Review Epidemiologic Approaches to the Study of Parkinson’s Disease Etiology Harvey Checkoway! and Lorene M. Nelson’ ‘The etiology of Parkinson's disease has heen enigmatic to clinicians, skins, and haste scientists since the clin teal synlrome wis first described in US17. Mendelian inher tince pashubly acevnnts for sal proportion of Parkinsons lsease. Apart from an increasing risk with age, the most wonsistent logic observation has been an inverse re Tation with cigarette smoking. Neither selective survival of pponsmokers nor behavioral characteristics of smokers can eX plain this seemingly protective association. Interest in enw mental exposures, particularly pesticides, mets nd indus- teal solvents, heightened substantially following the discovery fof Lmethyl--phenyl-,2,3 6-tetrahysopyriline (MPTP), 3 street drug contaminant, 36 9 cause of human parkinsonism, Epidemiologic and toxicologie research bas since been guiied Keywords: Parkinson’s disease, smoking, environmental exposures, genetic polymorph to 9 great extent, although not exclusively, hy med MPTP toxicity Efforts co characterize genefenvitonment in teractions have als» intensified in recent years In this review wwe evaluate recent evidence concerning the etiology of Par. Kinson's disease, with emphuisison enwionmental and liestyle expires and their potential interactions with genetic siacep bility rats. The most challenging aspects of epidemiologie research sar Parkinson's disease casition inclide methos!: logic ifficulties surrounding case definition, completeness of 19 of appropriate controls in case- control stulies, and assessment of environmental exposures We conclude with recommendations for future research rections, (Epislemiolegy 1999;10:527-336) isms of etiology. Parkinson's disease (PD) is a common, debilitating neu- rodegenerative disorder, second in frequency only to Abheimer's disease. The cardinal features of PD are bradykinesia, tremor of resting muscles, muscular rigid ity, and postural reflex impairment. The syndrome now known as Parkinson’s disease (PD) was frst described as a'shaking palsy” of unknown origin by James Parkinson in 1817.' The clinical manifestations of PD, which in- clude both motor, and in advanced cases, cognitive dysfunction, are attributable to selective destruction of pigmented neurons in the substantia nigra with conse- quent loss of dopamine and other aminergic neurotrans mitters.” Parkinson's disease should be distinguished from parkinsonism, a general term used for clinical sin- sdromes that have some or most of the signs of Parkin. son’s disease, but which also involve ocher signs and symptoms not characteristic of PD.! The term parkine Uist W Seamie ‘Reprint tH vr Sahel tide, sane C8. Abe Heath Ca nde ts Hines Ch be Enon Heh S TH amd Nr Isat Nour sal secs ptt bee 21s TIDE Fp bs Rose Ie sonism is also used for syndromes where the etiology is Known, such as parkinsonian signs due to stroke, infec- tious causes, neuroleptic medications, and toxic agents. Despite the passage of nearly 2 centuries since Par- kinson’s original description, and a sustained scienti interest, the etiology of PD remains largely obscure. Throughout the first half of the 20ch Century, several epidemiologic hypotheses were entertained, including PD asa late sequela of the 1918-19 influenza pander ick however, most research was limited to clinical de scriptions of PD presenting signs and prognostic factors.” In contrast, during the past 20 year, epidemiologic research into risk factors for PD and concomitant toxi- ccologic research on pathogenetic mechanisms have tensitied. A notable impetus for the growth of PD. search, especially of environmental risk factors, was the identification of a confirmed exogenous cause of human parkinsonian (-methyl-phenyl-1,2,3.6-tetrahydropy ridine MPTP)" In this paper, we review some of the more compelling: evidence conceming the etiology of PD, with emphasis oon environmental and lifestsle exposures and theit po tential interactions with genetic susceptibility traits. Our reciew isnot intended to be comprehensive: instead, we will focus on what we consider the most prominent research findings. More thorough recent reviews of PD, epidemiology are available.”* We abo point out some of the major challenging aspects of epidemiologic invest zations of PD and offer recommendations tor future research,328 CHECKOWAY AND NELSON, Descriptive Epidemiology of Parkinson’s Disease Most information on population frequencies of PD is based on prevalence data because of difficulties in ob- taining suitable incidence data. Mortality rates are not fully reflective of disease incidence because PD does nor have a high case fatality and death certificate data are often incomplete.’ Comparisons of PD prevalence (and incidence) between geographic regions fs seriously ham- peted by differences between studies in diagnostic crite ra and case ascertainment methods. Almost all diagnos tic classifications have included the cardinal signs of PD, but differ in terms of which combinations of these signs must be present to satisfy diagnostic eriteria. In addition, some classification systems incorporate information on duration of symptoms, the presence of asymmetry, and therapeutic responsiveness to antiparkinsonian medica tion. de Rijk et al! applied eight different sets of case definition criteria to assess the effect on epidemiologic research results, and they concluded that the choice of diagnostic eriteria can have a substantial influence on disease prevalence estimates. In spite of these limitations, several generally consis: tent findings appear in the literature, The prevalence of PD in North America and Western European countries is approximately 150 per 100,000," and it has heen. cstimated that the lifetime risk of developing PD may reach 1 in 40.” Corresponding annual incidence rates typically range from 10-20 per 100,000." Elevated prevalences have been reported in Japan‘! and Argent nna. although intemational differences in prevalence are dificule to interpret because of variable case defini- tion and ascertainment practices, Some reports are based oon door-to-door surveys," whereas others rely on hospital or clinical practice records!" There are also several instances of PD occurrence measured within defined population-based cohorts assembled previously for studies of cardiovascular and other diseases." PD incidence and prevalence rise sharply beginning at age 50 and increase throughout life"""-2° In some series, however, PD incidence does not continue to rise beyond age 80; this pattern may be due to difficulties diagnosing PD among elderly individuals with co-morbid condi- tions. PD is exceptionally rare before age 40, although, there are juvenile forms that are probably inherited The boundary between early- and late-onset PD has heen defined mainly at age 40 in studies addressing variable clinical and etiologic profiles" Many, but not all population-based surveys indicate a small male pre- ponderance of 20-30%." Intemational comparisons of PD prevalence do not indicate clear racial or ethnic risk differences, In the U.S., PD prevalence and mortal: ity are slightly higher among whites than African Amer- icans."*" Time trends are most reliably determined from mortality data; increasing rates among persons aged 75, years and older have been nored in the United States, many Western European countries, and Japan, whereas PD mortality rates at younger ages have generally re- mained stable or declined slightly within the past 30 years. In summary, the descriptive epidemiology of Epidemiology May 1999, Volume 10 Number 3 PD does not reveal any striking genetic or environmen- tal associations 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) and Proposed Models of Parkinson's Disease Induction Interest in possible toxicant-related causes of PD wats stimulated in. 1983, when Langston et al" identified several young intravenous drug users in California who developed irreversible signs of parkinsonism after inject inga synthetic narcotic contaminated with L-methyl-4- phenyl-1,2,3,6-etrahydropyridine (MPTP). Unlike other insonism-causing toxicants, which characteristically injure multiple brain regions and are associated with other neurologic signs. in addition to parkinsonism, MPTP caused a pure parkinsonian syndrome with patho logic changes confined to the substantia nigra and other ented neurons. The striking pathologic and clinical imilarities between idiopathic PD and MPTP-induced parkinsonism suggested that che two disorders may share common pathogenetic mechanisms. Subsequent studies in experimental animals, including nonhuman primates, confirmed that MPTP induces clinical parkinsonian fea- tures and selective pathologie destruction of substantia nnigea cells. Further research into the metabolism and neurotoxic mechanisms of MPTP established several important findings that have guided experimental and spidemiologic investigations. First, systemically-admin istered MPTP crosses the blood brain barrier and enters astrocytes where it i converted by the enzyme mono- amine oxidase type B (MAO-B) to the ultimate tox cant, I-methyl-4-phenylpyridinium ion (MPP+)." Sec: cond, MPP+ enters dopaminergic neurons through the dopamine re-uptake system, where it depletes ATP lev tls by Hlocking mitochondrial respiration, particularly at the Complex I ubiquinone binding site." Third, the hepatic eytochrome P450 enzyme, debrisoquine hydrox- ylase (CYP2D6), which is also expressed in substantia nigra dopaminergic cells,""_ may detoxify MPTP. Fourth, MPP+ bears chemical structural similarities to the herbicide paraquat," suggesting a possible role for this and other pesticides in PD etiology. Loss of striatal dopamine and decreased motor func~ tion with normal aging are well-recognized