Final Research Plan

Principle Investigators (Mutaz Ahmed/Salah Ibrahim)

NPRP No. :

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Research Plan (Items 1-8 not to exceed 25 pages) 1. Background and significance (maximum two pages) Aggressive periodontitis Aggressive periodontitis (AP) is a debilitating oral disease that results in rapid destruction of the periodontal tissues. It is a less common form of periodontal disease than chronic periodontitis and principally affects young patients. The estimated prevalence of aggressive periodontitis ranges from 0.1% to 15% among Caucasians, Hispanics and African Americans, with a greater prevalence in African Americans when compared to Caucasians. (1) It occurs in localized and generalized forms that differ in many respects with regard to their aetiology and pathogenesis. Localized aggressive periodontitis (LAP) and generalized aggressive periodontitis (GAP) were previously called “localized and generalized juvenile periodontitis” or “early-onset periodontitis” respectively. Features of aggressive periodontitis that are common to both the localized and generalized forms of the disease are: Primary features: Except for the presence of periodontitis, patients are clinically healthy; rapid attachment loss and bone destruction; familial aggregation. Secondary features (often present): Amounts of microbial deposits are inconsistent with the severity of periodontal tissue destruction; elevated proportions of Aggregatibacter actinomycetemcomitans and, in some

populations,

Porphyromonas

gingivalis

may

be

elevated;

phagocyte

abnormalities;

hyperresponsive macrophage phenotype, including elevated levels of prostaglandin E2 (PGE2) and interleukin-1β (IL-1β); progression of attachment loss and bone loss may be self-arresting. (2) Some types of aggressive periodontitis seem to be inherited in a Mendelian manner, and both autosomal modes and X-linked transmission have been proposed. Genetic segregation analyses have been carried out using family pedigrees and the distribution of family members with aggressive periodontitis. Most of the evidence for a genetic predisposition to aggressive periodontitis comes from segregation analyses of families with affected individuals in two or more generations, and the results in different sets of families are consistent with both autosomal-dominant and autosomal-recessive inheritance, as well as X-linked dominant inheritance, but no single inheritance mode that would include all families has been established. (3)

QNRF Form (Revised 09)

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Principle Investigators (Mutaz Ahmed/Salah Ibrahim)

NPRP No. :

09 - 953 - 3 - 248

Diabetes mellitus Diabetes mellitus is a group of metabolic disorders manifested by abnormally high levels of glucose in the blood. The hyperglycemia is the result of a deficiency of insulin secretion caused by pancreatic b-cell dysfunction (Type 1) or of resistance to the action of insulin in liver and muscle (Type 2), or a combination of these. Diabetes is a syndrome and it is now recognized that chronic hyperglycemia leads to long-term damage to different organs including the heart, eyes, kidneys, nerves, and vascular system (4). Both types of diabetes are familial and emerge in individuals in whom genetic susceptibility is triggered by environmental determinants. Genetic susceptibility to Type 1 diabetes resides largely in the genes encoding the HLA (human leukocyte antigen) molecules of the MHC (major histocompatibility complex) located on the short arm of chromosome (5). The incidence of diabetes is escalating worldwide. A recent cross sectional study found that the overall prevalence of diabetes mellitus among adult Qatari population was high (16.7%) with diagnosed DM (10.7%) and newly diagnosed DM (5.9%) (6). The impact of diabetes mellitus on the oral cavity has been well documented. Oral health complications of diabetes include caries, periodontal disease, candidal infections and dry mouth. A large body of evidence demonstrates that diabetes is a risk factor for gingivitis and periodontitis (7). The degree of glycemic control is an important variable in the relationship between diabetes and periodontal diseases, with a higher prevalence and severity of gingival inflammation and periodontal destruction being seen in those with poor control (8). Large epidemiological studies have shown that diabetes increases the risk of alveolar bone loss and attachment loss approximately three-fold when compared to nondiabetic individuals (9). These findings have been confirmed in meta-analyses of studies in various diabetic populations (10). In longitudinal analyses, diabetes increases the risk of progressive bone loss and attachment loss over time (11). The degree of glycemic control is likely to be a major factor in determining risk. For example, in a large epidemiological study in the U.S adults with poorly controlled diabetes had a 2.9-fold increased risk of having periodontitis compared to nondiabetic subjects; conversely, subjects with well-controlled diabetes had no significant increase in the risk for periodontitis (12). Similarly, poorly controlled type 2 diabetic subjects had an 11-fold increase in the risk for alveolar bone loss over a 2-year period compared to nondiabetic control subjects (13). On the other hand, well-controlled type 2 patients had no significant increase in risk for longitudinal bone loss compared to nondiabetic controls. Specific aims and Timeline: QNRF Form (Revised 09)

