not significant
Yavuzyilmaz Turkey DS: NR; 30 (DS: 15; C: 15) DS: 19 (0.5) y; PI***; PI##: 68.0 (10.7) DS and 21.0 (16.0) C
and Colleagues,20 C: NR C: 23 (6.07) y## PD; PD##: 2.68 (0.03) DS and 1.8 (0.06) C
1993 PeI PeI##: 1.56 (0.04) DS and 0.28 (0.02) C
Cornejo and Argentina DS: specialized 172 (DS: 86; 3-19 y GI††† GI##: 3-6 y: 0.10 (0.05) DS and 0.11 (0.04) C; not significant
Colleagues,21 centers; C: 86) 7-9 y: 0.56 (0.11) DS and 0.17 (0.05) C; < .01
1996 C: regular 10-13 y: 0.57 (0.13) DS and 0.11 (0.08) C; < .01
schools 14-16 y: 0.56 (0.15) DS and 0.31 (0.09) C; < .02
17-19 y: 1.00 (0.20) DS and 0.27 (0.11) C; < .02
Halinen and Finland DS: NR; 18 (DS: 9; C: 9) 9-17 y PI; Four patients with DS were considered clinically healthy, and
Colleagues,22 C: NR GB; 5 patients had periodontal disease. In the control group,
1996 PD there were no clinical signs of periodontal disease
López-Pérez and Mexico DS: specialized 64 (DS: 32; C: 32) 15-39 y OHI; OHI##: 0.7 (0.6) DS and 0.5 (0.4) C; not significant
Colleagues,23 centers; GI; GI: 96.9% DS and 87.5% C; not significant
2002 C: NR AL‡‡‡ AL: 78.1% DS and 75.6% C; not significant
Bagic and Croatia DS: specialized 142 (DS: 71; 9-34 y CPITN Do not need treatment: 0.1 DS and 1.7 C; < .01
Colleagues,24 centers; C: 71)
2003 C: NR
Sakellari and Greece DS: specialized 191 (DS: 70; 8-28 y OHI; OHI##: 8-13 y: 84.81(7.67) DS and 48.21 (14.10) C,
Colleagues,25 centers; C: 121) CPITN; BOP; 13-19 y: 88.29 (12.41) DS and 47.84 (18.17) C,
2005 C: dental college periodontal 19-28 y: 84.23 (16.72) DS and 42.87 (18.95) C; .000
disease; CPITN: Patients with DS display statistically significantly
attachment greater needs for intensive treatment (grades 3 and 4)
level than do C.
BOP##: 8-13 y: 62.33 (21.23) DS and 29.52 (9.92) C,
13-19 y: 66.91 (24.82) DS and 33.26 (17.42) C,
19-28 y: 67.94 (20.84) DS and 26.14 (12.32) C; .000
Periodontal disease##: 8-13 y: 1.81 (0.26) DS and 1.31
(0.20) C,
13-19 y: 1.86 (0.36) DS and 1.32 (0.18) C,
19-28 y: 2.09 (0.58) DS and 1.30 (0.15) C; .000
Attachment level##: 8-13 y: 1.78 (0.24) DS and 1.31
(0.18) C,
13-19 y: 1.86 (0.34) DS and 1.33 (0.17) C,
19-28 y: 2.33 (0.89) DS and 1.30 (0.15); C .000
* DS: Down syndrome. † C: Control patient. ‡ PeI: Periodontal index. § OHI: Oral hygiene index. { BOP: Bleeding on probing. # PD: Probing depth. ** SC: Subgingival
calculus. †† ABL: Alveolar bone loss. ‡‡ CPITN: Community Periodontal Index of Treatment Needs. §§ NR: Not reported. {{ GB: Gingival bleeding. ## Data are
mean (standard deviation). *** PI: Plaque index. ††† GI: Gingival index. ‡‡‡ AL: Attachment loss.

Table 2. Continued
PARTICIPANT NO. OF PARTICIPANT PERIODONTAL RESULTS FOR PERIODONTAL DISEASE;

STUDY COUNTRY LOCATION PARTICIPANTS AGE INDEX P VALUE
Yoshihara and Japan DS: dental 153 (DS: 41; 2-14 y PI; PI: not significantly different between groups
Colleagues,26 college; C: 112) PD; PD: not significantly different between groups
2005 C: dental college papillary Papillary marginal attached index##: < 5 y: 0.312 (0.179) DS
marginal and 0.052 (0.06) C; < .001
attached index > 10 y: 0.422 (0.122) DS and 0.244 (0.140) C; < .001
Zigmond and Israel DS: specialized 58 (DS: 30; C: 28) DS: 23.3 (4) y; BOP; BOP##: 35.7 (25.2) DS and 23.8 (15.8) C; not significant
Colleagues,27 centers; C: 22.8 (5) y## PD; PD##: 3.07 (0.94) DS and 2.40 (0.28) C; .002
2006 C: dental college attachment Attachment level##: 3.09 (0.93) DS and 2.43 (0.32) C; .002
level
Ronald and China DS: specialized 98 (DS: 49; C: 49) 17-42 y PI; PI##: 81.5 (19.1) DS and 61.9 (16.0) C; < .001
Colleagues,28 centers; BOP; BOP##: 76.3 (25.8) DS and 55.6 (21.4) C; < .001
2007 C: public PD > 4 mm; PD > 4 mm: 85.2% DS and 79.6% C; .795
hospitals PD > 6 mm PD > 6 mm: 49% DS and 24.5% C; .021
Khocht and United DS: public 143 (DS: 55; 18-84 y PI; PI##: 1.6 (0.10) DS and 1.2 (0.08) C; < .001
Colleagues,29 States hospitals; C: 88) GI; GI##: 0.9 (0.04) DS and 0.7 (0.03) C; < .001
2010 C: public BOP; BOP##: 40.6 (3.78) DS and 24.8 (2.98) C; < .001
hospitals AL AL##: 2.7 (0.10) DS and 2.2 (0.08) C; < .001
Yamazaki-Kubota Japan DS: dental 28 (DS: 14; C: 14) 6-18 y OHI; BOP; PD OHI##: 1.95 (1.1) DS and 1.68 (0.62) C; < .05
and Colleagues,30 college; BOP##: 14.9 (16.7) DS and 3.51 (2.82) C; < .05
2010 C: dental college PD##: 2.89 (0.43) DS and 2.57 (0.44) C; not significant
Mathias and Brazil DS: specialized 138 (DS: 69; 13-85 mo OHI; GI OHI##: 1.11 (0.58) DS and 1.37 (0.66) C; .017
Colleagues,31 centers; C: 69) GI##: 2.64 (2.45) DS and 0.31 (0.40) C; < .001
2011 C: NR
Al Habashneh Jordan DS: specialized 206 (DS: 103; 12-16 y OHI; GI; OHI: 40% DS and 23% C; < .001
and Colleagues,32 centers; C: 103) PD GI##: 39.9 (9.1) DS and 15.9 (8.0) C; < .001
2012 C: regular PD##: 2.27 (0.2) DS and 1.81 (0.32) C; < .00
schools
Komatsu and Japan DS: public 137 (DS: 66; 1-66 y GI; GI##: 1-12 y: 0.34 (0.48) DS and 0.22 (0.31) C, 30-62 y: 1.12
Colleagues,33 hospitals; C: 71) PD (0.38) DS and 0.90 (0.39) C; not significant
2013 C: public PD##: 1-12 y: 1.34 (0.44) DS and 1.62 (0.38) C, 30-62 y:
hospitals 2.51 (0.47) DS and 2.29 (0.47) C; not significant
Al Sarheed,34 Saudi DS: specialized 192 (DS: 93; 7-15 y PI; PI: 46.9% DS and 34% C; < .001
2015 Arabia centers; C: 99) GI GI: 72% DS and 69% C; not significant
C: regular
schools
Moreira and Brazil DS: specialized 131 (DS: 60; 6-12 y PI; PI##: 17.31 (17.49) DS and 27.14 (22.19) C; .09
Colleagues,35 centers; C: 71) BOP BOP##: 25.89 (17.81) DS and 37.74 (17.91) C; < .001
2015 C: regular
schools
Carrada and Brazil DS: specialized 60 (DS: 30; 3-12 y PI; PI##: 0.49 (0.44) DS and 0.43 (0.44) C; .516
Colleagues,36 centers; C: 30) BOP BOP: 36.70% DS and 13.30% C; .037
2016 C: dental college
the reviewers capable of analyzing the remaining titles and abstracts for the preselection of articles.
We obtained full texts for studies that met the inclusion criteria. When abstracts were unavailable
or had insufficient information with which to make a decision about inclusion, we read the full text
and analyzed it to make a decision. We then obtained and carefully analyzed the full texts of the
preselected studies. We resolved disagreements by means of consensus and a discussion with a third
reviewer (C.C.M.). When necessary, we contacted authors to provide additional information or to
provide the full text when not available. We identified no unpublished studies with the potential to
be included. We extracted study design, local setting in which the investigators collected data,
sample size, age, parameters used for periodontal disease, statistical analysis, and outcomes data
(Table 2).14-36
Methodological quality appraisal