phenome- nna, yet increasingly there are reasons to suspect that idiopathic nonfamilial PD is not merely an inevitable consequence of aging. Although there is no single ac- cepted model of PD pathogenesis, there is increasing support for a general model whereby environmental or endogenously formed toxicants accelerate loss of dopam- ine-producing neurons, and culminate in clinical PD when striatal dopamine is reduced below levels required to maintain motor function.” Toxicity. mechanisms for exogenous and endogenously formed chemicals that provoke oxidative stress reactions, including generation of reactive oxygen species (eg hydroxyl radical), have gained prominence in recent years! Other relevant mechanisms that may contribute to dopamine cell de- struction, either independently o¢ in combination withEpidemiology May 1999, Volume 10 Number 3 PARKINSON'S DISEASE EPIDEMIOLOGY 329 TABLE 1. Recent Epidemiologic Studies of Cigarette Smoking and Parkinson's Disease Autor (Yes) Lecation Relative Rik Estimate Ever ws Never Hiuhew Smoking Caesony (Cahn seals ‘Sacra PafenFupser (190) us Canine ee 138) Hwa Caecvmtnl stale ‘teem ot al (1991) NJ Penn Times limes eal (1992) Shain Barcel real (1998) Sree, Werhinawn cue al (1994) New York Helcbrind ea (1997 Genany Cec eral (1998) Warkinen 97 27 (40 cigaatsilay) OF 02 (hortét pack year) 05 . 07 03 (20 cyarettestla) 04 os 26 (230 packoyeand 05 OU (540 puckeyean) 03 89 (243 puck) oxidative stress reactions, include reduced cellular en ergy (ATP) production, excessive cellular excitoroxity and accelerated programmed cell death (apoptosis) MPTP has been the predominant test agent in toxicity mechanism research, and its induction of parkinsonism in monkeys" is the best available animal model for PD. Additionally, there is both empirical experimental evi- dence, and considerable speculation, that various exog- ‘enous exposures (eg MPTP-like pesticides), of endoge- nous chemicals, such as tetraisoguinolines! and some metabolites of dopamine" that reach dopaminergic neu rons can trigger the cascade of cellular events that result in clinical PD. Risk Factors for Parkinson’s Disease CCloaRETTE Swoxine Apart from the increasing incidence of PD with age, the most consistently reported epidemiologic finding has heen an inverse association with cigarette smoking. Decreased risks, by about 50%, among smokers com pared ro nonsmokers have heen reported from many case-control studies," " some of which demonstrated stron inverse dose-response relations." Cohort stud- tes in which smoking data were obtained before cases’ dliagnoses substantiate the negative association with smoking.*- Neither selective survival of nonsmoking PD cases nor pre-morbid (eg risk averse) personality type! chat predisposes to smoking avoidance provides a satisfactory explanation for the seemingly protective ef- fect of cigarette smoking. A summary of some recent epidemiologic studies on smoking and PD is given in Table 1. To our knowledge, cigar and pipe smoking or exposure to environmental (passive) tobacco smoke have not been investigated in connection with PD. The biochemical bass for neuroprotection trom ciga- rette smoke may involve effects of nicotine or other ‘components of cigarette smoke on the enzyme mono- amine oxidase B (MAO-B). Two functions of MAO-B have particular relevance in PD pathogenesis: carabo lism of dopamine” and activation of MPTP to MPP- Positron emission tomography scanning studies show reduced MAO-B activity in brains of smokers* Based on these observations. it might be posited, perhaps sim- plistically, chat blunted MAO-B enseme activity pro- tects against accelerated dopamine catabolism and acti- vation of pro-neuroroxicant chemicals. Experimental evidence for reduction of MPTP toxicity by either to- bacco smoke or nicotine has been inconsistent," how- DIET ‘Most epidemiologic research on dietary factors in PD has focused on antioxidants that might protect against neu ronal damage from free radicals, which would be consis- tent with the putative oxidative stress hypothesis. Di- etary factors of interest include foods with high contents of Vitamins A, C, and E and antioxidant vitamin sup- plements. Thus far, epidemiologic findings have been Inconsistent and contradictory in some instances. Some studies suggested reduced risks among persons with the highest levels of vitamin consumption, primarily Vita- min E,(*-" whereas others failed to identify consistent assoctations.