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Principle Investigators (Mutaz Ahmed/Salah Ibrahim)

NPRP No. :

09 - 953 - 3 - 248

Our long-term objective is to establish the prevalence of oral disease with special reference to periodontal diseases. This should provide the basis for future oral health strategy in Qatar. According to a study funded by QNRF, diabeteic patients still have low awareness about the disease. We expect the oral health awareness is no better. We hope this study will increase the awareness and help in education of the patients with two serious conditions that can lead eventually to loss of teeth. The specific aims of this proposal are as follows: 1. To investigate the prevalence of aggressive periodontitis among students aged 13 to 19 years at public and private schools in Qatar. 2. T 3. To determine periodontal condition of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) and their association with increased prevalence and extent of periodontal disease within adult population in Qatar. Timeline: In the first year our plan is to conduct the study of aggressive periodontal disease (Aim 1. In the second year, the periodontal condition of diabetic patients in Qatar will be investigated Aim 2). The following Time line will be followed during the whole study period:

Year 1 Phase 1: - Review of the literature - Training &Calibration of examiners

Duration 2 months

Phase 2: - Data Collection

4 months

Phase 3: - Data analysis

3months

Phase 4: – Writing and presenting the first report to QNRF – Submit 1st paper for publication

3months

Duration Year 2

QNRF Form (Revised 09)

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Principle Investigators (Mutaz Ahmed/Salah Ibrahim)

NPRP No. :

Phase 1: - Review of the literature - Calibration of examiners

2 months

Phase 2: - Data Collection

6months

Phase 3: - Data analysis

2months

Phase 4: – Writing and presenting the second report to QNRF – Submit 1st paper for publication

2months

1.

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Preliminary data or studies. N/A

2. Significance The World Health Organization (WHO) Global Oral Health Programme has been working hard over the past few years to increase the awareness of oral health worldwide as an important component of general health and quality of life. Meanwhile, oral disease is still a major public health problem in high income countries and the burden of oral disease is growing in many low- and middle income countries. In the World Oral Health Report 2003, the WHO Global Oral Health Programme formulated the policies and the necessary actions for the improvement of oral health. The strategy is that oral disease prevention and the promotion of oral health needs to be integrated with chronic disease prevention and general health promotion as the risks to health are linked. The diabetes incidence is on the rise in Qatar, with an estimated prevalence of 17% of the population. It is clearly that there is a desire need for clinical research to assess the of oral health status of diabetic patients and also investigate the early onset periodontal disease. This will certainly open the doors for future work to establish the treatment needs and enhance the promotion of oral health in the country.

3. Research design and methods QNRF Form (Revised 09)

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Principle Investigators (Mutaz Ahmed/Salah Ibrahim)

NPRP No. :

09 - 953 - 3 - 248

Phase 1: Prevalence of aggressive periodontitis in young population from Qatar Study population Based on the data from the Ministry of Education, the total number of registered students aged 12 to 19 years in Doha is 61226, of which 30319 were males and 30907 were females. In this project, a simple random method will be used for sampling. Sample size will be calculated using the software StatCalc, Epi Info 6.0, Centers for Disease Control and Prevention, Atlanta, GA. We will assume that the default proportion of 7.6%, with 1% error for event occurrence, will be acceptable. An estimated sample size of 00.00 is found to be necessary for the statistical significance with P <0.05. Accordingly, our study will consist of 800 students aged 12 to 19 years from Doha public schools: 0,000 females and 0,000 males. The numbers of females and males will not be significantly different. It is decided that the study population should be comprised of individuals aged 12 years onward, because that is the age in which, in most cases, all the permanent teeth are completely erupted. Thus, the target population for this particular study will be drawn from subjects within the 12-19 years age. The Ministry of Education in Doha will be informed, and the study will be conducted in accordance with the Helsinki Declaration of 1975, as revised in 2000. Entry into the study will include written informed consent (from the parent if the patient was a minor), completion of a questionnaire, and a signature before each oral examination. The date of examination, gender, birth date, toothbrushing habits, date of the last dental visit, and medical and dental histories will be recorded. All the individuals will be examined at their schools using mobile dental units.

