Case-Control Study of IDDM - Diabetes Care

Case-Control Study of IDDM

Insulin-dependent diabetes mellitus (IDDM) may be caused by a combination of genetic predisposition and environmental insults. However, there are few solid leads concerning human diabetogenic environmental agents. A case-control study was carried out to investigate the possible relationships between IDDM and various biological, chemical, and psychological factors. All 161 cases of IDDM among children aged 0-17 yr occurring in Montreal from 1983 to 1986 were included. The parent of each newly diagnosed diabetic subject was asked to provide the names of two of the child's friends or neighbors who would be age and sex matched to serve as controls. For those unable to do so, matched controls were selected from a hospital emergency room. Parents of cases and controls were interviewed concerning many factors. There was little or no difference between cases and controls with regard to parental smoking habits, exposure to pets, and consumption of meat products high in nitrosamines. In univariate analyses, there was some indication of elevated risk for children who had not been breast-fed, who attended day care or nursery before age 5 yr, who lived in a crowded household at age 3 yr, or who had a history of asthma or eczema, although in multivariate analyses the only variables that had any effect were crowding and day-care attendance. In univariate and multivariate analyses, there was high risk of IDDM among children who had experienced selected stressful life events during the 12 mo preceding onset of IDDM or who had exhibited symptoms of social or

From the Centre de recherche en £pide>niologie et me'decine preventive, Institut Armand-Frappier, Laval-des-Rapides; the Department of Epidemiology and Biostatistics, McGill University; and the Montreal Children's Hospital, McGill University Research Institute, Montreal, Quebec, Canada. Address correspondence and reprint requests to Professor J. Siemiatycki, Centre de recherche en e'pide'miologie et me'decine preventive, Institut Armand-Frappier, 531 boulevard des Prairies, Laval-des-Rapides, Quebec H7V 1B7, Canada.

DIABETES CARE, VOL. 12, NO. 3, MARCH 1989

Jack Siemiatycki, PhD Eleanor Code, MD Sally Campbell, MSc Ron A.D. Dewar, MSc Mimi M. Belmonte, MD

psychological dysfunction during that time. Some of these apparent effects may have been due, in part, to biases induced by the method of selecting controls and to the interview process. Diabetes Care 12:209-16,1989

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he etiology of insulin-dependent diabetes mellitus (IDDM) remains obscure. There is strong evidence for a genetic susceptibility associated with antigens of the major histocompatibility complex, i.e., HLA. Among individuals in whom diabetes occurs before age 16 yr, 90-96% are HLA-DR3 or HLA-DR4 (1,2). Identical twins and HLA-identical siblings of children with IDDM have a greatly increased risk of developing disease. However, even among individuals at highest risk (HLA-identical siblings and monozygotic twins), only 30-50% develop overt disease (3-5). Hypotheses suggest that genetic factors enhance susceptibility and one or more environmental insults lead to pancreatic insufficiency (6). Among the various factors that have been hypothesized to be environmental diabetogenic factors are viral infection (7-10), diet (11,12), and psychological stress (13). We have maintained a population-based registry of all children with IDDM under the age of 17 yr diagnosed in Montreal since 1971. In an effort to identify nongenetic risk factors for IDDM, we conducted a case-control study in conjunction with our ongoing registry during 1983-1986. Information obtained about the exposure of cases and controls was attributed to numerous factors, including some in the above list and other ones. The purpose was not to test a specific hypothesis but to explore various factors to generate plausible hypotheses.