The independent reviewers assessed the methodological quality of the selected studies by using the
scale proposed by Fowkes and Fulton in 1991,37 which contains study design appropriate to ob-
jectives, study sample representative, control group acceptable, quality of measurements and

Table 3. Study quality according to the Fowkes and Fulton scale.*
CONTROL GROUP
STUDY STUDY DESIGN APPROPRIATE TO OBJECTIVES? STUDY SAMPLE REPRESENTATIVE? ACCEPTABLE?
Treatment Cause
Prognoses or Case-Control, Source Entry Definition Source
Prevalence or or Controlled Crosssectional, of Sampling Sample Criteria and of of
Crosssectional Cohort Trial Experimental Sample Method Size Exclusions Nonrepondents Controls Controls
Kroll and NA† NA NA 0‡ 0 0 þ§ þþ{ 0 0 þ

Colleagues,14 1970
Cutress,15 1971 NA NA NA 0 0 0 þ þþ 0 0 0
Orner,16 1975 NA NA NA 0 0 0 þ þþ 0 0 þ
Modéer and NA NA NA 0 0 0 þþ þþ 0 0 0
Colleagues,17 1990
Stabholz and NA NA NA 0 0 0 þþ þþ 0 0 0
Colleagues,18 1991
Barr-Agholme NA NA NA 0 þ 0 þþ þ 0 0 þ
and Colleagues,19 1992
Yavuzyilmaz and NA NA NA 0 þ 0 þþ þ 0 0 þþ
Colleagues,20 1993
Cornejo and NA NA NA 0 0 0 0 þ 0 0 0
Colleagues,21 1996
Halinen and NA NA NA 0 þ 0 þþ þ 0 0 þþ
Colleagues,22 1996
López-Pérez and NA NA NA 0 0 0 þþ þ 0 0 þ
Colleagues,23 2002
Bagic and NA NA NA 0 0 0 þ þþ 0 0 þþ
Colleagues,24 2003
Sakellari and NA NA NA 0 0 0 þ þþ 0 0 þ
Colleagues,25 2005
Yoshihara and NA NA NA 0 0 0 þþ þ 0 0 þ
Colleagues,26 2005
Zigmond and NA NA NA 0 0 0 þþ þþ 0 0 þ
Colleagues,27 2006
Ronald and NA NA NA 0 0 0 0 þþ 0 0 0
Colleagues,28 2007
Khocht and NA NA NA 0 0 0 0 0 0 0 0
Colleagues,29 2010
Yamazaki-Kubota NA NA NA 0 0 0 þþ þ 0 0 þ
and Colleagues,30
2010
Mathias and NA NA NA 0 0 0 þ 0 0 0 þ
Colleagues,31 2011
Al Habashneh and NA NA NA 0 0 0 þ þþ 0 0 0
Colleagues,32 2012
Komatsu and NA NA NA 0 0 0 þ þþ 0 0 þþ
Colleagues,33 2013
Al Sarheed,34 2015 NA NA NA 0 0 0 þþ þþ 0 0 þ
Moreira and NA NA NA 0 0 0 0 þ 0 0 þ
Colleagues,35 2015
Carrada and NA NA NA 0 0 0 þþ 0 0 0 þ
Colleagues,36 2016
* Source: Fowkes and Fulton.37 † NA: Not applicable. ‡ 0: No problem. § þ: Minor problem. { þþ: Major problem.
outcomes, completeness, and distorting influences criteria. We rated each item as a major problem,
a minor problem, no problem, or not applicable (Table 3).14-37
The examiners standardized the evaluation for each question of the quality scale. For sample size,
we considered it a minor problem when the investigators had not performed or reported sample size
calculation, and we considered it a major problem when, despite there being a minor problem, there
were fewer than 50 participants. For entry criteria and exclusions, we considered it no problem

Table 3. Continued
CONTROL GROUP QUALITY OF MEASUREMENTS AND
ACCEPTABLE? OUTCOMES? COMPLETENESS DISTORTING INFLUENCES
Drop outs Extraneous Changes Distortion

Matching/ Comparable Repro- Quality and Missing Treatments or Over Confounding Reduced by
Randomization Characteristics Validity ducibility Blindness Control Compliance Deaths Data Contamination Time Factors Analyses
þ þ 0 þ NA þþ NA 0 NA NA þ þþ þþ
þ 0 0 þ NA þþ NA 0 NA NA 0 þþ þþ
þ þ 0 þþ NA þþ NA 0 NA NA þ þþ þþ
0 0 0 0 NA þþ NA 0 NA NA þ þþ þþ
0 0 0 0 NA þ NA 0 NA NA 0 þþ þþ
0 þ 0 0 NA þþ NA 0 NA NA þ þþ þþ
þ þþ 0 þ NA þþ NA 0 NA NA þ þþ þþ
0 0 0 þ NA þþ NA 0 NA NA þ þþ þþ
0 þþ 0 þ NA þþ NA 0 NA NA þ þþ þþ
0 þ 0 0 NA 0 NA 0 NA NA þ þþ þþ
0 þþ 0 þ NA þþ NA 0 NA NA þ þþ þþ
0 þ 0 0 NA þþ NA 0 NA NA þ þþ þþ
þ þ 0 0 NA þþ NA 0 NA NA þ þþ þþ
þ þ 0 0 NA þþ NA 0 NA NA þ þþ þþ
0 0 0 0 NA 0 NA 0 NA NA þ þþ þþ
þ þ 0 þþ NA 0 NA 0 NA NA þ þþ þþ
0 þ 0 þ NA 0 NA 0 NA NA þ þþ þþ
þ þþ 0 0 NA þþ NA 0 NA NA þ þþ þþ
þ þ 0 þ NA 0 NA 0 NA NA þ þþ þþ
0 þ 0 0 NA 0 NA 0 NA NA 0 þþ þþ
0 þ 0 0 NA 0 NA 0 NA NA 0 þþ þþ
when the investigators had reported entry and exclusion criteria, we considered it a minor problem
when the investigators had reported either just the entry or just the exclusion criteria, and we
considered it a major problem when the investigators had reported neither of the criteria. For source
of control patients, we considered it no problem when the source of patients without DS was similar
to the place or institution as the source of patients with DS, we considered it a minor problem when
the patients with DS and the control patients were from different places or institutions, and we
considered it a major problem when the investigators had not reported this information. For

reproducibility, we considered it no problem when the study investigators had reported clearly how
they had performed the diagnostic examination of periodontal disease, enabling the repeatability of
the main measures in other studies; we considered it a minor problem when the investigators had
reported the diagnostic examination of periodontal disease without enough detail for reproduc-
ibility; and we considered it a major problem when the investigators had reported only the main
measures for the diagnostic examination of periodontal disease.
For validity, we assigned problem levels when there was no training or calibration of the ex-
aminers. We considered it a minor problem when there was no training or calibration of the ex-
aminers, even if the investigators had reported a single examiner, and we considered it a major
problem when the investigators had not reported information about training or calibration in the
study. For confounding factors, we assigned problem levels when the investigators had not
controlled for possible confounding factors. We considered it a minor problem when the in-
vestigators had identified confounding factors in the study, and we considered it a major problem
when the investigators had not reported the confounding factors. For distortion reduced by analyses,
we considered it no problem when the investigators had adjusted for confounding factors in the
statistical analyses, we considered it a minor problem when the investigators had not adjusted, and
we considered it a major problem when investigators had not reported this information.
Statistical methods and data synthesis

