2012 Ph.D. APPLIED EXAM Department of Biostatistics University of Washington

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1 2012 Ph.D. APPLIED EXAM Department of Biostatistics University of Washington Background Dental caries is an infectious, transmissible bacterial disease that is a common childhood condition in the United States. In 2000, a Surgeon General s report on oral health (US Department of Health and Human Services, 2000) stated, dental caries (tooth decay) is the single most common chronic childhood disease - 5 times more common than asthma and 7 times more common than hay fever. It reported that the majority (52%) of children aged 5 to 9 years had at least one carious lesion or filling. Furthermore, there are striking disparities in dental disease. Nationally representative surveys have found that children in families living below the poverty level experience more dental decay than those who are economically better off. Furthermore, caries seen in poor children is more likely to be untreated (as opposed to treated with a dental restoration) than caries in those living above the poverty level. More than 19% of poor children aged 6 to 19 have one or more untreated decayed permanent teeth compared to 8% of non-poor children. Billions of dollars are spent in the United States each year to provide treatment and to deal with the consequences of this highly prevalent but preventable disease. The larger part of these expenditures is by the Federal and State governments through Medicaid. Early preventive interventions have the potential to greatly reduce later downstream costs to the Medicaid program. An NIH Consensus Conference (NIH, 2001) on the Diagnosis and Management of Dental Caries throughout Life evaluated preventive practices and identified those with substantive benefit. Key among these recommended practices are parental oral health education, promotion of tooth brushing with fluoridated toothpaste, topical fluorides, and dental sealants. However, these practices have achieved limited impact on caries reduction particularly among low income children and ethnic minorities because recommended practices often do not reach the populations at greatest risk. In fact, national data shows a recent rise in tooth decay among children. The NIH Consensus Conference also identified sugarless and xylitol containing products as potentially beneficial. Xylitol products have received little study or application in the United States. Xylitol is a naturally occurring 5-carbon sugar polyol (also called a sugar alcohol ) currently approved for use in foods, pharmaceuticals and oral health products in more than 35 countries (Burt, 2006). It is found naturally in various trees, fruits and vegetables and is an intermediate product of the glucose metabolic pathway in man and animals. Although structurally dissimilar, it has approximately the same sweetness as sucrose or table sugar and an FDA-approved caloric content of 2.4 kcal/g compared with 4.0 kcal/g for sucrose. Due to the above properties, xylitol has been FDA approved as a dietary food additive and has been used in dietary food for diabetic patients. It has been shown that post-prandial blood glucose level and insulin requirement were significantly less after equivalent dose of xylitol versus sucrose were added to a breakfast meal. Currently, xylitol can be found in the ingredients list of general market products such as gums, mints, candies, lozenges, soft drinks, toothpastes, and dietary food. To date, after nearly 30 years of xylitol product usage, there is no known reported case of major detrimental side effects related 1

2 to the use of xylitol in food, gum, or syrup. Children can tolerate a daily dose of 45g without developing side effects while the effective dosing range is thought to be several fold lower. Side effects include laxative effects and are self limiting. There are reasons to believe that xylitol products could have beneficial effects on prevention of caries (van Loveren, 2004; Burt, 2006). Chewing gum or other types of chewy candy or sucking on hard candies or lozenges can by itself prevent cavities by stimulating salivary flow. However, gums or other products containing some sweeteners such as sucrose and fructose feed oral bacteria that create acid and cause tooth decay. The harmful effects of the sugar more than offsets the benefits of increased salivary flow. On the other hand, xylitol and other types of sweeteners that are used as sugar replacements have been shown to lack such cariogenic effects. Thus, consuming sugar-free products that contain sweeteners such as xylitol are considered to be a useful anti-caries measure. Beyond their effects on saliva, products containing xylitol may have additional anti-caries activity due to specific effects of xylitol on oral bacteria that cause tooth decay. Specifically, xylitol has been shown to interfere with the metabolism and adherence to tooth surfaces of cariogenic bacteria. For example, it has been shown that when S. mutans are exposed to xylitol, both in long-term and short-term consumption, they develop xylitol-resistant strains which may be less virulent in the oral environment. These xylitol resistant bacteria adhere less well to tooth surfaces and produce less acid than do xylitol sensitive bacteria. Xylitol resistant mutant S. mutans can persist in both saliva and plaque for many years after xylitol is removed from the diet. Evidence from controlled clinical studies of xylitol indicates that there is selective decrease in levels of cariogenic bacteria in plaque and saliva, possible decrease in plaque quantity, and increased remineralization of enamel with xylitol use (Maguire and Rugg-Gunn 2003). This research suggests that xylitol could have benefits on caries prevention that persist after the exposure to xylitol ends. There is preliminary evidence from clinical studies that xylitol is effective in reducing caries rates. These studies have involved children of various ages as well as a variety of modes of delivery of xylitol, including candies, lozenges, chewing gum, etc. Studies of xylitol products have often also included the use of fluoridated toothpaste and/or behavior modification as adjuncts, in line with suggestions by the NIH Consensus Statement of using combined intervention to reduce dental caries (NIH, 2001). However, previous research on anti-caries effects of xylitol has suffered from methodological limitations that have prevented clear conclusions. There does not exist clear evidence that xylitol products have specific anti-caries effects beyond those that might be due to increased salivary flow. Several reviews of the previous research have been published (e.g., van Loveren, 2004; Burt, 2006; Mickenautsch et al., 2007; Antonio et al., 2011). The Study A group-randomized trial was performed to determine the effect of xylitol on prevention of caries in young children. Xylitol was delivered by providing the children with chewy candies ( gummy bears ). The trial participants were all children who were enrolled at the beginning of a given school year in kindergarten classes in 15 schools within an urban community located in the 2