209

CASE-CONTROL STUDY OF IDDM

MATERIALS AND METHODS Cases. The details of our registry have been described elsewhere (14) as has an evaluation of our case-finding system (15). Cases consisted of children with IDDM who were diagnosed between 1 September 1983 and 28 February 1986, were ^17 yr of age at the time of diagnosis, and lived in the metropolitan Montreal area (as defined by the 1981 census). Insulin dependency was defined as hyperglycemia (>12 mM), ketonuria, and a requirement for insulin to maintain growth and avoid ketoacidosis. Our case-finding system allowed for immediate identification of all new cases occurring in the Montreal area. A total of 161 cases were identified during the study period. Parents of cases were contacted and interviewed within 4 wk of diagnosis. Controls. The interviewed parent was asked to provide the names of two other children to serve as controls for his/her child. We asked that these controls be matched to the case for sex and as closely as possible for age, preferably within 2 yr. Siblings were not admissible. The controls were usually nearby residents who were playmates of the case. Occasionally, a control was a cousin of the case or a friend who lived in a different part of the city. Sometimes a case parent either refused or was unable to provide us with names of one or both potential controls. This usually happened when the propositus was very young and did not have regular playmates. In these situations, we obtained controls through the emergency unit at one of the two large pediatric hospitals in Montreal. These controls were matched for sex, age within 2 yr, approximate date of admission, and socioeconomic level of the neighborhood of residence. Unfortunately, we could not match for hospital because we could only obtain controls from one of the two pediatric hospitals. Interviews were conducted with the parents of 161 diabetic cases and 321 matched controls (for 1 case only one hospital control could be matched), of which 269 were neighborhood controls (children suggested by the parents of cases) and 52 were selected from hospital emergency admissions. It was expected that this solicitation of controls from among acquaintances of the cases would have the effect of matching by ethnic group and socioeconomic class, two general factors that have been shown to influence IDDM risk (16). This would allow for the evaluation of more specific factors that might otherwise be confounded by ethnicity and socioeconomic class. Questionnaire. The questionnaire was administered by telephone to one parent of each case and control (usually the mother). No one refused to be interviewed. Some questionnaire items concerned factors already known or suspected to influence the risk of developing IDDM; others were asked to generate hypotheses. To assess the matching, there were items concerning basic sociodemographic characteristics such as place of birth, parents' education, and family size. Among the potential risk factors included for evaluation were type of housing

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and degree of crowding in early childhood and before disease onset, history of breast-feeding, the presence of pets in the home before onset of disease, a history of school attendance, parental smoking, consumption of selected foods known to contain high levels of N-nitroso compounds, history of illness in the year before IDDM diagnosis, and history of immune diseases and tonsillectomy. We also investigated the possible role of stress in precipitating the onset of IDDM. There was a checklist of presumably stressful events such as accidents, hospitalization, death or removal from the house of a relative, and parents' loss of job or separation. Other indicators of stress in children included problems in school, maintaining friendships, difficulty going to sleep, and frequent occurrence of nightmares. It is clear that some of the variables such as diet, symptoms, and behavioral characteristics might have changed since the onset of IDDM. Because we were interested in these variables as putative etiologic risk factors rather than as sequelae of IDDM, it was necessary to obtain the information for the time period predating disease onset. Therefore, for most questions the interviewer asked the respondent to ignore the period since the perceived onset of clinical symptoms and to retrospectively estimate the situation from the point of onset backward in time. Thus, if a case had symptom onset on 1 January 1986 and his parent was interviewed in February 1986, then the stressful events part of the questionnaire was referred to the period preceding 1986. To promote comparability in response quality between cases and controls, we instituted a policy of having each control refer to the same temporal time frame as his/her matched case. Thus, if the control for the above-mentioned case was interviewed 2 wk after the case in February 1986, the stressful events part of the questionnaire was also referred to the period preceding 1986. Sociodemographic characteristics of cases and controls. Numerous characteristics of our study population are shown in Table 1. The distributions of birthplace for cases and controls and their respective parents are similar. However, both mothers of controls and controls themselves were less likely to have been born outside of Canada than mothers of cases and cases. Slightly more parents of control children had higher education than those of diabetic children. There was no difference in family size between cases and controls. Although there was no question that directly asked about socioeconomic status (SES), we did have information on census tract of residence for all subjects. Census tracts in Canada are delineated to maximize socioeconomic homogeneity; therefore, the average household income of the census tract is a reasonable proxy for a family's SES. Table 1 shows that the cases and controls were distributed similarly across SES categories. Analysis. An odds ratio (OR) and corresponding 95% confidence interval (Cl) was computed for each risk factor evaluated by extension of the Mantel-Haenszel procedure to multiple matched controls per case (17). The OR estimates can be considered to be adjusted for all


