Movemeni Disorders Vol. 1 1 , No. 2, 1996, pp.

201-206 0 1996 Movement Disorder Society

Occupation, Education, and Parkinsons Disease: A Case-Control Study in an Italian Population

Walter A. Rocca, *Dallas W. Anderson, tFrancesca Meneghini, tFrancesco Grigoletto, SLetterio Morgante, SArturo Reggio, IlGiovanni Savettieri, and SRaoul Di Perri
Department of Health Sciences Research, Mayo Clinic m d Mayo Foundation, Rochester, Minnesota, U . S . A . ; *Biometry and Field Studies Branch, National institute of Neurological Disorders and Stroke, Bethesda, Maryland, U.S.A.; tinstitufe o f Hygiene, University of Padua, Paduai Italy; $Department of Neusology, University of Messina, Messina, Italy; 9L)epartment of Neurology, University of Catunia, Catania, Italy; and \Department of Neurology, University of Palermo, Palesmo, Italy

Summary: Current epidemiologic data on the association between occupational exposures and Parkinsons disease (PD) are inconsistent. In a case-control study, we investigated the associations between occupation and PD and between education and PD. The cases (n = 62) were those identified in a prevalence survey (door-to-door, two-phase) of three Sicilian municipalities, as of November 1, 1987. We then randomly selected from the general population two controls for each case, matched for age (21 year), sex, and municipality (n = 124). Information on current and past occupations and education for cases

and controls was obtained during the survey. Subjects who worked for most of their lives as farmers were not at increased risk of PD (OR = 0.6; 95% CI = 0.3-1.3). Neither were subjects who worked for most of their lives in other occupations (e.g., housewives, fishermen, factory workers, salesmen, craftsmen, clerks). PD was not associated with low education. Our findings suggest that farming, as a broad occupational category, does not play a major role in the causation of PD. Key Words: Parkinsons disease-Risk factors-Case-control studiesOccupation-Education.

A prevalence survey of Parkinsons disease (PD) was conducted in three municipalities of Sicily, Italy. The field work involved door-to-door screening of eligible subjects and neurologic evaluations of those who had screened positive (1). Only three other similar surveys have been fully reported thus far: in Copiah County, Mississippi (2), in six cities of the Peoples Republic of China (3), and in Parsi communities of Bombay, India (4). The age-specific prevalence figures in the Sicilian survey were greater than those found in these other surveys (1). It is possible that Sicily is a high-risk area for PD, although methodologic influences (e.g., case finding, diagnostic criteria) might be a partial explanation for the greater prevalence fig__ __
Accepted September 12, 1995. Address correspondence and reprint requests to Dr. W. A. Rocca at Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, M N 55905, U 5.A.

ures (1). Because of budget constraints, we were unable to undertake an extensive case-control study in conjunction with the Sicilian survey or following it. Nevertheless, because we had collected sociodemographic information for essentially the entire population of the three municipalities, we proceeded to investigate the relationship between occupation and education and PD. This research is the focus of the present article. An association between farming and farmingrelated exposures and PD was shown by three studies (5-7), but not confirmed in five others (8-12). To our knowledge, there have been no published reports linking education and PD. However, we decided to investigate a possible link because of analogies between PD and Alzheimers disease (13,14). Several studies recently reviewed by Mortimer and Graves (15) have reported a decreased risk of Alzheimers disease with increased education. By contrast, some other studies did not confirm the association (16,17).

201

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W . A . ROCCA ET AL.