We used a software program (Comprehensive Meta-Analysis, Version 2, Biostat) for the meta-
analysis. We determined statistical heterogeneity by using the I2 test. We used a fixed effects
model when I2 was less than 25% (indicating low heterogeneity) and a random effects model when
I2 was greater than 25%.38
We grouped studies for meta-analysis if they were similar and if there was a minimum of 3 studies.
We tried a meta-analysis for periodontal parameters (primary outcome) and indexes of oral hygiene
performance (secondary outcome) with comparable diagnosis. We performed a sensitivity analysis
to test the consistency of the data. We removed outlier studies when I2 was greater than 80%38
because the studies could be too statistically heterogeneous to conduct meta-analysis.38 It was
only possible to group at least 3 studies for the oral hygiene index (OHI) (index of oral hygiene
performance). Although it is an ordinal index, study investigators reported it as the mean and
standard deviation, so we used the standard mean difference.
We calculated 95% confidence intervals (CIs). We evaluated publication bias qualitatively rather
than using funnel plots because of the number of studies was insufficient to be included in a funnel plot.39
Strength of the evidence assessment

We assessed the strength of the evidence from the selected studies for the meta-analysis by using a
modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) sys-
tem.40 We assessed the quality of evidence across several domains, such as risk of bias, inconsistency,
indirectness, and imprecision. The GRADE guidelines rate evidence as being very low, low,
moderate, or high (Table 4).40
RESULTS
We used EndNote Web (Clarivate Analytics) to organize the list of references. We retrieved 399
studies during the search of the electronic databases. After the removal of duplicates, with 305
selected records, we analyzed the full texts of 50 studies. Twenty-three case-control studies were
eligible for the systematic review, and we submitted 3 case-control studies to a meta-analysis
(eFigure 1, available online at the end of this article).13 A list of excluded studies is available on
request from the authors (eTables 1 and 2, available online at the end of this article).
The investigators conducted the studies in Jordan,32 Japan,26,30,33 Croatia,24 Sweden,17,19 China,28
Argentina,21 New Zealand,15 Finland,22 the United States,14,16,29 Mexico,23 Brazil,31,35,36 Greece,25
Israel,18,27 Saudi Arabia,34 and Turkey.20 Publication dates ranged from 197014 through 2016.36
The investigators recruited the participants with DS from specialized centers in 14
studies,15,16,18,21,23,24,25,27,28,31,32,34-36 public hospitals in 4 studies,17,29,33,34 dental schools in 3
studies,14,26,30 a public school in 1 study,14 and private dental offices in 1 study.14 The investigators
reported no description of the participant selection process in 3 studies.19,20,22 The investigators
recruited control patients from regular schools in 6 studies,14,18,21,32,34,35 dental schools in 6

Table 4. Grading of Recommendations Assessment, Development and Evaluation* analyses: patients with Down syndrome compared with patients
without Down syndrome for periodontal disease.
ORAL HYGIENE INDEX CERTAINTY ASSESSMENT EFFECT CERTAINTY
Relative Absolute
(95% (95%
No. of Study Risk of Confidence Confidence
Studies Design Bias Inconsistency Indirectness Imprecision Other Considerations Interval) Interval)
3 Observational Serious† Very serious‡ Serious§ Very serious{ All plausible residual None Standard mean Very low
studies confounding would reduce difference (standard
the demonstrated effect deviation) 0.05
(0.55 to 0.65)
higher
* Grading of Recommendations Assessment, Development and Evaluation.40 Working Group grades of evidence are as follows: High quality indicates further research is
very unlikely to change confidence in the estimate of effect. Moderate quality indicates further research is likely to have an important effect on confidence in the
estimate of effect and may change the estimate. Low quality indicates further research is very likely to have an important effect on confidence in the estimate of effect
and is likely to change the estimate. Very low quality indicates uncertainty about the estimate. † Risk of bias: not serious (no problem), serious (major or minor
problem in at least 8 items), very serious (major or minor problem in more than 8 items). ‡ There is variation of effect estimates: absence of overlap of 95% CIs (the
variation between the study results is more than expected by chance), high I2, significant P value. § Studies have populations with different age ranges. { The lower
and upper boundaries of 95% CIs might lead to different recommendations; small sample size.
studies,14,25-27,30,36 and public hospitals in 5 studies,14,17,28,29,33 whereas investigators evaluated

control patients at their homes in 2 studies15,16 and at private offices in 1 study.14 Investigators in 6
studies did not report how they selected the control group.19,20,22-24,31
Investigators in 1 study used a census sample,21 investigators in 3 studies estimated the power of
the sample,29,35,36 and investigators in the remaining studies did not clarify how they calculated the
sample size. The sample size ranged from 18 through 687 patients, with ages ranging from 2 to 84
years.
There was clinical heterogeneity among the studies regarding the diagnosis of periodontal disease
(Table 2).14-36 In the qualitative analysis of the individual studies, the following periodontal pa-
rameters were associated significantly with DS: Community Periodontal Index of Treatment
Needs,24 gingival index (GI),29,31,32,33 gingival bleeding,19 probing depth (PD) of 4 millimeters or
greater,19 PD of 5 mm or greater,17,28 mean PD,20,25,27,32 bleeding on probing (BOP),17,25,27,28,30,36
clinical attachment level,27 attachment loss,29 alveolar bone loss,17,19 papillary attachment
level,25,26 papillary marginal attached index,26 periodontal disease,25 and periodontal index.15 The
indexes of oral hygiene performancedplaque index (PI)28,29,34 and OHI25,30,31dalso had associ-
ation with DS in some studies. In other studies, these parameters had nonsignificant associations
with DS: PI,26,36 OHI,23 Community Periodontal Index of Treatment Needs,18 GI,21,23,33,34 PD of 4
mm or greater,28 mean PD,26,32,33 BOP,18,36 clinical attachment loss,16 and subgingival calcu-
lus.17,19 Investigators in only 2 studies found a significantly greater occurrence of periodontal pa-
rameters (BOP35 and GI23) and indexes of oral hygiene performance (PI35 and OHI23) in control
patients than in patients with DS.
We evaluated methodological quality by using the Fowkes and Fulton scale.37 We attributed
major problems to sample size, entry criteria and exclusions, source of control patients, comparable
characteristics, reproducibility, quality control, confounding factors, and distortion reduced by
analyses (Table 3).14-37
The meta-analysis results revealed no differences between groups in the OHI (standard mean
difference, 0.05; 95% CI, 0.55 to 0.65; I2 ¼ 0.0%) (eFigure 2, available online at the end of this
article).23,30,31 As Table 440 shows, on the basis of the GRADE measure, we classified the strength
of the evidence as very low for the index of oral hygiene performance.
DISCUSSION
Results from most studies in the qualitative analysis showed that the prevalence of some periodontal
parameters was higher among patients with DS than among those without DS.15,16,19,27-33,34,36
However, investigators in other case-control studies found no statistically significant differences
between groups with regard to periodontal disease.17-19,21,23,27,30,33 In 2 studies, periodontal
disease was more frequent among the control patients, which occurred with 2 parametersdBOP35
and GI23dand 2 indexes of oral hygiene performancedPI35 and OHI.23