I. SIEMIATYCKI AND ASSOCIATES

TABLE 1 Characteristics of cases and controls

immune status, none was significantly related to IDDM, although the ORs for asthma and eczema were suggestive. There were questions on disabling illness, regardControls Cases less of cause, in the preceding 3-12 mo. There was increased risk of IDDM for those who reported recent n 321 161 illness with the OR attaining statistical significance for Age (yr) illness in the past 3 mo. Housing density may reflect 19.9 19.9 0-4 risk of infection. Two indices of housing density were 32.9 33.3 5-9 the number of people per room in the household and 10-14 47.2 46.7 55.1 55.3 Males whether the child shared a bedroom. It was not selfBirthplace of father evident whether the effective period of exposure was 71.4 65.2 Quebec province immediately preceding disease onset or at some time in Canada excluding Quebec 8.2 6.0 early childhood. We therefore examined the crowding Outside Canada 26.6 22.6 indices at two times, immediately preceding onset and Birthplace of mother at age 3 yr (excluding children who were 11 yr was not statistically significant. School or day-care at83.5 More than one sibling 83.9 tendance before the age of 5 yr was associated with Census tract income quintile elevated risk. Children of separated (including divorced) 14.7 1 (poorest) 16.1 parents had no greater risk of IDDM than children of 2 19.3 17.9 parents living together. 17.2 3 18.0 There were questions concerning numerous recent 4 24.1 20.5 5 (wealthiest) 26.1 26.0 events that might be sources of stress to children. A relative (mother, father, sibling, or grandparents living Values are percentages of n. in home) having left home in the past year, a parent losing or changing his/her job in the past year, and the child changing schools in the past year for reasons other variables that were kept constant by means of matching than a normal progression to a higher grade were all by sex, age, and to a lesser extent socioeconomic class, associated with statistically significant elevated risk. ethnic group, and neighborhood of residence. An ad- Other stressful events listed in Table 2 were associated ditional set of analyses was carried out to adjust for the with some elevation in risk, but did not attain statistical various risk factors that produced elevated OR in the significance. There was some evidence of dose response above univariate analyses. The multivariate analyses were with greater risk associated with greater number of events based on conditional logistic regression techniques and experienced. also produced ORs and CIs (18). When the term statisFinally, the questionnaire enumerated six problem tically significant is used, it implies that the lower 95% areas that the respondent was asked to comment on that Cl exceeded 1.0; however we do not use this as an were intended to measure symptoms of social or emoabsolute criterion for making inferences. tional distress or dysfunction in children. This section of the questionnaire was administered only for children 2:5 yr. The ORs between these symptoms and IDDM risk were high and statistically significant; the more of the RESULTS symptoms reported, the higher the risk. A preexisting family history of IDDM was a strong risk Multivariate analyses. All results related above were factor, but it was one to which only a handful of cases univariate, that is, apart from cofactors that were effecwere attributable. There were eight cases but only one tively controlled in the study design (age, sex, social control with a diabetic parent with an OR of 17.1 (95% and ethnic factors), there may have been mutual conCl 2.1-138.0). Similarly, there were five cases but only founding among the factors that were analyzed. Logistic one control with a diabetic sibling, resulting in an OR regression analyses were conducted to provide estimates of 10.0(95% Cl 1.2-86.5). of ORs adjusted for the possible confounding effect of Table 2 shows the relationship between IDDM and other risk factors. We chose variables that, according to the various environmental and psychosocial variables the univariate analyses presented in Tables 1 and 2, that were under scrutiny. Among the few morbid con- apparently differed between cases and controls. These ditions that may have immune components or effects on selected variables included breast-feeding, crowded


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TABLE 2 Univariate odds ratios between IDDM and each factor under study Exposed (n)**

Positive history versus negative history for Asthma Eczema Food allergy Hay fever Tonsillectomy Sick in last year versus not sick in last year* Sick in last 3 mo versus not sick in last year* Crowded household versus uncrowdedt At age 3 yr Currently* Shared bedroom versus alone At age 3 yr Currently* Smoking parent versus no smoking parent§ Mother Father Both Had pets versus never had Cat Dog Other Frequent consumption versus infrequent consumption of|j Bacon Bologna Salami Sausages Pepperoni Smoked meat Never breast-fed versus breast-fed Attended day care or nursery versus remained home until age 5 yr Parents separated or divorced versus parents still together Selected stressful events in 12 mo preceding IDDM onset Hospitalization Serious accident Relative left home Relative died Parent changed or lost job Change in school for other than normal progression 1 of the above 2 or more of the above Selected indicators of psychological dysfunction in 12 mo preceding onsets Learning problems versus none Dislikes school or is indifferent versus likes school Problems with peers versus none Has no close friends versus has friends Problem sleeping versus no problem Nightmares versus no nightmares 1 or 2 of the above versus none 3 or more of the above versus none