Cases We included all the cases of PD identified during the aforementioned Sicilian survey. That survey investigated the prevalence of PD and other types of parkinsonism among subjects who resided as of November I , 1987, in any of three municipalities: Riposto in Catania Province, Santa Teresa di Riva in Messina Province, and Terrasini in Palermo Province. All subjects living in households and those institutionalized were included. Cases were ascertained through a two-phase approach. In the first phase, medically trained interviewers administered a brief screening instrument that included symptom questions and physical tests. In the second phase, study neurologists used specified diagnostic criteria to evaluate those subjects who screened positive. Diagnoses were reviewed for each municipality by the local senior neurologist; in addition, they were adjudicated by a study panel to increase homogeneity across the three municipalities. For subjects who could not be clinically examined, relevant medical information was sought from close relatives and from their general practitioners (1). Further details regarding the Sicilian survey were reported elsewhere (1,18-20). A diagnosis of PD required the presence of at least two cardinal signs (resting tremor, rigidity, bradykinesia, impaired postural reflexes) in a subject not receiving antiparkinsonian therapy or at least one sign in a patient specifically treated. PD, or idiopathic parkinsonism, was defined by excluding other causes of parkinsonism through medical history information and direct patient examination. Specified diagnostic criteria were used for druginduced parkinsonism, parkinsonism in vascular disease, and postencephalitic parkinsonism; other less common types of parkinsonism were defined by routine clinical diagnosis without specified criteria (1). Cases of parkinsonism for which the clinical information was insufficient to reach an etiologic classification were also excluded from this study (I). Controls Two population controls were matched by age ( & I year), sex, and municipality to each case included in the study. The controls were selected among all residents included in the Sicilian survey and found to be free of parkinsonism, as of November 1, 1987. No other exclusion or inclusion criteria

were applied; in particular, the presence of neurologic diseases other than parkinsonism was not an exclusion criterion. When more than two potential controls were available for a given case, two of them were selected using a table of random numbers. Data Collection During the Sicilian survey, the interviewers who administered the screening instrument (see above) also gathered information about occupation and education. This was accomplished for cases and controls with a structured questionnaire. Subjects were asked about all their current and past occupations; because most of them had held only one occupation, a principal lifetime occupation was usually straightforward to derive. Housewives of farmers were classified as farmers if they had regularly participated in farming activities. Subjects were asked whether they were literate; they were also asked to give the number of years that they completed in school. If a subject was unavailable or judged unable to respond, the questions were put to a proxy respondent (closest available relative of the subject) (20). Data Analysis Consistent with the study design, matched triplet analyses were used, and the odds ratio served to estimate the relative risk (21). For each study variable, we computed a maximum likelihood estimate of the relative risk, an approximate 95% confidence interval, and a p value (two-tailed test, alpha = 0.05) (21,22). For education, we also investigated dose-effect contrasts using conditional logistic regression for matched sets (21). Education was categorized in three classes, and 3 5 years of education served as the reference.

RESULTS
Of the 63 prevalent cases of PD in the three municipalities surveyed, 62 were included in the current study. The remaining case of PD was excluded because no suitable controls were available for matching. Although our diagnostic criteria included patients with at least one sign of parkinsonism when specifically treated, all of the 62 cases of PD included in this study happened to have two or more cardinal signs. More extensive details about the clinical characteristics of our case series were reported elsewhere (1). Table 1 shows the distribution of cases by age and sex. By virtue of the matching,

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TABLE 1. Age and sex distribution of the 62 cases of Parkinson's disease"
~ ~~

203

Women Age (years) No. Percentage No.

Men Percentage
7.4 11.1 33.3 44.4 3.7 100.0 7.4 22.2 44.4 25.9 100.0

Total No.
3 6 26 23 4 62 3 13 31 15 62

Percentage
4.8 9.7 41.9 37.1 6.5 100.0 4.8 21 .o 50.0 24.2 100.0

At onset of Parkinson's disease 1 2.9 2 4049 3 3 8.6 50-59 17 48.6 9 60-59 12 11 31.4 70-79 1 3 8.6 80-89 27 Total 35 100.0

At the time of the studyb

50-59 m 9 70-79 8&89 1 7 19 8 35 2.9 20.0 54.3 22.9 100.0 2
6

Total

12 7 27

a One case of Parkinson's disease (a woman 93 years old on the prevalence day) was excluded from the case-control study because no suitable controls were available. Age on November 1, 1987.