3 United States. The community was chosen as the site for the trial because the children in the community experience very high dental caries rate and have poor access to or utilization of local private dental care. The community has a high level of poverty as indicated by more than 90% of children qualifying for a federal free and reduced lunch program. The trial was performed as a group-randomized trial in which groups of children (all children enrolled within a given classroom) are randomized together to a given treatment condition. This type of randomization is preferable to individual randomization of children because of the high likelihood that children within the same classroom would share gummy bears with each other. Of the 15 schools, 3 schools had 4 classrooms each and 12 had 2 classrooms each. Randomization was performed just before the beginning of the kindergarten school year using the list of classrooms available at that time. Within each school, classrooms were randomized to one of the two treatment arms in such a way that there were equal numbers of classrooms on each treatment arm. However, by the end of the trial there were only 32 classrooms remaining in the trial. The reason for this is that after the start of the school year, some classrooms were merged due to enrollment levels being lower than anticipated. The merging of classrooms occurred prior to any study treatment being given. As a result data are available from 32 classrooms (2 schools with 1 participating classroom each, 10 schools with 2 classrooms, 2 schools with 3 classrooms, and 1 school with 4 classrooms). All school teachers, study observers (hygienists, dentists, outreach workers), and parents were blinded to the assigned treatments for the classrooms. Xylitol was delivered by providing the children with chewy candies ( gummy bears ) that contained 1.3 mg of xylitol per candy. The control condition was gummy bears that were identical to the xylitol candies except that they contained an alternate sweetener to match for sweet taste. The alternate sweetener is known to have no effects on tooth decay, i.e., it has neither caries preventive or caries promoting activity. Children were given 3 candies 3 times per day (9 candies total) for the duration of the school year (9 months). In the xylitol group the total amount of xylitol contained in the candies was 11.7g per day. A log was maintained to record on each school day which children were present and had been observed by the teacher to consume at least one gummy bear. The children were instructed to finish eating their gummy bears in the classroom and not to take them outside at recess or lunch time, to help reduce the amount of sharing of gummy bears between children in different classrooms in the same school. The number of school days in the year was approximately 200 and varied little across schools or classrooms. The children were not given any gummy bears by the researchers after the end of the kindergarten school year. During the kindergarten year, approximately 2% of the children switched from one classroom (or school) to another within the 15 schools participating in the trial, in which case they started receiving the type of gummy bear assigned to the new classroom when they started attending that classroom. Information about such transfers of children is not available on an individual child level. At the start of the school year, before study treatments started, a dental exam was performed on each child. Caries was recorded using the International Caries Detection and Assessment System (ICDAS), which is a clinical visual system developed by researchers from the United Kingdom, the United States, and Europe to evaluate early stages of dental caries ( The ICDAS criteria record the severity of the lesions on all surfaces for each tooth present in the mouth. The tooth surfaces are called occlusal (biting), buccal (adjacent to cheek), lingual 3