Cases

Controls

18 12 7 13 20 95 56

25 14 14 26 12 166 67

1.6 1.8 1.0 1.0 1.0 1.4 2.2

0.8-3.2 0.8-4.0 0.4-2.5 0.5-2.1 0.6-1.7 0.9-2.2 1.2-4.0

70 60

113 116

1.6 1.1

1.0-2.5 0.7-1.6

50 46

82 83

1.3 1.2

0.8-2.1 0.7-1.8

48 71 28

88 123 46

0.8 0.9 0.8

0.5-1.4 0.6-1.4 0.4-1.5

55 60 89

127 139 167

0.8 0.8 1.1

0.5-1.2 0.5-1.2 0.7-1.7

91 66 78 120 83 55 116 54 28

183 127 142 243 165 118 215 81 58

1.0 1.1 1.2 0.9 1.0 0.9 1.3 1.7 1.0

0.6-1.5 0.7-1.6 0.8-1.8 0.6-1.5 0.7-1.5 0.6-1.3 0.8-2.1 1.0-2.8 0.6-1.6

5 15 14 14 22 13 46 12

9 20 11 24 26 8 53 4

1.1 1.6 1.7 1.2 1.8 3.4 2.1 5.9

0.3-3.7 0.8-3.2 1.2-6.1 0.6-2.4 1.0-3.2 1.3-9.1 1.3-3.5 1.6-21.1

23

2.1 1.9 3.5 6.0 8.9 7.5 4.9 20.3

21 23 17 32 33 15 55 18

27 11 12 11 4 40 3

Odds ratio

95% Confidence interval

1.1-4.1 1.0-3.6 1.5-8.0 2.9-12.3 3.7-21.1 2.4-23.8 2.7-9.0 3.4-122.0

*Sick before IDDM onset such that he/she could not carry on usual activities. tCrowded, ^0.8 people/room; uncrowded, 5 yr of age. Denominators: cases, 134; controls, 270. **Denominator, cases 161; controls 321.

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household at age 3 yr, attended day care or nursery, history of asthma, history of eczema, ill in the preceding 3 mo, the stressful events checklist, the psychological dysfunction checklist, mother's place of birth, and mother's educational attainment. The last two are variables that we had hoped would be controlled by the study design, but as it turned out they were not equal between cases and controls (Table 1). Although the two variables were included in the logistic regression models, it would not make sense to present their corresponding ORs because these ORs only represent the residual effect due to incomplete matching. Many of these variables had missing values for very young children (e.g., the psychological dysfunction variables, crowding at age 3 yr). It turned out that there were too few young children with valid values on all the variables to provide useful multivariate data. Therefore, multivariate analyses were restricted to children aged 5-14 yr. There were 128 matched sets comprising 128 cases and 255 controls. The results from two different multivariate models are shown in Table 3 with each column representing a separate regression analysis. For both models the outcome variable was case or control status. Model 2 included all the independent variables listed above. Model 1 inTABLE 3 Multivariate odds ratios between IDDM and selected factors among subjects aged 5-14 yr Regression modelt 1

Factor* Never breast-fed Attended day care or nursery Crowded housing in childhood History of asthma History of eczema Sick in past 3 mo Stressful events (n) 1 >2 Psychological dysfunction symptoms (n) 1 or 2 >3