Information such as PD, BOP, gingival retraction, dental mobility, presence of bifurcation
lesions, and evaluation of the color and shape of the gingival tissues is established criteria for
the diagnosis of periodontal disease. However, investigators in most of the studies included in
this systematic review also collected additional periodontal measures such as the presence of
plaque and the level of hygiene that are considered indicators of oral hygiene performance but
not periodontal parameters. In patients with DS, although bacterial plaque, calculus, and local
irritants (diastema, tooth crowding, high insertion of the lip brake, and malocclusion) are
present and oral hygiene is poor, the severity of periodontal destruction exceeds that explained
only by local factors.41
The results of the meta-analysis revealed no statistically significant differences between pa-
tients with DS and control patients with regard to the OHI. To avoid clinical heterogeneity, we
compiled similar parameters in the meta-analysis. Although investigators in some studies used
the OHI to diagnose periodontal disease, this index is an indicator of oral hygiene performance,
which alone cannot be used to determine the presence of the disease.41
Investigators report several factors related to the higher prevalence of periodontal disease in
these patients. Immune disorders may be the main reason for gingivitis and periodontitis in
patients with DS because of reduced activity of neutrophils and T lymphocytes, as well as
increased production of inflammatory mediators and proteolytic enzymes.30,32 The compromised
immunity of patients with DS is responsible for altering their defense mechanism. With the
deficiency of the inflammatory response in the presence of bacterial plaque, these patients are
more susceptible to developing periodontal disease. Thus, although inadequate oral hygiene
because of neurologic and motor deficiencies also is reported as a reason for the higher prev-
alence and severity of periodontal disease in patients with DS, the prevalence and severity of
gingival inflammation may increase even in the presence of low levels of plaque.41 Other factors
that may explain the periodontal status of patients with DS include macroglossia, malocclusion,
short roots, loss of normal masticatory function, bruxism,15,21,26,30 changes in saliva compo-
nents, and a greater frequency of periodontopathogens in the microbial composition of sub-
gingival plaque and saliva.19,21,22,25,26,31
In addition to the high prevalence, results of some studies have shown that the severity of
periodontal disease increases with advancing age. In children with DS, the disease is often of
early onset.36 Periodontal destruction affects both the primary and the permanent teeth in a
generalized manner, although the lesions are more severe around the anteroinferior teeth.26 In
children, the teeth most affected by the disease are the mandibular incisors and maxillary first
molars; canines are the least affected teeth.17 In adults with DS, the manifestations of peri-
odontal disease are characterized by marginal gingivitis, necrotizing ulcerative gingivitis,
advanced periodontitis, gingival recession, and pocket formation. Also found with great fre-
quency are vertical bone loss with suppuration; mobility of posterior and anterior teeth; and
frequent loss of teeth, especially in the anterior mandibular region. Children with DS can have
a greater tendency for periodontal tissue bleeding and early onset of gingival inflammation than
children without DS.36
The lack of standardization of criteria for the diagnosis of periodontal disease increasingly is
described as an important limitation among the topics important to investigating a possible
association between the disease and patients with DS. The correct definition of periodontal
disease is an important issue for epidemiologic surveillance of this disease. In 1999, the
American Academy of Periodontology classified periodontal disease as necrotizing periodon-
titis, chronic periodontitis, aggressive periodontitis, and periodontitis as a manifestation of
systemic disease.42 Patients with DS were included in the latter group. There is a possibility of
confusion between periodontitis as a manifestation of systemic disease and the aggressive and
chronic forms of periodontal disease when a systemic component is suspected. Periodontitis as
a manifestation of systemic disease is the diagnosis used when the systemic condition is the
major factor predisposing a patient to periodontal disease and local factors are not clearly
evident, as is the case of patients with DS. In cases in which periodontal destruction is the
result of local factors, the diagnosis should be chronic periodontitis modified by the systemic
condition.41
Limitations exist for associations between DS and periodontal disease for the periodontal
parameters evaluated in the studies included in this systematic review. We attributed the

major problems identified to the risk of bias domain because investigators in some studies
presented major or minor problems in more than 8 items in the quality classification by using
the Fowkes and Fulton scale37 and to the imprecision domain because investigators in some
studies presented a small sample size. Other problems that downgraded the evidence were
inconsistency and imprecision due to the variation of effect estimates of the meta-analysis,
high statistically significant heterogeneity, and the indirectness due the age range of the
populations included.
There is a large variance in the sample size of the studies included in the systematic review.
Large samples provide more accurate estimators of population parametersdthat is, when
sample size increases, the precision of the estimators increases. However, the studies
with small samples and, therefore, with low sensitivity, carry a considerable uncertainty
regarding the statistical inference. Thus, we evaluated this variation by quality scale in the
item sample size.
Among the case-control studies, the major shortcoming involved confounding factors. The
investigators in the studies included in this systematic review did not examine other factors
known to affect periodontal disease outcomes, such as patients with chronic medical conditions,
medication use, smoking, and the presence of caregivers. Another shortcoming involved distor-
tion reduced by analyses, attributed to the fact that no study investigators had undertaken any
form of stratification or adjustment procedure in the analyses to minimize confounding factors.
However, for the sampling method, we identified no problem. DS can be diagnosed in the
gestational period with examinations such as amniocentesis, collection of chorionic villus, blood
tests, and ultrasonography and after birth through the phenotypic characteristics of the child and
confirmation with karyotype examination. In the studies included in this review, the investigators
verified this diagnosis by means of medical reports, reports of the parents, or the fact that the
patients were in specialized institutions.43 In the same way, for sampling method, nonrespondents,
definition of control patients, validity, and dropouts, we attributed no shortcoming to any study
included in this systematic review.
One of the limitations was the inclusion of studies with different clinical parameters for the
diagnosis of periodontal disease, given that such heterogeneity could hinder a more definitive
conclusion. Other researchers also have identified the diversity of methodologies and definitions as a
challenging issue for evidence in systematic review. This continuous creation of new and improved
clinical parameters in periodontal research is probably an important factor in false-positive
conclusions.41
This systematic review had no bias in relation to the country of study. Although there are
cultural differences, the populations surveyed are comparable among studies. To avoid time
bias, we used no restrictions regarding date of publication. This method resulted in the in-
clusion of studies from 1970 through 2016, which can be considered a confounding factor
because the years can reflect different tendencies. Investigators conducted some studies at a
time when patients with DS were taken from their families and confined to institutions with
little or no oral health support, presenting a great disparity between the reality of the case group
(DS) and that of the control group (without DS).14-16,19,27-31,33,34,36 We made a cutoff point to
analyze data according to date of publication. Among 4 studies14-17 from the 1970s through
1990s, investigators in 2 found that periodontal parameters were more prevalent among those
with DS.15,16 Investigators found similar results among studies after the 1990s. Investigators in
13 studies found that patients with DS also had more prevalence of periodontal parameters than
did control patients.19,20,24,25,27-34,36
We found that the studies included in this systematic review had high internal validity because
the investigators controlled research bias for the most part. We used the quality scale to evaluate
bias in the studies included in the systematic review (Table 3).14-37 It is not possible to control all
biases, but it is expected that there will be as few as possible. However, the external validity of this
study is low because it is not possible to generalize the results obtained here to other populations
because they deal with particular samples and situations.
Investigators in a previous systematic review showed the importance of the early exposure
of patients with DS to prevention programs and periodontal therapy. Thus, the participation
of parents, caregivers, or institutional attendants in supervising or performing oral hygiene is
essential to the prevention and control of periodontal disease in this population.7