-" Diets high in lipids and animal fats are also of interest because of the potential for free radical generation during lipid peroxidation, and there is recent evidence of elevated risks related to intake of animal fats.2"" Logroseino et al reported an odds ratio of 90 for the highest quartile of animal fac intake, but no association with dietary iron, In that study, there was an apparent synergy between animal fat consumption and serum ferritin levels, suggesting thac iron binding (and hence concentration of free iron), rather than toral iron Intake, might be an effect modifier of high fat incake. ENVIRONMENTAL AND OCCUPATIONAL EXPOSURES Episodes reported since the 19th Century of sevete par- Kinsonism in occupational cases of manganese" and carbon disulfide poisoning’ provide the historical bac crop for suspecting environmental causes of PD. Exam- ples of specific coxicants that can cause dopaminergic cell loss and parkinsonism include manganese, carbon monoxide. carbon disulfide, and evanide: however, the role of these toxicants in idiopathic Patkinson’s disease ‘snot known.” In recent epidemiologic studies of PD, environmental and occupational exponutesto pesticides, metals (lead, mercury, aluminum, copper, manganese).330 CHECKOWAY AND NELSON, Epidemiology May 1999, Volume 10 Number 3 TABLE 2. Recent Case-Control Studies of Pesticides and Parkinson's Disease Relative Rik Author (yest Location Exntne Estate Stern otal U1 oan, SP Tnseericads 8 Hebd oy Sennchuc otal 1992)" Caluay Heres Mt Ivecticaks i Fungi 16 ured eal (1998) Oregon, Washington Herbihkes (210 ree) 4 ected (210 tes) wo Fumigwrd hrnse lever? 53 Hui er al 19931 Kam Posncides 33 rman et a9) Baitoh Columb Peels 20 Imscicides oF Herbeakes be Fungal 85 Seidler l (1996) Germans Herbie 2 Insctcaks 2 Ly eal UT) Tawar Parag 64 Gorter al (19989° Michigan Heres s4 Tnsecricns 32 Fingieu 5 and solvents have received most attention as risk factors. We will limit our discussion co epidemiologic evidence for associations with pesticides which have been an especially prominent focus. The established neurotoxic properties of some widely used pesticides (eg organo- phosphorus insecticides) and the chemical similarity of paraquat and MPP* are logical reasons to focus on these exposures ‘The overwhelming majority of the information on pesticides and PD derives from population-based case control studies in which pesticide exposures were ascer tained from questionnaire responses. Exposures to pesti- cides occur primarily from their application in farming, pest control, and home gardening. Most attention has been directed at agticultural occupational pesticide ex- posures. Alehough results are nor fully consistent and are ‘often statistically imprecise, there are reports of elevated risks related to exposures to the nonspecific category of “pesticides” 7" and more pointedly to insecticides and herbicides." Table 2 provides a summary of find- ings from some recent investigations of pesticides and PD. Some studies"'** have demonstrated associations with the herbicide paraquat, which was of particular ineerest because of the earlier suggestion that paraquat say have some of the toxic properties of MPTP." Be- cause of the difficulties of obtaining information on use and amounts of specific pesticides, quantification of ex- posure-response trends for individual or categories of pesticides has not been achieved. Nonetheless, wo re- cent studies, one from Germany® and another from Taiwan," suggest increasing risk gradients with years of application of organophosphates and various herbicides. ‘The ambiguity of some case-control data is illustrated by results from a study in rural British Columbia” in which fan increased risk was noted for “pesticides,” yet no effects were seen for the main pesticide types: insecti cides, herbicides, and fungicides. There are also studies in which no association with pesticides was seen = Only tentative inferences regarding pesticide exposure effects can he reached from information on rural resi dence and history of farming occupation, and predict- ably, findings feom ecological and case-control stulies have heen ineonsistent.* * GENETIC FACTORS Several observations suggest that genetic suscepibiliy is fan important determinant of PD risk. In most popula: tion-based series, patients with familial PD represent @ small fraction of cases (10% or less)."" Although most familial cases do not demonstrate a Mendelian form of inheritance, several large kindreds have been reported where PD was present in an apparently autosomal dom- inant pattern" In 1996, a defect in chromosome 4 in the gene that encodes alpha-synuclein, a presynaptic nerve terminal protein, was identified in affected mem bets of one Italian and three Greek families with rare autosomal dominant PD." Some, including the popu- lar press, heralded this observation as the discovery of the "Parkinson's gene.” Nevertheless, subsequent studies in familial and sporadic PD cases have failed to identify the alpha-synuclein gene (G209A missense) mutation among patients with more typical disease.”