2

eluded the same variables except the psychological and stress variables. All variables in model 1 were included as binary variables. In model 1 there were significant or borderline significant effects due to the variables sick in the past 3 mo, day-care attendance, and household crowding at age 3 yr. The ORs for breast-feeding and eczema were somewhat elevated but not approaching statistical significance. In model 2 we evaluated the joint effects of the six variables in model 1 and the stress and psychological dysfunction variables. However, because of the considerable intercorrelation among the stress variables and the psychological variables, the resulting coefficients and ORs for individual stress and psychological factors were unstable. These two sets of variables were included by simply creating composite variables (counts of the number of events or characteristics reported). The stressful events composite variable was categorized into three categories: none, one, and more than one. The psychological symptoms composite variable was categorized slightly differently: none, one or two, and more than two. (The different categorizations for the two scales were due to different distributions of the counts.) The inclusion of the psychological and stress variables had the effect of reducing ORs for the six variables that were in model 1. None were statistically significant, although ORs for crowding and day-care attendance remained high. There was a significant and clear relationship between IDDM and number of stressful events reported. For the number of psychological dysfunction variables reported the relationship was even stronger. In-depth analyses showed that the components that contributed most strongly to the difference between cases and controls were trouble sleeping and frequent nightmares.

Odds ratio

95% Confidence interval

95% Odds Confidence interval ratio

1.3

0.7-2.5

1.2

0.6-2.5

DISCUSSION

1.9

1.0-3.6

1.8

0.9-3.6

1.6 1.1 2.2 1.9

0.9-2.7 0.5-2.5 0.8-6.1 1.1-3.2

1.6 1.2 1.1 1.3

0.9-3.0 0.5-2.9 0.3-3.8 0.7-2.3

C

2.4 4.0

1.2-4.5 1.2-13.0

4.4 17.0

2.2-8.5 4.4-66.1

*AII questions referred to the period preceding IDDM onset (e.g., sick in past 3 mo referred to the pre-IDDM period). tBased on conditional logistic regression with 128 sets of cases and controls comprising 128 cases and 255 controls. For each model, case-control status was the dependent variable and independent variables comprised those variables for which odds ratios are presented in the corresponding column of this table, plus the variables mother's birthplace and mother's educational attainment.


urrent concepts of the pathogenesis of IDDM are based on a model in which an immunemediated (3-cell destruction is initiated in genetically susceptible individuals. It is not known what the nature of the factors are that might initiate or promote this process, or is it known how long the interval might be between initiation and clinical onset. This study was designed to assess the diabetogenic potential of various factors. Medical history. Whereas there was no persuasive evidence of any relationship between IDDM and the five preexisting medical conditions that were on the checklist, there was weak evidence of a relationship between IDDM and whether the child had been ill in the 3 mo preceding onset. If real, this relationship could support the hypothesis of an infection triggering the onset of insulin dependency. However, even if the evidence were statistically reliable, it could be due to differential recall of morbidity between cases and controls or to the possibility that a sickness in the 3 mo before disease onset

213


was actually an early clinical manifestation of IDDM. Crowding. Studies of paralytic disease associated with polio virus and Hodgkin's disease with Epstein-Barr virus have positted a model in which a late infection with a common virus results in more severe disease than when that infection occurs early in life. With such a model, we would expect household crowding in early childhood to be protective. However, neither of the two indices of crowding that we examined was protective. If anything, there was slight evidence of greater risk with greater crowding, although OR was not significant. Thus, by contrast with the polio analogy, the risk of IDDM may be associated with early infection with a slow virus. This hypothesis would also be supported by our finding that children who attended day care or nursery had higher risk than children who were at home until they started school, although this also was not statistically significant. Selected environmental exposures. Our results indicate that parental smoking carries no risk of IDDM. Nor is there evidence that contact with pets, often carriers of infectious agents, increases risk of IDDM. The chemical streptozocin is known to be an experimental diabetogenic agent (19). Because this is an N-nitroso compound, it has been postulated that chronic ingestion of foods containing such compounds might precipitate IDDM in susceptible individuals, and some experimental and human evidence has supported this hypothesis (11,20). However, we found no association between IDDM and consumption of meat products preserved with nitrates. It has previously been reported that breast-feeding protects the child against IDDM (12), although another study contradicted this (21). We also found a protective effect in the univariate analyses, although it was not statistically significant and virtually disappeared when other confounders were taken into account. Stress and personality. The most striking finding in our study was the apparent increased risk of IDDM associated with social and psychological dysfunction in children, and to a lesser extent, with recent stressful life events. The possibility that psychological factors are involved in the pathogenesis of diabetes mellitus has both experimental and clinical support. Whereas early clinical studies were methodologically weak, there were several pieces of suggestive evidence of an association (22-25). However, there was also evidence of lack of association (26,27). More recently Robinson and Fuller (13), with a standardized life-events questionnaire, showed that young adults with IDDM reported more stressful events than did their siblings in the period preceding onset. There is clear experimental evidence of stress affecting immune system functioning (28). In animal models of diabetes, there have been reports of stress increasing the risk of diabetes (29) and of stress decreasing the risk (30). Methodologic limitations and potential sources of bias. There are two major potential sources of bias in a study such as this: inappropriate control group and re-