Ethical considerations Permission to carry out this study will be obtained from the Ministry of Education and Ministry of Oral Health in Doha. The study protocol and the informed consent forms will be approved by the Ethics Committee of Hamad Medical Corporation. In case of difficulties of understanding, the informed consent form will be read to all eligible individuals. All subjects who will agree to participate - or, in the case of children, an adult guardian – will be asked to sign the informed consent form to attest to their understanding of its contents and acceptance to participate in the study. As a large need for dental treatment will be expected, a partnership will be established with the Health Authority, in Doha. Whenever needed, pain-relief treatment will be administered by a dentist from the

QNRF Form (Revised 09)

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Principle Investigators (Mutaz Ahmed/Salah Ibrahim)

NPRP No. :

09 - 953 - 3 - 248

primary health care Units. Subjects detected with diseases or conditions of non-dental origin will be referred to the nearest health centre located in Doha.

Interviews and clinical examinations All eligible and consenting subjects will be visited at their schools and invited to participate in an interview that will be performed by a trained dentist and dental assistant based on a structured written questionnaire. The following information will be collected through the interview: age (years), gender, occupation, household size, presence of cash-income (yes/no) and, if applicable, its approximate monthly amount in Qatari currency ("riyals"), illiteracy (yes/no), years of education, and if they had ever received urgency treatment (yes/no). The frequency of tooth cleaning and smoking habits (if applicable) will also be investigated. If applicable, the participants will be identified by questions as either current smokers (had smoked>50 cigarettes in their lifetime and currently smoked), former smokers (had smoked>50 cigarettes in their lifetime, but were not currently smoking) or never smokers (had not smoked>50 cigarettes in their lifetime). Other questions pertaining to smoking habits will include the duration of current and former smoking (years); time since cessation for former smokers (years), type of tobacco-containing items used, as well as the number of items smoked on a daily basis. The clinical examinations will be carried out by two specialist (MFA, Consultant/specialist in restorative dentistry, and SOI, periodontal specialist) assisted by two dental assistants. All clinical examinations will be performed using mobile dental units. Probing depth (PD), measured as the distance (mm) from the free gingival margin (FGM) to the bottom of the pocket; and gingival recession (GR), measured as the distance from the cementumenamel junction (CEJ) to the FGM, will be determined at 6 sites per tooth (mesiobuccal, midbuccal, distobuccal, distolingual, midlingual, and mesiolingual sites) in all permanent teeth present, excluding third molars, using a mouth mirror (Mirror nº #5, Hu Friedy, Chicago, IL, USA) and either a World Health Organization 621 pattern probe or a manual periodontal probe (PCPUNC-15, Hu Friedy, Chicago, IL, USA). The measurements will be rounded to the lowest whole mm, and the highest score for each sextant will be recorded. When the CEJ is located coronally to the FGM, it will be given a negative sign. Clinical attachment level (CAL) will be calculated as the sum of the PD and GR values for each site. Two sites per tooth (midbuccal and midlingual) will be assessed for the presence of visible plaque (yes/no) and supragingival calculus (yes/no). Supragingival calculus will be defined as QNRF Form (Revised 09)

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Principle Investigators (Mutaz Ahmed/Salah Ibrahim)

NPRP No. :