respondents were used for one case of PD (subject incapacitated) and six controls (three subjects incapacitated, one refused, two unreachable). The proxy respondents were one offspring for the case, and three offspring, one spouse, one sibling, and one niece or nephew for the controls. Table 2 shows the case-control results for principal lifetime occupation and education; none were statistically significant. We note two suggestive findings-that farmers had a decreased risk and illiterates an increased risk for PD. Because of the finding for illiterates and the postulated analogy with Alzheimer's disease, we also conducted doseeffect analyses contrasting multiple levels of education. These analyses failed to show a more definite association between education and PD.
DISCUSSION Table 3 lists the case-control studies that have investigated associations between PD and farming practices. In terms of case finding, our study is unique because we included all prevalent cases of PD from a door-to-door survey (the aforementioned Sicilian survey). That survey had achieved high re-

the 124 population controls had a similar age and sex distribution. The information regarding occupation and education was obtained for all cases and controls; therefore, all triplets (case, control 1, control 2 ) were complete for analysis. However, proxy

TABLE 2. Association between Parkinson's disease and categories of occupation and education (62 cases and 124 controls)
Outcome among case-control triplets (case, control 1, control 2) Factor Principal lifetime occupation" Farmer (1 = yes; 0 = no) Fisherman (1 = yes; 0 = no) Factory worker (1 = yes; 0 = no) Craftsman ( I = yes; 0 = no) Salesman (1 = yes; 0 = no) Clerk (1 = yes; 0 = no) Housewife (1 = yes; 0 = no) Other (1 = yes; 0 = no) Educational levelb Illiterate (1 = illiterate; 0 = all other) Under 5th grade (1 = 4 t h grade; 0 = all other)
~~

+-I
2 6 4 3 4 3

+++-+
3 2 0
0

+++
1
0 0 0 0 0
10

---

__+
16 3 8 9 6 10 8

-+-

-++ 5
0 0 0 0 0 3 0 0 9

Odds ratio (95% CI) 0.6 (0.3-1.3) 1.9 (0.4-10.6) 1.5 (0.54.3) 0.9 (0.3-2.5) I .o (0.3-3.5) 0.8 (0.3-2.2) 1.1 (0.5-2.6) 1.4 (0.5-3.3) 1.9 (0.94.4) 1.1 (0.6-2.2)

P
0.34 0.69 0.64 0.92 0.72 0.92 0.94 0.69 0.15 0.79

30

55
48 49
53

0 0
9

48 29 43 35 6

I
9
7

I
6 19

0 0
10

I1
12
11

* Each occupation was contrasted to all others using dichotomous contrasts.

We also investigated dose-effect contrasts using conditional logistic regression for matched sets. Using 3 5 years of education as reference (OR = l . O ) , we obtained: OR = 1.8 (CI: 0.7-4.8) for illiterates and OR = 0.9 (CI: 0.5-1.8) for subjects with <5 years of elementary school. None of these contrasts were statistically significant.

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W . A . ROCCA ET AL.
TABLE 3 . Comparison with previous case-control studies of the association between farming practices und Parkinson's disease
Author, year (country) Type and no. of cases Hospital outpatients, n = 100 Hospital and nursing homes, n = 35 Hospital outpatients, n = 150 Hospital, n = 106 General practice patients, n = 57 Case register, n = 130 Hospital outpatients, n = 63 Hospital outpatients, n = 63 Prevalent cases; door-to-door survey. n = 62 Type and no. of controls Hospital outpatients, n = 200 Hospital and nursing homes, n = 105 Hospital outpatients, n = 150 Spouses, n = 106 Population members, n = 122 Population members, n = 260 Hospital outpatients or volunteers, n = 75 Hospital outpatients or volunteers, n = 75 Population members, n = 124 Odds ratioY
0.6

Comments 'nd definition., Inverse direction fo: village residenceb Farming for >20 years Ever farmed as an crccupation Exposure to farm animals Ever worked in an orchard Agricultural work Farming as an occupation was not different in c'tses and controls Inverse direction. ever lived or worked on a f x m Inverse direction, farming ar principal lifetime occupation