214

call bias. There is rarely a perfect control group in retrospective case-control studies. Each plausible strategy provides a different perspective on reality. Whereas the use of a battery of different control groups would provide the most useful information, this is rarely feasible and was certainly not within our resources to implement. To control closely for ethnic group, socioeconomic class, and age, we used as controls healthy children who were acquaintances of the index cases. This matching strategy may have induced two different types of bias. The first, overmatching, is well known, and results from the controls were more similar to the cases than would be a random sample of the base population from which the case arises. It is plausible that even within a given socioeconomic class/ethnic subgroup, acquaintances share similar dietary and other social practices more often than do nonacquaintances. This bias would lead to spuriously low risk estimates, and in our data, would most plausibly be operative for factors such as diet, breast-feeding, parental smoking, and current household crowding. Most of these factors had low risk estimates and this source of bias must be considered as a possible explanation. A second type of bias that might be induced by the use of friends as controls, is more subtle and would operate in the opposite direction, namely to inflate risk estimates. When any set of children's parents are asked to provide names of acquaintances who could serve as controls, it is likely that the controls named will be disproportionately sociable and well regarded by peers. The social misfit is less likely to be named as a control than the popular friendly child. Some variables, notably psychological and stress factors, may be strongly related to popularity. It was therefore likely that our controls provided an underestimate of the true prevalence of social and psychological dysfunction in the population from which the cases arose. This would have led to spuriously high risk estimates for psychological dysfunction and even the stressful events checklists and may explain, in part, the apparent strong relationship between IDDM and these factors. Recall bias is a particular danger when there is retrospective questioning of cases and healthy controls. We explicitly requested information about the case concerning the time before disease onset. For example, questions about recent morbidity, diet, and stressful events explicitly referred to the period before disease onset. When questioning the control parent we focused on the same retrospective time period as for the corresponding case, but we cannot be certain that the recall was equivalent. The existence of a temporal landmark such as IDDM onset of a child among cases but not among controls could facilitate the recall process for cases. Furthermore, it is possible that parents of cases search out their memories more assiduously than parents of controls to mentally find and report the characteristic or event being questioned. A final methodological caution concerns the multiple



inference nature of the study. There was no specific hypothesis being tested; rather, the study was intended to provide OR estimates for numerous factors. Given these factors, it was inevitable that some might be significant by chance. Whereas some statistical methods have been developed to accomodate multiple comparisons, it is our view that these methods are rarely appropriate in a study that examines multiple hypotheses, and that the result for each association could legitimately be interpreted as if it were the only factor studied (31). Despite these possible limitations, this study is one of the first case-control studies to have explored environmental risk factors for IDDM and provides useful leads for future research. The results suggest that an elevated risk of developing IDDM was associated with crowded housing during early childhood and attendance at day care or nursery before the age of 5 yr. Numerous factors seem unrelated to risk, i.e., parents' smoking, pets, allergic diseases, consumption of meat products high in nitrosamines, and, less convincingly, breast-feeding, and acute illness. The most striking finding was a strong association between the risk of IDDM and indicators of stress and dysfunction in children. However, this set of variables is the most vulnerable of all to recall bias and friendly control bias. We recommend caution in the interpretation of these findings and hope other studies will be undertaken with different control group strategies (e.g., population controls, hospital controls) and more refined questionnaire instruments.

6. 7.

8. 9. 10. 11. 12.

13.

14.

15.

ACKNOWLEDGMENTS We are grateful to Marie-Paule Sarazin-Crepeau, who diligently ascertained and interviewed cases. Dr. R. Poirier of I'Hopital Ste-Justine and Dr. R. Rosenfeld of I'Hopital Maisonneuve-Rosemont were instrumental in providing access to patients. This research was supported by the National Health Research and Development Program of Canada.

16.

17. 18. 19.

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