09 - 953 - 3 - 248

the calcified deposits located on exposed crowns and root surfaces extending up to 1 mm below the FGM. Excessive amounts of supragingival calculus compromising assessment of the periodontal conditions will be removed by periodontal curettes (Gracey Curettes, Hu Friedy, Chicago, IL, USA) before probing. Finally, A code number will be given to each sextant according to the following criteria: 4 = pathologic pockets ≥6 mm or deeper; 3 = pathologic pockets 4 or 5 mm deep; 2 = supraor subgingival calculus; 1 = gingival bleeding after gentle probing; 0 = no signs of disease; and X = only one or no teeth present in a sextant. Thus, a subject or a sextant is classified according to TN into one of the following treatment categories: TN0 = no treatment (code 0); TN1 = improvement in personal oral hygiene (code 1); TN2 = TN1 + scaling (codes 2 and 3); and TN3 = TN1 + TN2 + complex treatment (code 4). Any individual with two or more sextants or teeth with CPITN code 3 or one sextant with code 4 will be scheduled for radiographs and further clinical examination at the public dental clinics. For individuals found in need for periodontal treatments, vertical bitewing radiographs of the molar regions and periapical radiographs of the incisor region will be obtained from each participant. A full-mouth periodontal examination will be performed; probing depths and clinical attachment level measurements will be made around the mesio-buccal, disto-buccal, mesio-labial, and disto-labial aspects of each tooth. Recording will be done using a periodontal status tooth diagram where pocket depth (4 sites), tooth mobility, bleeding points, furcation involvement, dental plaque and bleeding perecent will be registered. The oral examinations will be carried out by a periodontal specialist (SOI), and the radiographs will be read by three examiners. A second specialist (MFA) will examine 10% of the patients (randomly selected); in 90% of the cases, the clinical findings will be compared to those of the initial examination. Patients will be diagnosed as having LAgP based on the following criteria: good health; involvement of more than one first molar; radiographic evidence of alveolar bone loss ≥2 mm on more than one surface of the permanent tooth involved; probing depth at diseased sites >5 mm; and extensive bone loss with respect to the low levels of plaque and calculus unlike typically observed in chronic periodontitis. Patients with obvious molar and incisor bone loss consistent with LAgP, but who also may have plaque and calculus, will be considered to have LAgP. The deep periodontal pockets in sextants scoring as code 3 or 4 will be thoroughly examined. The students having alveolar bone loss ≥2 mm on more than one surface and >5 mm probing depth at diseased sites in their first

QNRF Form (Revised 09)

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Principle Investigators (Mutaz Ahmed/Salah Ibrahim)

NPRP No. :

09 - 953 - 3 - 248

molars will be diagnosed as having LAgP only if symmetrical bone loss characteristic of LAgP is obvious on radiographs.

Measurement reproducibility The clinical examiners will be trained and calibrated for the clinical examinations 15 days before and 4 months after the start of the study. Intra-examiner reproducibility assessments will be carried out under the same field conditions that will be used in all clinical examinations, and will be assessed by double recordings in selected number of subjects (x sites) (~6-10% of the study population). The repeat recordings will be made 7 days after the first clinical examination. The intra-class correlation coefficient at the site level and at the subject level for mean CAL will be calculated.

Data analysis In this study, the following case definitions of AgP will be employed (1) Age group 12-14 years: subjects with CAL > 4 mm in > 4 teeth; (2) Age group 15-19 years: subjects with CAL > 5 mm in > 4 teeth. Midbuccal and midlingual surfaces will not be excluded from the analysis, since the tradition of oral hygiene habits is expected to be limited in the study group. Moreover, the data will also be presented as prevalence and extent of CAL and PD > 4 mm,> 5 mm, and > 6 mm. Extent will be defined as the percentage of sites affected per person. The candidate predictor variables that will be considered for inclusion in a logistic regression analysis will include age (12-14/15-19); gender; education years (< 4 years/> 4 years), familiar illiteracy (yes/no); presence of pain-relief treatment (yes/no); % of sites with visible plaque (< 70%/> 70%); % of sites with supragingival calculus (< 30%/> 30%); as well as smoking status (nonsmoker/smoker). Exposure to smoking will be accounted for by current and former smokers combined. To explore and quantify the association between the candidate predictor variables and the periodontal outcome variable (AgP presence), a multivariable logistic regression analysis will be performed using the "logit" procedure in the STATA program (Stata 9.2 for Windows, Stata Corporation, College Station, TX, USA). All candidate predictor variables associated with the outcome at p < 0.25, as evidenced in a univariable logistic regression analysis, will be included in the full model. Predictor variables will be removed from the model one at a time, until the log-likelihood ratio test indicates that no more variables can be removed. A variable will be considered a confounder if its removal from the QNRF Form (Revised 09)

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Principle Investigators (Mutaz Ahmed/Salah Ibrahim)

NPRP No. :

09 - 953 - 3 - 248

model will result in changes in the β estimates by more than 15%. Model fit will be evaluated using the Hosmer & Lemeshow Goodness-of-fit-test and by calculation of the area under the ROC curve, which describes the ability of the logistic model to correctly predict outcome variable status.