-'® These findings suggest that alpha-synuclein gene _mucations will ultimately account for only a very small percentage of families with autosomal dominant PD, and may be limited to families of Mediterranean descent. Neverthe- less, further research to elucidate the function of the mutant alpha-synuclein protein may give insight into the pathogenesis of idiopathic PD. Since the discovery of the alpha-synuclein gene locus on chromosome 4, other investigators have reported linkage of the PD phenotype with a locus on chromosome 2p13.! To- gether these findings suggest that PD is likely charaeter- ized hy genetic heterogeneity, with one or more discase- causing genes associated with rare autosomal dominant parkinsonism and pethaps other genetic loci contribut- ing to susceprbility among those with sporadic PD. ‘Most twin studies have consistently found litle dif: ference in concordance between monozygotic and diEpidemiology May 1999, Volume 10 Number 3 otic twins, § although a recent study identified a higher concordance rate for monozygotic than {wins among probands with early onset PD before aye 50.!* Less direct evidence for a genetic contribution comes from case-control studies in various seetinys in which family history of PD, determined by questionnaire responses, was found to be a consistently strong risk factor." Nevertheless, posible reporting bias and inadequate diagnostic documentation of PD in family members are limitations of some of the findings. To date, nw specific gene has been co explain familial clustering of PD. There isan increasing: recognition that gene-enviton- iment interactions may explain the development of many dliseases, including PD. Consequently, the search tor host susceptibility factors that render certain. persons more vulnerable to nonfamilial (sporadic) PD induces! by exposures to exogenous agents has heen a distinct focus of laboratory and epidemiologic investigation. Re search into potential genefenvironment interactions in PD has largely consisted of investigations of mutant forms of genes encoding enzymes involved in aetivation and detoxification of environmental chemicals, dopa- mine metabolism, and cigarette smoking. Enzymes pertinent to smoking include those involved in cigarette smoke toxicokinetics'-''' and potential markers of ad- dictive behavior, such as dopamine receptors."8 Vir- tually all of this research has used the case-control de- sign. We will illustrate the development of this line of genetic polymorphism research with the two most fee- quently investigated enzymes, CYP2D6 and MAO-B, Barbeau et all” hypothesized thar deficient metabo. lism of debrisoquine hydroxylase (CYP2D6) might pre dict a diminished ability to detoxify enviconmental chemicals that are causally related to PD: pesticides were suggested in connection with this hypothesis. The orig- inal investigations of the CYP2D6 enzyme were pheno- rypic studies in which extensive and poor metabolizer status was inferred from measurements of urine concen trations of metabolized (bydroxylated) and unmetaho- J debrisoquine (an anti-hypertension drug). The col- lective evidence from Barkeau et als” and subsequent Phenotypic studies!" dal not demonstrate convine- ingly that PD is associated with deficient CYP2D6 me- tabolism. Uncontrolled confounding by medication use an possible metabolic disturbances secondary to disease were probahly the main sources of ambiguous results ancl Fias. Phenotypic studies of debrisoguine hrdroxvlase have become virtually obsolete since the wlentification of the CYPZD6 gene locus" and development of poly merase chain reaction (PCR-based assays to char ize metabolicer status yenotypically."> Unlike measure- ments of metabolic profiles or ensyme activities in accessible tissues, genotyping results are nor influenced by existing health. stacus, medications, of nuteition. Three genetic polymorphisms of the CYP2D6 ene ac count for 9% of poor metabolizers in Caucasians: a polymorphism leading to a splicing defect (the “B” al- Tele) is the most common mutant form." Genorspicalls determined poor metabolicer starus was associated with, PARKINSON'S DISEASE EPIDEMIOLOGY 331 an approximate doubling of PD risks in two ofthe earlie studies in. the UK" however, subsequent studies have produced conflicting results, with some stucies inglicating elevated risks related to mutane alleles!” > and others finding no associations." Findings for CYP2D6 in early-onset and familial PD have also been ‘A sound rationale for investigating MAO-B genetic polymorphisms is provided hy several established func tions of this enzyme: involvement in dopamine me olism, activation of MPTP, and its reduced activity as a consequence of cigarette smoke. Furthermore, the MAO-B inhibitor, selegtine, is used therapeutically to retant progression of PD symptoms!" Initial investi tions of MAO-B in PD were mainly limited to measure: ments of enzyme activity in platelets; not surprisingly the results were highly variable, and essentially uninter pretable.!