4 (adjacent to tongue), and distal and mesial surfaces (between the teeth towards the back or the front of the mouth). At most 20 primary teeth and a maximum of 100 surfaces were scored (most children have 20 primary teeth after all have erupted typically by the time of kindergarten). Each surface was scored on a scale ranging from 0 to 6, in which 0 represents a sound (disease-free) surface, 1 represents initial visual changes in tooth enamel, and levels 2-6 represent increasingly severe lesions. Additional codings exist to record tooth surfaces found to have a dental filling and for teeth that were missing due to caries (when there was evidence that a tooth previously erupted had to be extracted due to caries). The data available are based on classification of each tooth surface as either (1) diseased, if the ICDAS score was 3 or higher or if there was a filling present or if the tooth was recorded as missing due to caries, or (2) disease free, otherwise. The data are available as the total counts of diseased surfaces for each child. Information on gender and race/ethnicity of the children was also collected. Race/ethnicity was provided for 424 enrolled children, of whom 406 were African-American. (Data on race/ethnicity is not included in the data provided for this exam.) Dental exams were also performed at two follow-up times: 1) at the end of the kindergarten school year (in June), and 2) at the end of the following school year (first grade). These exams were performed in a similar way as for the exam at the start of the kindergarten year. However, the information recorded at each of these exams was the number of surfaces with new disease that had not been observed at baseline. Therefore, tooth surfaces that had been scored as diseased at baseline would not be counted as diseased at a follow-up exam. The definition of disease used was the same as for the baseline exam, namely ICDAS score of 3 or higher, dental filling, or evidence of tooth extraction due to caries. Note that both follow-up exams were compared with baseline results for purposes of scoring; therefore, disease at the final follow-up is disease that is new relative to baseline (not new relative to the previous follow-up exam). For each of the follow-up exams, some children were not examined either because they had transferred out of the school district, moved away, or were absent from school on all of the dental examination days. Only children who were listed as being enrolled at the start of the kindergarten year were included in the dental exams (i.e., children who enrolled in the school part way through the kindergarten year or in the following year were not examined). Note that there could be some undercounting in the decay counts. In all children, primary teeth are lost naturally (exfoliate) when the permanent teeth begin to erupt which typically begins during first grade. Although the trained dental examiners were dentists trained to be able to distinguish teeth that had exfoliated naturally from those that had to be extracted due to caries, some misclassification inevitably occurs. For example, a tooth surface that is scored as being diseased at the first follow-up and then is subsequently extracted due to disease, could be mistakenly recorded as naturally exfoliated at the second follow-up. Another type of misclassification occurs when a tooth with a cavity that has been restored with tooth colored material might be scored as sound simply because the filling is not obviously visible. For all these reasons, the number of tooth surfaces scored as being diseased could decrease from one follow-up exam to the next. The Data 4

5 The data is available in a comma delimited file. There are 526 records and the following variables: 1. id (1 526) 2. school (1-15) 3. classroom (numbered within school from 1 to number of classrooms within the school) 4. treatment (1=Control, 2=Xylitol) 5. gender (-9=NA, 1=female, 2=male) 6. days (total number of days of gummy bear consumption) 7. dmfs0 (number of decayed, missing, or filled primary surfaces at the start of the kindergarten year) 8. dmfs1 (number of new decayed, missing, or filled surfaces at the end of the kindergarten year, where new is relative to start of kindergarten year) 9. dmfs2 (number of new decayed, missing, or filled surfaces at the first grade exam, where new is relative to start of kindergarten year) Scientific Questions. 1. Describe the evidence from this trial for a preventive effect of xylitol on prevention of caries in primary teeth in children. 2. Is there evidence that the effect of xylitol varies according to the child s prior caries history as assessed at the beginning of kindergarten? 3. Is there evidence for a dose-response relationship between the amount of xylitol consumed and the incidence of caries on primary teeth? References A.G. Antonio, V.S. da Silva Pierro, L.C. Maia (2011). Caries preventive effects of xylitol-based candies and lozenges: a systematic review. Journal of Public Health Dentistry 71(2): Burt B.A. The use of sorbitol- and xylitol-sweetened chewing gum in caries control. Journal of the American Dental Association 137(2): Maguire, A., A.J. Rugg-Gunn (2003). Xylitol and caries prevention is it a magic bullet? British Dental Journal 194(8): S. Mickenautsch, S.C. Leal,V. Yengopal et al. (2007). Sugar-free chewing gum and dental caries a systematic review. Journal of Applied Oral Science 15(2):

6 NIH (2001). "NIH Consensus Development Conference on Diagnosis and Management of Dental Caries Throughout Life. Bethesda, MD, March 26-28, Conference Papers." J Dent Educ 65(10): USDHHS (2000). "Oral health in America: a report of the Surgeon General." Rockville, MD. U.S Department of Health and Human Services. National Institute of Dental and Craniofacial Research, National Institute of Health. van Loveren C. (2004). Sugar alcohols: what is the evidence for caries-preventive and cariestherapeutic effects? Caries Research 38(3):