CONCLUSIONS
Although results from most of the included studies showed a higher prevalence of periodontal
disease in patients with DS in qualitative analysis, one should analyze this result carefully. Evalu-
ations of the Fowkes and Fulton scale37 point to many methodological problems in the studies
evaluated. Further research is needed so that clinicians do not underestimate prevention and
treatment of periodontal disease in this population. In particular, investigators should use well-
designed studies and avoid the deficiencies identified in the studies in this review. Thus, cohort
studies with better control of confounding factors are needed to confirm the scientific evidence. n
SUPPLEMENTAL DATA
Supplemental data related to this article can be found at: https://doi.org/10.1016/j.adaj.2018.03.010.
Dr. Scalioni is a PhD student, School of Dentistry, Federal University of Dr. Paiva is a professor, Department of Pediatric Dentistry and Ortho-
Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. dontics, School of Dentistry, Federal University of Minas Gerais, Belo
Dr. Carrada is a PhD student, School of Dentistry, Federal University of Horizonte, Minas Gerais, Brazil.
Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. Disclosure. None of the authors reported any disclosures.
Dr. Martins is a professor, Department of Pediatric Dentistry and Or-
thodontics, School of Dentistry, Federal University of Minas Gerais, Belo The National Council for Scientific and Technological Development,
Horizonte, Minas Gerais, Brazil. Address correspondence to Dr. Martins at Coordination for the Improvement of Higher Education Personnel, Minas
Faculty of Dentistry, Federal University of Minas Gerais, Avenida Antônio Gerais State Agency for Research and Development, and Pro-Rectory of
Carlos 6627, Pampulha, Belo Horizonte, Minas Gerais, Brazil 31270-901, Research of the Federal University of Minas Gerais supported this study.
e-mail carolcm10@hotmail.com.
Dr. Ribeiro is a professor, Department of Pediatric Dentistry, School of Drs. Scalioni and Carrada equally contributed as co-first authors.
Dentistry, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais,
Brazil.
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eTable 1. List of titles selected for abstract analysis and reason for exclusion.
TITLES SELECTED FOR ABSTRACT ANALYSIS REASON FOR EXCLUSION

Dow RS. A preliminary study of periodontoclasia in Mongolian children at Polk State School. Am J Ment Different language
Defic. 1951;55(4):535-538.
Cohen MM, Winer RA, Schwartz S, Shklar G. Oral aspects of mongolism, I: periodontal disease in mongolism. Oral Surg Review
Oral Med Oral Pathol. 1961;14:92-107.
Baer PN, Kilham L. Rat virus and periodontal disease, I: the periodontium in the mongoloid hamster. Oral Surg Oral Med Different outcome*
Oral Pathol Oral Radiol. 1962;15:756-763.
Kisling E, Krebs G. Periodontal conditions in adult patients with mongolismo (Down’s syndrome). Acta Odontol No control group
Scand. 1963;21:391-405.
Swallow JN. Dental disease in children with Down’s syndrome. J Ment Defic Res. 1964;8(suppl):102-118. Review
Cohen MM, Winer RA. Dental and facial characteristics in Down’s syndrome (mongolism). J Dent Review
Res. 1965;44(suppl):197-208.
Kaczmarczyk T, Walczynski Z, Kaczmarczyk J. Parodontopathy appearing with Down’s syndrome [in Polish]. Czas Different language
Stomatol. 1966;19(11):1265-1270.
Kostic A, Hadzimejlic N. Mouth examination in oligophrenic children: Mongolian idiots. Stomatol Vjesn. 1968;2(1- Different outcome
6):149-151.
Meskin LH, Farsht EM, Anderson DL. Prevalence of Bacteroides melaninogenicus in the gingival crevice area of Different outcome
institutionalized trisomy 21 and cerebral palsy patients and normal children. J Periodontol. 1968;39(6):326-328.
Sznajder N, Carraro JJ, Otero E, Carranza FA Jr. Clinical periodontal findings in trisomy 21 (mongolism). No control group
J Periodontal Res. 1968;3(1):1-5.
Baxter JA. Dental disease in the mentally handicapped. Dent Delin. 1969;20(1):7-9. Different outcome
Cutress TW, Suckling GW, Brown RH. Periodontal disease and serum citric acid levels in trisomy-21 (mongolism). Arch Review
Oral Biol. 1969;14(9):1129-1131.
Harndt R. Periodontopathies in childhood. Dtsch Zahnarztl Z. 1969;24(12):1062-1077. Different outcome
Russell BG. Down’s syndrome: a review and a discussion of the problems with odontological treatment. Review
Tandlaegebladet. 1969;73(1):21-34.
Shapiro S, Gedalia I, Hofman A, Miller M. Periodontal disease and blood citrate levels in patients with trisomy 21. J Dent No control group
Res. 1969;48(6):1231-1233.
Claycomb CK, Summers GW, Hall WB, Hart RW. Gingival collagen biosynthesis in mongolism. J Periodontal Different outcome
Res. 1970;5(1):30-35.
Cohen MM, Blitzer FJ, Arvystas MG, Bonneau RH. Abnormalities of the permanent dentition in trisomy G. J Dent Res. Different outcome
1970;49(6 suppl):1386-1393.
Cohen MM Sr, Cohen MM Jr. The oral manifestations of trisomy G-1 (Down syndrome). Birth Defects Orig Artic Ser. Different outcome
1971;7(7):241-251.
Cutress TW, Suckling GW, Brown RH. Periodontal disease and serum citric acid levels in trisomy-21: further study. Arch Review
Oral Biol. 1971;16(11):1367-1370.
Keyes PH, Bellack S, Jordan HV. Studies on the pathogenesis of destructive lesions of the gums and teeth in mentally No control group
retarded children, I: dentobacterial plaque infection in children with Down’s syndrome. Clin Pediatr
(Phila). 1971;10(12):711-718.
Rcsu M, Scintei V, Dobresuu G, Marcus M, Socolovschi M. Histological appearance of periodontal disease in mongolism. Different outcome
Rev Stomatol Chir Maxillofac. 1972;73(2):113-122.
Steinbicker B, Steinbicker V, Euchler HB. Changes in the maxillofacial region in patients with Langdon-Down’s disease. Review
Dtsch Stomatol. 1972;22(6):452-466.
Giansanti JS, McKenzie WT, Owens FC. Gingival fibromatosis, hypertelorism, anti-mongoloid obliquity, multiple Review
telangiectases and cafe au lait pigmentation: a unique combination of developmental anomalies.
J Periodontol. 1973;44(5):299-302.
Jensen GM, Cleall JF, Yip AS. Dentoalveolar morphology and developmental changes in Down’s syndrome (trisomy 21). Different outcome
Am J Orthod. 1973;64(6):607-618.
Loesche WJ, Nafe D. Reduction of supragingival plaque accumulations in institutionalized Down’s syndrome patients by Different outcome
periodic treatment with topical kanamycin. Arch Oral Biol. 1973;18(9):1131-1143.
Jago JD. The epidemiology of dental occlusion: a critical appraisal. J Public Health Dent. 1974;34(2):80-93. Different outcome
Sznajder N. Oro-dental disease in handicapped children and its treatment. Rev Asoc Odontol Argent. 1974;62(4):97-103. Different outcome
Cohen MM Sr. Chromosomal disorders. Dent Clin North Am. 1975;19(1):87-111. Different outcome
* Indicates studies that did not evaluate periodontal disease in individuals with Down syndrome.
639.e1 JADA 149(7) n http://jada.ada.org n July 2018

eTable 1. Continued

Tannenbaum KA. The oral aspects of mongolismo. J Public Health Dent. 1975;35(2):95-108. Review
Brown JP, Schodel DR. A review of controlled surveys of dental disease in handicapped persons. ASDC J Dent Review
Child. 1976;43(5):313-320.
Cutress TW, Mickleson KN, Brown RH. Vitamin A absorption and periodontal disease in trisomy G. J Ment Defic Different outcome
Res. 1976;20(1):17-23.
Ehmer U. Genetic studies in patients with trisomy 21 with special evaluation of morphology and pathogenesis in the Review
orofacial region: condition of periodontal and oral hygiene in trisomy 21. Zahn Mund Kieferheilkd
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eTable 1. Continued

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eTable 1. Continued

Hodge P, Michalowicz B. Genetic predisposition to periodontitis in children and young adults. Review
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eTable 1. Continued

Lee SR, Kwon HK, Song KB, Choi YH. Dental caries and salivary immunoglobulin A in Down syndrome children. J Paediatr Different outcome
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eTable 1. Continued

Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Rosiglitazone for type 2 diabetes mellitus. Cochrane Different outcome
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Hyg. 2009;7(3):182-187.
Bostanci N, Emingil G, Saygan B, et al. Expression and regulation of the NALP3 inflammasome complex in periodontal Different outcome
diseases. Clin Exp Immunol. 2009;157(3):415-422.
Casamassimo PS. A life without teeth. Acad Pediatr. 2009;9(6):386-387. Review
Dellavia C, Allievi C, Pallavera A, Rosati R, Sforza C. Oral health conditions in Italian Special Olympics athletes. Spec Care Control group not healthy
Dentist. 2009;29(2):69-74.
Iwamoto T, Yamada A, Yuasa K, et al. Influences of interferon-gamma on cell proliferation and interleukin-6 production No control group
in Down syndrome derived fibroblasts. Arch Oral Biol. 2009;54(10):963-969.
Janson M, Janson G, Sant’Ana E, Tibola D, Martins DR. Orthognathic treatment for a patient with Class III malocclusion Review
and surgically restricted mandible. Am J Orthod Dentofacial Orthop. 2009;136(2):290-298.
Kumar S, Sharma J, Duraiswamy P, Kulkarni S. Determinants for oral hygiene and periodontal status among mentally Different outcome
disabled children and adolescents. J Indian Soc Pedod Prev Dent. 2009;27(3):151-157.
Soory M. Redox status in periodontal and systemic inflammatory conditions including associated neoplasias: antioxidants Different outcome
as adjunctive therapy? Infect Disord Drug Targets. 2009;9(4):415-427.
Teitelbaum AP, Pochapski MT, Jansen JL, Sabbagh-Haddad A, Santos FA, Czlusniak GD. Evaluation of the mechanical No control group
and chemical control of dental biofilm in patients with Down syndrome. Community Dent Oral
Epidemiol. 2009;37(5):463-467.
Anders PL, Davis EL. Oral health of patients with intellectual disabilities: a systematic review. Spec Care Dentist. Review
2010;30(3):110-117.
Dumitrescu AL, Kobayashi J. Genetic Variants in Periodontal Health and Disease. New York, NY: Springer; 2010:135. Review
Scully C, Hegarty A. The oral cavity and lips. In: Burns T, Breathnach S, Cox N, Griffiths C, eds. Rook’s Textbook of Different outcome
Dermatology. 8th ed. Oxford, UK: Blackwell Science; 2010:69.3557-3686.
Shore S, Lightfoot T, Ansell P. Oral disease in children with Down syndrome: causes and prevention. Community Review
Pract. 2010;83(2):18-21.
Alrayyes S, Hart TC. Periodontal disease in children. Dis Mon. 2011;57(4):184-191. Review
de Castilho AR, Pardi V, Pereira CV. Dental caries experience in relation to salivary findings and molecular identification of No control group
S. mutans and S. sobrinus in subjects with Down syndrome. Odontology. 2011;99(2):162-167.
Haritha A, Jayakumar A. Syndromes as they relate to periodontal disease. Periodontol 2000. 2011;56(1):65-86. Review
Mdivani M, Betaneli M, Margvelashvili V, Kharabadze M. Ways of optimization of pregnancy gingivitis treatment. Different outcome
Georgian Med News. 2011;(190):24-27.
Areias C, Sampaio-Maia B, Pereira MD, et al. Reduced salivary flow and colonization by mutans streptococci in children Different outcome
with Down syndrome. Clinics. 2012;67(9):1007-1011.

eTable 1. Continued

Cavalcante LB, Tanaka MH, Pires JR, et al. Expression of the interleukin-10 signaling pathway genes in individuals with No control group
Down syndrome and periodontitis. J Periodontol. 2012;83(7):926-935.
Diouf M, Cisse D, Faye A, et al. Prevalence of necrotizing ulcerative gingivitis and associated factors in Koranic boarding Different outcome
schools in Senegal. Community Dent Health. 2012;29(2):184-187.
Estcourt L, Stanworth S, Doree C, et al. Prophylactic platelet transfusion for prevention of bleeding in patients with Different outcome
haematological disorders after chemotherapy and stem cell transplantation. Cochrane Database Syst Rev.
2012;5:CD004269.
Freire IR, Aguiar SMHCÁ, Oliveira SHP. Functional activity of neutrophils and systemic inflammatory response of Down’s No control group
syndrome patients with periodontal disease. Braz J Oral Sci. 2012;11:422-427.
Frydman A, Nowzari H. Down syndrome-associated periodontitis: a critical review of the literature. Compend Contin Review
Educ Dent. 2012;33(5):356-361.
Gautami PS, Ramaraju AV, Gunashekhar M. Adjunctive use of tetracycline fibers with nonsurgical periodontal therapy in Review
an adult with Down syndrome: a case report. Spec Care Dentist. 2012;32(2):61-65.
Giguère A, Légaré F, Grimshaw J, et al. Printed educational materials: effects on professional practice and healthcare Different outcome
outcomes. Cochrane Database Syst Rev. 2012;10:CD004398.
Itabe H. Oxidize low-density lipoprotein as a biomarker of in vivo oxidative stress: from atherosclerosis to periodontitis. J Different outcome
Clin Biochem Nutr. 2012;51(1):1-8.
Masamatti SS, Kumar A, Virdi MS. Periodontal diseases in children and adolescents: a clinician’s perspective, part 2. Dent Review
Update. 2012;39(8):541-544, 547-548, 551-552.
Minami-Sugaya H, Lentini-Oliveira DA, Carvalho FR, et al. Treatments for adults with prominent lower front teeth. Different outcome
Cochrane Database Syst Rev. 2012;5:CD006963.
Qu H, Wen T, Pesch M, Aumailley M. Partial loss of epithelial phenotype in kindlin-1-deficient keratinocytes. Am J Different outcome
Pathol. 2012;180(4):1581-1592.
Schuurs A. Pathology of the Hard Dental Tissues. Hoboken, NJ: John Wiley & Sons; 2012:50-95. Review
Siegfried N, Irlam JH, Visser ME, Rollins NN. Micronutrient supplementation in pregnant women with HIV infection Different outcome
Tanaka MH, Giro EM, Cavalcante LB, et al. Expression of interferon-gamma, interferon-alpha and related genes in Different outcome
individuals with Down syndrome and periodontitis. Cytokine. 2012;60(3):875-881.
Unkel JH, Edwards JS, Piscitelli WP, Tye GW. Dental surgery and anesthetic precautions of a patient with Down syndrome Review
and juvenile rheumatoid arthritis: a case report. Pediatr Dent. 2012;34(7):517-520.
Areias C, Sampaio-Maia B, Macho V, Leal I, Melo P, de Andrade C. Does the chemistry in the saliva of Down syndrome Different outcome
children explain their low caries prevalence? Eur J Paediatr Dent. 2013;14(1):23-26.
Cabras T, Pisano E, Montaldo C, et al. Significant modifications of the salivary proteome potentially associated with Different outcome
complications of Down syndrome revealed by top-down proteomics. Mol Cell Proteomics. 2013;12(7):1844-1852.
Chou JP, Effros RB. T cell replicative senescence in human aging. Curr Pharm Des. 2013;19(9):1680-1698. Review
Ekfeldt A, Zellmer M, Carlsson GE. Treatment with implant-supported fixed dental prostheses in patients with congenital Different outcome
and acquired neurologic disabilities: a prospective study. Int J Prosthodont. 2013;26(6):517-524.
Macho V, Palha M, Macedo AP, Ribeiro O, Andrade C. Comparative study between dental caries prevalence of Down Different outcome
syndrome children and their siblings. Spec Care Dentist. 2013;33(1):2-7.
Martinez-Martinez RE, Loyola-Rodriguez JP, Bonilla-Garro SE, et al. Characterization of periodontal biofilm in Down No control group
syndrome patients: a comparative study. J Clin Pediatr Dent. 2013;37(3):289-295.
Niscola P, Tendas A, Scaramucci L, et al. Gingival myeloid sarcoma in myelodysplastic syndrome. Support Care Different outcome
Cancer. 2013;21(4):917-918.
Reuland-Bosma W. Dissertations 25 years after date 35: periodontal disease in Down syndromedan immunological Different outcome
disorder [in Dutch]. Ned Tijdschr Tandheelkd. 2013;120(10):541-545.
Trombelli L, Farina R. A review of factors influencing the incidence and severity of plaque-induced gingivitis. Minerva Review
Stomatol. 2013;62(6):207-234.
Tsilingaridis G, Yucel-Lindberg T, Modéer T. Altered relationship between MMP-8 and TIMP-2 in gingival crevicular fluid Different outcome
in adolescents with Down’s syndrome. J Periodontal Res. 2013;48(5):553-562.
Agostino P, Ugolini A, Signori A, Silvestrini-Biavati A, Harrison JE, Riley P. Orthodontic treatment for posterior crossbites. Different outcome
Albandar JM. Aggressive and acute periodontal diseases. Periodontol 2000. 2014;65(1):7-12. Review