*!” Genotypic investigations have mainly fo cused on genetic polymorphisms of intron (noncoding) regions of the MAO-B gene, especially a polymorphism in intron 13, consisting of a single base difference (A or G). The A allele was found to be more common in PD cases than conteols in case-control stles in the United States! and the United Kingdom," whereas ni ass0- ciation was found! in a Japanese study." A recent U.S, study indicated an excess related to the G allele, with oxids ratios of roughly 2 in men and 5 in women.” Further analysis of this polymorphism and smoking su gested an interactive association, as the typical inverse relation between smoking and PD was confined to per- sons with the G allele.'# There have been some attempts to explore genetic polymorphisms that may be shared among PD and other nuradegencrative diseases. Notable examples are ge- netic polymorphisms of copper/:inc-lependent superox- ide dismutase (SODI) which has been associated with familial amyottophic lateral sclerosis and the 4 allel ‘of apolipoprotein-E that isa risk factor for Alcheimer’s disease." Thus far, however, there is little support for shared genetic polymorphisms among PD and other new rodegenerative diseases. 4° Discussion Saying that the advancement of knowles ology san pathogenesis of a particular disease reguites coonlinated contributions from epidemiology and the basic sciences is usually a statement of the obvions. yet is certainly true in the case of Parkinson's disease. Re search finglings from epidemiology, toxicology, gene molecular biology. and other Risic hiomedical cienc have been mutually reinforcing in suggesting PD risk {and protective) factors and theie modes of action. [b lustrative examples are epidemiologic observatians of invere assoctations with cigarette smoking that have stimulared lakveatory research, and whole animal anit tio experiments with MPTP that have prompted! ept dlemiokigic assessments of presumably similar environ: mental chemicals. Despite recent progress, however ic is ifficult to gause whether new epidemiologic insights fon the eti-332, CHECKOWAY AND NELSON are emerging at an acceptably rapid pace, and ultimately how influential epidemiologic findings will be for pre vention of PD. As should be evident from our brief, albeit selective, review of the epidemiologic literature, PD undoubtedly has a complex etiology, with no single environmental or genetic cause identified yet that can account fora substantial fraction of cases. An exception to the last statement might be cigarette smoking, which is a common exposure and seems consistently to reduce PD incidence by 50% or more. ‘One major impediment to identifying etiologic clues has been the paucity of population-based dara on PD frequency within and among various countries. A fun- damental problem has been the lack of uniformity of case definition methods, despite well-known standard- ized diagnostic! and disease staging criteria." Even in instances where standard diagnostic procedures have been followed, some studies fail to distinguish true idio- pathic PD from secondary parkinsonism due to medica- tions of other medical conditions (eg cerebral hemor- rhage). de Rijk et al!? recommended that diagnostic criteria for population-based PD studies should include at least two of the following clinical features: resting ‘tremor, bradykinesia, or rigidity, inthe absence of other apparent causes of parkinsonism. For furure studies, in- vestigators might consider collecting enough clinical information such that altemative case definitions could the applied to allow direct comparison of disease rates with other studies. Another difficulty has been great variability in the types and quality of disease frequency data for PD. There exist no population-based PD registries. This situation difier from that for cancer, for which some countries maintain regional or national cancer registries. Instead, PD case identification typically relies on convenient ad hoc procedures (eg door-to-door surveys, reviews of med: ication use records or medical practice reports). Thus, prevalence differences by geographic region may be ar- tifacts of variable hospital referral practices or case de- tection methods in community surveys."® There is no simple remedy for this problem, although mortality data, despite being incomplete measures of disease occurrence, are useful for geoss comparisons of risk by gender, race, ethnicity, and geographic region. Identifying incident PD cases poses another difficulty because of the variable time course of clinical presentation. There is seldom a sharp time of disease onset that Teads to a rapid diagno sis. Instead, prodromal periods may persist for several years before PD is ultimately diagnosed.” Conse- quently, the majority of cases in epidemiologic studies represent prevalent rather than ineident PD, which may result in survivorship, information, and other more sub- tle manifestations of bias. Inclusion of prevalent rather than incident cases in case-control studies is problematic because a prevalent case series generally