Tanner et al., 1989 (China) Ho et al., 1989 (Hong Kong) Koller et al., 1990 (Kansas, U.S.A.) Globe et al., 1990 (New Jersey, U.S.A.) Hertzman et al., 1990 (British Columbia, Canada) Semchuk et al., 1992 (Alberta, Canada) Hubble et al., 1993 (Kansas, U.S.A.) Butterfield et al., 1993 (Oregon and Washington, U.S.A.) Present study (Sicily, Italy)

5.2"
1.3 1.3
3.4"

1.9"

0.4"

0.6

Statistically significant. Also inverse direction for pig, chicken, or other livestock raising. and for wheat, corn, or soybean growing; no association with fruit or ricse growing.

sponse rates: 92% of eligible persons were directly or indirectly screened, and 99% of those who screened positive were examined or indirectly evaluated (1). Also, in a small investigation of validity, the screening instrument for PD was found to be both sensitive and specific (19). Five of the nine studies in Table 3 were based on hospital series of both cases and controls (5,8,9,11,12). One study was based on a hospital series of cases, with spouse controls (10). Two studies obtained cases through general practice lists or a morbidity register, with population controls (6,7). These two studies are somewhat more comparable to ours and can be considered population-based rather than hospitalbased. Our odds ratio (OR = 0.6) suggested, if anything, a negative association between PD and farming as an occupation, but that finding is not unprecedented (8,12). To interpret this odds ratio, it is important to keep in mind that (a) we considered only the principal lifetime occupation rather than all occupations held; (b) we did not obtain data on duration or chronological sequence of occupations ; and (c) we did not investigate specific tasks or occupational exposures. Because we restricted our attention to broad categories of occupation, we were unable to distinguish between subcategories of farmers who raised particular crops or used specific pesticides or herbicides. It is possible, therefore, that although farmers in general were not at increased risk for PD,

those who worked with specific toxins were at increased risk. By means of the Sicilian survey, we gained access to many previously undiagnosed cases of PD that never would have come to light if case finding had been restricted to health-care providers such as hospitals, clinics, or physicians. The characteristics of the 21 (34%) cases of PD diagnosed during the Sicilian survey (by the survey team) differed in several ways from the characteristics of the 41 (66%) cases of PD diagnosed before the survey. ]Droportionately ,for the newly diagnosed cases, there were more women, more subjects with later onset, more with shorter duration of symptoms, fewer with tremor, and more with impaired postural reflexes. The proportion of newly diagnosed cases increased with advancing age for women but not for men (1). We emphasize that all newly diagnosed cases of PD, as well as all those previously diagnosed, happened to have two or more cardinal signs of parkinsonism. The previously undiagnosed cases of PD would, of course, be missing from any health-care provider series. The differences between previously undiagnosed and previously diagnosed cases of PD may create an important referral (or admission rate) bias in studies based on hospital series and, to a lesser degree, in studies based on series from other healthcare providers (23). Occupation, education, and other socioeconomic factors may influence the like-

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205

lihood and the timing of a case coming to medical attention. The potential impact of hospital referral bias in epidemiologic studies was recently illustrated for Alzheimers disease in a study conducted in Rochester, Minnesota (24). The study showed that population-based cases of Alzheimers disease differ from hospital referral cases in their distribution by sex, age at onset of symptoms, education, occupation, living arrangement, and marital status (24). By analogy, a case-control study of PD based on a hospital series may yield spurious findings regarding occupation and education (i.e., creating an artifactual association or concealing a real one). Although our study design is strong against the referral bias, it is weak against a second type of selection bias, the prevalence-incidence (or Neyman) bias (23), because we used prevalent cases of PD instead of incident cases. If, for example, farming was an important negative prognostic factor for PD, we could have underrepresented in our case pool those farmers who developed PD and died shortly thereafter. This bias would obscure the association between PD and farming. A similar bias could obscure the association between PD and education. The information on occupation and education was obtained by trained interviewers at the time of screening and, therefore, before the diagnosis of PD was established or excluded in a subject. We attempted to limit the risk of exposure suspicion bias (23) by keeping the study hypotheses from the interviewers. In this endeavor, the scope of the Sicilian survey worked in our favor because exposure data and screening information for several diseases were collected at the same time. Nevertheless, the interviewers were all physicians, and it is difficult to know the extent to which they linked any specific question to any specific disease. With regard to the subjects with PD, we cannot rule out a recall bias (23) in those (66%) diagnosed before the Sicilian survey. For cases and controls, direct interviews were usually used to elicit information about occupation and education. The few indirect interviews with proxy respondents were unlikely to introduce any asymmetry into the data collection, because they were a small percentage (4%) of all interviews and because proxy respondents were found in other studies to be reliable for basic questions such as those regarding occupation and education (25,26). As our sample size was relatively small, we may have failed to detect associations between PD and various categories of occupation or education for