eTable 1. Continued

Al-Sufyani GA, Al-Maweri AS, Al-Ghashm AA, Al-Soneidar WA. Oral hygiene and gingival health status of children with No control group
Down syndrome in Yemen: a cross-sectional study. J Int Soc Prev Community. 2014;4(2):82-86.
Eyselbergs M, Vanhoenacker F, Hintjens J, Dom M, Devriendt K, Van Dijck H. Unilateral giant cell lesion of the jaw in Different outcome
Noonan syndrome. JBR-BTR. 2014;97(2):90-93.
Gerreth K, Gerreth P. Occurrence of oral trauma in young epileptic patients. Eur J Paediatr Dent. 2014;15(1):13-16. Different outcome
Khocht A, Albandar JM. Aggressive forms of periodontitis secondary to systemic disorders. Review
Periodontol 2000. 2014;65(1):134-148.
Rivollat M, Castex D, Hauret L, Ancient AMT. Down syndrome: an osteological case from Saint-Jean-des-Vignes, Review
northeastern France, from the 5-6th century AD. Int J Paleopathol. 2014;7:8-14.
Shukla D, Bablani D, Chowdhry A, Thapar R, Gupta P, Mishra S. Dentofacial and cranial changes in Down syndrome. Review
Osong Public Health Res Perspect. 2014;5(6):339-344.
Sperandio FF, Carli ML, Guimaräes EP, Pereira AA, Hanemann JA. Noninvasive treatment choice for an aged Down Case report
syndrome patient presenting a residual periapical cyst. J Contemp Dent Pract. 2014;15(2):254-257.
Subramaniam P, Girish Babu K, Mohan Das L. Assessment of salivary total antioxidant levels and oral health status in Different outcome
children with Down syndrome. Spec Care Dentist. 2014;34(4):193-200.
Tsilingaridis G, Yucel-Lindberg T, Concha Quezada H, Modéer T. The relationship between matrix metalloproteinases Different outcome
(MMP-3, -8, -9) in serum and peripheral lymphocytes (CD8þ, CD56þ) in Down syndrome children with gingivitis. J
Periodontal Res. 2014:49(6):742-750.
Zizzi A, Piemontese M, Gesuita R, et al. Periodontal status in the Down’s syndrome subjects living in central-eastern Italy: No control group
the effects of place of living. Int J Dent Hyg. 2014;12(3):193-198.
Byrd G, Quinonez RB, Offenbacher S, Keels MA, Guthmiller JM. Pediatr Dent. 2015;37(4):381-385. Case report
Cochrane Pregnancy and Childbirth Group. 2015. Available at: http://pregnancy.cochrane.org/pregnancy-and-childbirth- Different outcome
groups-trials-register. Accessed March 20, 2016.
de Sousa MC, Vieira RB, dos Santos DS, et al. Antioxidants and biomarkers of oxidative damage in the saliva of patients Different outcome
with Down’s syndrome. Arch Oral Biol. 2015;60(4):600-605.
Dittmann C, Doueiri S, Kluge R, Dommisch H, Gaber T, Pischon N. Porphyromonas gingivalis suppresses differentiation Different outcome
and increases apoptosis of osteoblasts from New Zealand obese mice. J Periodontol. 2015;86(9):1095-1102.
Fleming PS, Fedorowicz Z, Johal A, El-Angbawi A, Pandis N. Surgical adjunctive procedures for accelerating orthodontic Different outcome
treatment. Cochrane Database Syst Rev. 2015;6:CD010572.
Gross A, Kay TM, Paquin JP, et al.; Cervical Overview Group. Exercises for mechanical neck disorders. Cochrane Database Different outcome
Syst Rev. 2015;1:CD004250.
Marques-Rocha JL, Samblas M, Milagro FI, Bressan J, Martínez JA, Marti A. Noncoding RNAs, cytokines, and Review
inflammation-related diseases. FASEB J. 2015;29(9):3595-3611.
Mehr AK, Zarandi A, Anush K. Prevalence of oral Trichomonas tenax in periodontal lesions of Down syndrome in Tabriz, Control group not healthy
Iran. J Clin Diagn Res. 2015;9(7):ZC88-ZC90.
Rahul VK, Mathew C, Jose S, Thomas G, Noushad MC, Feroz TP. Oral manifestation in mentally challenged children. J No control group
Int Oral Health. 2015;7(2):37-41.
Tanaka MH, Rodrigues TO, Finoti LS, et al. The effect of conventional mechanical periodontal treatment on red complex Review
microorganisms and clinical parameters in Down syndrome periodontitis patients: a pilot study. Eur J Clin Microbiol Infect
Dis. 2015;34(3):601-608.
Futamura-Masuda M, Yokota-Honda M, Anraku T, et al. Effect of Asiasarum root extract and its constituents on Different outcome
interleukin-1b-stimulated matrix metalloproteinase-1 secretion from human gingival fibroblasts. Biol Pharm Bull.
2016;39(5):823-831.
Kamer AR, Fortea JO, Videla S, et al. Periodontal disease’s contribution to Alzheimer’s disease progression in Down Review
syndrome. Alzheimers Dement (Amst). 2016;2:49-57.
Limeres Posse J, López Jiménez J, Ruiz Villandiego JC, et al. Survival of dental implants in patients with Down syndrome: a Different outcome
case series. J Prosthet Dent. 2016;116(6):880-884.
Martins F, Simões A, Oliveira M, Luiz AC, Gallottini M, Pannuti C. Efficacy of antimicrobial photodynamic therapy as an Different outcome
adjuvant in periodontal treatment in Down syndrome patients. Lasers Med Sci. 2016;31(9):1977-1981.
Mulimani P, Ballas SK, Abas ABL, Karanth L. Treatment of dental complications in sickle cell disease. Cochrane Database Different outcome
Syst Rev. 2016;4:CD011633.
Tasoulas J, Patsouris E, Giaginis C, Theocharis S. Salivaomics for oral diseases biomarkers detection. Expert Rev Mol Different outcome
Diagn. 2016;16(3):285-295.

eTable 1. Continued

Alqahtani NM, Alsayed HD, Levon JA, Brown DT. Prosthodontic rehabilitation for a patient with Down syndrome: a Case report
clinical report. J Prosthodont. 2017. doi:10.1111/jopr.12595.
Altintas NY, Kilic S, Altintas SH. Oral rehabilitation with implant-retained overdenture in a patient with Down syndrome. Different outcome
J Prosthodont. 2017. doi:10.1111/jopr.12596.
eTable 2. List of titles selected for full-text analysis and reason for exclusion.
TITLES SELECTED FOR FULL-TEXT ANALYSIS REASON FOR EXCLUSION