Phase 2: Prevalence of periodontal disease among diabetics in Qatar This part of the study will be carried out as a cross-sectional, case-control study. In the period from January 2011 to December 2013, a total of 600 patients will be included (300 diabetic patients and 300 nondiabetics as controls). The patients will be recruited from the outpatient diabetic clinic in Doha. Included patients will be either type 1 or type 2 diabetes mellitus (DM) patients who are dentate persons aged 30 years and older with ≥ 6 remaining teeth. Patients who will be found edentulous will be excluded. The controls will be nondiabetic patients who were visiting the outpatient clinic for other reasons. All patients will be asked for an informed consent, and the study will be approved by the ethical committee of the Health Authorities in Qatar, Doha. The Ministry of Health in Doha will be informed, and the study will be conducted in accordance with the Helsinki Declaration of 1975, as revised in 2000. Entry into the study will include written informed consent, completion of a questionnaire, and a signature before each oral examination. The date of examination, gender, birth date, dietary habits, toothbrushing habits, date of the last dental visit, and full medical and dental histories will be recorded. All the individuals will be examined using mobile dental units. DM will be diagnosed according to the American Diabetes Association recommendations in 2002. Here, patients who are on drug treatment for diabetes will be considered diabetic. Education level will be calculated according to the number of years of school achievement. Patients who will be found as cigarette smokers will be considered smokers, whereas those who already quit smoking for at least for 5 year will be considered as x-smokers. Two specialists (MFA and SOI) and two dental assistants will perform the dental examinations. The oral health examination will include an examination of the oral cavity to assess tooth count and location. Flossing and brushing will be reported. Brushing 2 times per day with or without flossing will be considered proper dental care and considered doing brushing. We will use the periodontal probe PCP 11 (Hu-Friedy, Chicago, Illinois) to assess probing depth. The data will be collected when slight resistance to probe penetration is felt. The periodontal examination (tooth mobility, 4 sites pocket depth, furcation involvemen, bleeding points, and sites with dental plaque, clinical attachement level) will be carried out in 2 randomly selected quadrants, one maxillary QNRF Form (Revised 09)

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Principle Investigators (Mutaz Ahmed/Salah Ibrahim)

NPRP No. :

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and one mandibular. All fully erupted teeth in these 2 quadrants will be assessed carefully, excluding the third molars. A maximum of 14 teeth per individual will be examined for periodontal parameters. Advanced periodontitis will include persons with 2 or more teeth (or ≥ 30% of the examined teeth) with ≥ 5 mm probing depth, or 4 or more teeth (or ≥ 60% of the teeth) with ≥ 4 mm probing depth. Moderate periodontitis will include persons without advanced periodontitis with 1 or more teeth with ≥ 5 mm probing depth, or 2 or more teeth (or ≥ 30% of the teeth) with ≥ 4 mm probing depth. Mild periodontitis will include persons without moderate or advanced periodontitis who have 1 or more teeth with ≥ 3 mm probing depth. Persons with 6 or more teeth present and who are without the aforementioned criteria of periodontitis will be classified with no periodontitis. Statistical Analysis Continuous variables will be summarized as the mean ± SD. Categoric variables will be summarized as percentages. For statistical analysis a chi-square test will be used. A comparison of 2 means will be carried out with an unpaired Student t test. The level of significance will be set to be < .05 throughout the analysis.

4.

Anticipated results and evaluation criteria

QNRF Form (Revised 09)

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Principle Investigators (Mutaz Ahmed/Salah Ibrahim)

NPRP No. :

09 - 953 - 3 - 248

We expect this project would establish the baseline data about the periodontal condition of diabetic population as well as the children and adolescents with signs of early onset periodontal disease. We expect that oral hygiene would be generally poor and hence the severity of disease among the Qatari population to be would be higher. These results will be evaluated and compared to previous studies in regional countries such as Saudi and other developing and developed countries. Our evaluation criteria will also include the recommendations and expectations of the World Health Organization regarding oral health. 5. Strategy for project continuation We plan to continue this project by re-examining this group of patients 2 years later to monitor the progress of periodontal disease. We also intend to expand this project in the future to include other systemic disease such as cardiac conditions. Future projects are needed to investigate the impact of patient’s education, perception and response to treatments. 6. Plans for disseminating research results It is our intention to present our results in both national and international meetings and conferences such as International association for dental research. Results will be published in peer reviewed international journals such as International Dental Journal and Journal of Dentistry. Also, the contribution of QNRF will be acknowledged in any future publications. We intend to distribute our results and recommendations to the local health authorities in Qatar to help improving the current dental health. This research will definitely build bridges with international community especially the World health Organization and will provide the basis for any future prevention and collaborative programs.

7.

Rebuttal to the peer reviewer’s comments for resubmitted proposals (when applicable). N/A

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