lack of statistical power. To increase the power of the tests conducted in the study, we used a matched design with two controls for each case. For factors occurring in 15-60% of the controls (farmer, housewife, illiterate, <5 years of education), our study had a statistical power of at least 85% to detect a relative risk of 3.0 when alpha = 0.05 (two-tailed) (21). Specifically, for the factor farmer, the statistical power was 93%. On the other hand, our study had inadequate power to detect a relative risk of 2.0 or below for farming as reported by some authors (7,9,10). Distinguishing clinically between PD and other types of parkinsonism can be difficult even in the best of circumstances (27,28). It is possible that some of our cases were not PD, but another type of parkinsonism. Such a misclassification was more likely for those subjects who had never been diagnosed before the survey and were, therefore, evaluated only at one point in time. If this misclassification occurred, it would have lowered the statistical power of the study. We reduced the risk of misclassification by specifying the diagnostic criteria for other types of parkinsonism. Overmatching may have influenced our casecontrol result for farming. We matched cases and controls for municipality of residence; therefore, each case and corresponding controls were residents of the same small geographic area. If farmingrelated toxins tend to spread in the environment (e.g., through local water or food sources), it is possible that farmers and nonfarmers alike had the same risk. We do not believe, however, that this is an important explanation for our findings, since farmers seemed to have a reduced risk of PD. In addition, several studies using less strictly matched controls failed to show an association between PD and farming (8-12). Because exposure to herbicides and pesticides, rather than farming per se, was more consistently found to be associated with PD (7), our negative finding might reflect the type of farming practiced in the three Sicilian municipalities. Major agricultural activities in the study areas include growing vegetables and tending citrus and olive trees. The vast majority of farmers have been using pesticides for more than 20 years; herbicides are less commonly used. One herbicide used in the past was the pyridylium compound paraquat. Our finding of no association between PD and farming as an occupation does not appear to be related to a lack of exposure to farming-related toxins.

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W . A . ROCCA ET AL.
Finally, we n o t e that the absence of links between PD and occupation and between PD and education is consistent since occupation and education tend to b e related. Acknowledgment: This research was presented in part at the 45th meeting of the American Academy of Neurology, New York, April 1993. This investigation was financially supported by the Assessorato alla Sanita della Regione Sicilia (grant no. 58iP) and by Fidia Research Laboratories, Abano Terme, Italy. We thank the many persons of Riposto, Santa Teresa di Riva, and Terrasini who provided assistance during the study. In addition, we thank the field workers: Rita Bella, Biagio Castiglione, Maria Giuseppa Castiglione, Maria Angela Coraci, Valeria Costa, Antonio Crisafulli, Antonella DArpa, Pietro De Domenico, Domenico De S h o n e , Giuseppe Di Stefano, Alfio Mauro Finocchiaro, Francesco Patti, Rosa Maria Ricci, Concetta Ruello, Giuseppe Salemi, Raffaella Santangelo, Vincenzo Saporito, Carrnelo Staropoli, Giuseppe Troilo, and Angelo Xerra. We are also grateful to Karen Tennison for typing the manuscript.
11. Hubble JP, Cao T, Hassanein RES, Neuberger JS, Koller

12. 13. 14. 15. 16.

17.

18.

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