Cutress TW, Brown RH, Guy EM. Occurrence of some bacterial species in the dental plaque of trisomic No clinical results
21 (mongoloid), other mentally retarded, and normal subjects. N Z Dent J. 1970;66:153-161.
Brown RH. Necrotizing ulcerative gingivitis in mongoloid and non-mongoloid retarded individuals. Control group mentally retarded
J Periodontal Res. 1973;8:290-295.
Schier M, Wolfaardt J. The microbial population of the gingival sulcus of mongoloid and normal No clinical results
childrenea comparative study. Distema 1976;4(4):11-12.
Melnick M, Shields ED, Escobar VH, Elkafrawy A. Periodontal-disease and immunological competence Abstract only
in Down syndrome [special issue A]. J Dent Res. 1977;56:A59.
Miller MF, Ship II. Periodontal disease in the institutionalized mongoloid. J Oral Med. 1977;32(1):9-13. Control group not healthy
Saxen L, Aula S, Westermarck T. Periodontal disease associated with Down’s Syndrome: an Control group not healthy
orthopantomographic evaluation. J Periodontol. 1977;48(6):337-340.
Loevy HT. Periodontal disease in patients with Down’s syndrome. CDS Rev. 1979;72(3):23-6. Review
Wenstein R, Carrassi A, Ciancaglini R. Dento-periodontal pathology in a group of patients with Italian language
Down’s syndrome. Mondo Odontostomatol. 1983;25(2):7-9.
Reuland-Bosma W, Liem RS, Jansen HW, van Dijk LJ, van der Weele LT. Morphological aspects of the Repeated data in another article
gingiva in children with Down’s syndrome during experimental gingivitis. J Clin Periodontol.
1988;15(5):293-302.
Izumi Y, Sugiyama S, Shinozukaf O, Yamazaki T, Ohyama T, Ishikawa T. Defective neutrophil No clinical results
chemotaxis in Down’s syndrome patients and its relationship to periodontal destruction. J Periodontol.
1989;60(5):238-242.
Shapira J, Stabholz A, Schurr D, Sela MN, Mann J. Caries levels, Streptococcus mutans counts, Missing a results page
salivary pH, and periodontal treatment needs of adult Down syndrome patients. Spec Care
Dentist. 1991;11(6):248-251.
Figueiredo LC, Salvador SL, Padini LC, Marcantonio RA. Neutrophil chemotaxis and periodontal Only abstract
disease progression in Down’s syndrome patients. J Nihon Univ Sch Dent.1993; (35):91-95.
Barr-Agholme M, Dahllöf G, Modéer T, Engström E, Engström GN. Periodontal conditions and salivary Repeated data in another article
immunoglobulins in individuals with Down syndrome. J Periodontol. 1998;69(10):1119-1123.
Amano A, Kishima T, Kimura S, Takiguchi M, Ooshima T, Hamada S, Morisaki I. Periodontopathic No clinical results
Bacteria in Children with Down Syndrome. J Periodontol. 2000;71(2):249-255.
Figueiredo LC, Salvador SL, Marcantonio RA, Pardini LC. Longitudinal study of periodontal disease Abstract only
progression and neutrophil chemotaxis in Down's Syndrome. J Dent Res. 2000;79(5-8):231-231.
Figueiredo LC, Feres M, Salvador SL. Halitosis and periodontal disease in subjects with mental Control group with periodontal disease
disabilities. Oral Dis. 2005;2(1):83-85.
Mathias, Santos MTBR, Guare RO. Dental hygiene, gingival modified index (GMI) and simplified oral Book chapter
hygiene index (OHIS) in the primary dentition of Down syndrome children. Handbook of Down syndrome
research/Dominicus Jelinek and Gijs Dvorak, editors. Hauppauge, NY: Nova Biomedical Books, 2009.
Teitelbaum AP, Pochapski MT, Jansen JL, Sabbagh-Haddad A, Santos FA, Czlusniak GD. Evaluation of No control group
the mechanical and chemical control of dental biofilm in patients with Down syndrome. Community
Dent Oral Epidemiol. 2009;37:463-467.
Davidovich E, Aframian DJ, Shapira J, Peretz B. A comparison of the sialochemistry, oral pH, and oral Periodontal disease evaluated in the same group and not
health status of Down syndrome children to healthy children. Int J Paediatr Dent. 2010;20:235-241. compared between those with and those without Down
syndrome
Khocht A, Heaney K, Janal M, Turner B. Association of interleukin-1 polymorphisms with periodontitis Repeated data in another article
in Down syndrome. J Oral Sci. 2011;53(2):193-202.
El Housseiny AA. Aggregatibacter actinomycetemcomitans in Down’s syndrome children. Arch Health No clinical results
Inves. 2012;36(4):417-422.
Khocht A, Russell B, Cannon JG, Turner B, Janal M. Phagocytic cell activity and periodontitis in Down Repeated data in another article
syndrome. Oral Dis. 2012;18(4):346-352.

eTable 2. Continued
TITLES SELECTED FOR FULL-TEXT ANALYSIS REASON FOR EXCLUSION

Khocht A, Yaskell T, Janal M, Turner BF, Rams TE, Haffajee AD, Socransky SS. Subgingival microbiota Repeated data in another article
in adult Down syndrome periodontitis. J Periodontal Res. 2012;47(4):500-507
Tsilingaridis G, Yucel-Lindberg T, Modéer T. T-helper-related cytokines in gingival crevicular fluid from No clinical results
adolescents with Down syndrome. Clin Oral Investig. 2012;16:267-273.
Ahmed N, Parthasarathy H, Arshad M, Victor DJ, Mathew D, Sankari S. Assessment of Porphyromonas Control group and study group with periodontal disease
gingivalis and Aggregatibacter actinomycetemcomitans in Down’s syndrome subjects and systemically
healthy subjects: a comparative clinical trial. J Indian Soc Periodontol. 2014;18(6):728-733.
Khocht A, Russell B, Cannon JG, Turner B, Janal M. Oxidative burst intensity of peripheral phagocytic Repeated data in another article
cells and periodontitis in Down syndrome. J Periodontal Res. 2014;49(1):29-35.
Identification
Records identified through Additional records identified

database searching through other sources
(n = 399) (n = 0)
Records
after duplicates removed
(n = 94)
Screening
Records screened Records excluded

(n = 305) (n = 255)
Full-text articles assessed Full-text articles excluded,

Eligibility
for eligibility with reasons

(n = 50) (n = 27)
Studies included in
qualitative synthesis
(n = 23)
Included
Studies included in
quantitative synthesis
(meta-analysis)
(n = 3)
eFigure 1. Screening of articles.
Standard Difference Standard Standard Difference

Study in Means Error 95% CI P Value in Means, 95% CI
López-Pérez and Colleagues,23 2002 0.39 0.25 –0.10 to 0.89 0.120
Yamazaki-Kubota and Colleagues,30 2010 0.30 0.38 –0.44 to 1.05 0.426
Mathias and Colleagues,31 2011 –0.42 0.17 –0.76 to –0.08 0.015
0.05 0.30 –0.55 to 0.65 0.869
–2.00 –1.00 0.00 1.00 2.00

Decreases or Increases in Periodontal Disease
eFigure 2. Meta-analysis of three case-control studies evaluating Oral Hygiene Index comparing patients with Down syndrome and controls.
I2 ¼ 76.04%, random effect model.


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Systematic Review

Periodontal disease in patients with Down

628 JADA 149(7) n http://jada.ada.org n July 2018

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PARTICIPANT NO. OF PARTICIPANT PERIODONTAL RESULTS FOR PERIODONTAL DISEASE;

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Methodological quality appraisal

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Kroll and NA† NA NA 0‡ 0 0 þ§ þþ{ 0 0 þ

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Drop outs Extraneous Changes Distortion

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Harndt R. Periodontopathies in childhood. Dtsch Zahnarztl Z. 1969;24(12):1062-1077. Different outcome

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Scully C. Down’s syndrome: aspects of dental care. J Dent. 1976;4(4):167-174. Review

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TITLES SELECTED FOR ABSTRACT ANALYSIS REASON FOR EXCLUSION

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Dekker K. Is your knowledge up-to-date? Int J Dent Hyg. 2005;3(1):49-51. Review

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TITLES SELECTED FOR FULL-TEXT ANALYSIS REASON FOR EXCLUSION

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TITLES SELECTED FOR FULL-TEXT ANALYSIS REASON FOR EXCLUSION

Records identified through Additional records identified

Records screened Records excluded

Full-text articles assessed Full-text articles excluded,

for eligibility with reasons

eFigure 1. Screening of articles.

Standard Difference Standard Standard Difference

–2.00 –1.00 0.00 1.00 2.00

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