overrepresents long-lived cases, making it difficult to distinguish factors associated with prognosis from shove wth eto sig Case-conttol studies dominate the epidemiologic lit erature on PD, principally for reasons of efficient case Epidemiology May 1999, Volume 10 Number 3 accrual. The case-control design is particularly. well suited to examining multiple hypotheses of disease eti- ‘ology, yet the literature suffers from profound shortcom- ings: incomplete or inadequate exposure assessment methods, unavoidable errors attributable to faulty recall of past events, and low statistical precision for detecting associations related to all but the most common expo- sures (eg smoking). We recommend that ongoing and future case-control studies of PD should adopt some of the more creative and rigorous research strategies that hhave proven suecessful in cancer epidemiology. Multi- center studies enlarge staly size, thus enabling more precise estimation of dose-response gradients and assess- ments of effect modification among exposure and demo- graphic factors. Similarly, collaborative reanalyses of pooled existing data can address the problem of impre- cise results from small studies, but require attention to the sources and quality of data collected in multiple studies. Standardized protocols will he necessary for PD diagnostic and exclusion criteria, and such studies will need to maintain common, if not uniform, control se- lection strategies. For example, it may be desirable to include several types of controls (eg randomly selected from voter tolls, neighbors, spouses), depending on the types of research questions under consideration." Cer- tainly, improved methods of exposure assessment for dietary!® and environmental and occupational expo- sures! that have been developed primarily for epidem logic studies of eardivascular diseases and cancer should be exploited. As study hypotheses reganding exposures become more specific, there will be a need to collect more detailed information regarding the aspects of ex- posure (eg duration, timing, peaks) that may confer risk, and to use objective methods, especially blinded expo- sure ratings, that reduce the potential effects of reporting, biases." Genetic polymorphism research to identify PD sus- cceptibility traits and to help clarify pathogenetic mech- anisms, while still at an a faiely early stage, is expanding ata remarkable rate, Advances in genotyping methods and increased ease of DNA specimen collection and storage greatly facilitate this type of research.* Thus far, the MPTP model of PD induction has been the center: piece of toxicologic and epidemiologic thinking. Ge- netic variants associated with MPTP toxicity and related mechanisms clearly deserve thorough examination, yet ‘other mechanisms of PD induction should not be ig- nored. Genetic factors associated with the pharmaco- logic effects of cigarette smoke on neuronal cells, me- tabolism of dietary components, and activation ot detoxification of environmental agents warrant empha sis in future epidemiologic studies. Some discipline will be needed, however, given that one can readily envision a situation in the ‘not too distant future where the number of candidate genes and genotyping assays will approach the number of questionnaire items. Certainly, some guidance from neurotoxicologists and geneticists will be invaluable to epidemiologists. Banking of tissue specimens for future characterization of susceptibilityEpidemiology May 1999, Volume 10 Number 3 genes and biomarkers of exposure should facilitate ine vestigations of gene-environment interactions. Incorporating genotypic assays into case-control stud ies has nearly become standard practice, and this trend is likely to continue for the foreseeable future. Unfortu nately, most studies of genotype, even some that purport to explore gene/environment interactions, violate basic principles of case-control methodology, mainly by se- Jecting convenience controls without regard to their genetic ancestry. For answering questions about putative susceptibility genes, @ proper genetic control group is needed. In particular, case-control comparisons will be confounded by ethnicity when cases and controls differ with respect to ethnic admixture, and the prevalence of susceptibility alleles also varies among ethnic. groups Even well-designed case-control studies that measure highly pertinent genotypes may have study size problems for statistically precise estimation of effect modification, particulary for rae allelic forms." Multi-center studies using pooled datasets may offer the only practical solu- tion in such instances. PD incidence and risk factors have been studied in several conventional follow-up studies of population samples, such as cohorts assembled for investigating car- diovascular disease risk factors"; however, small num- bers and logistical difficulties of verifying PD diagnoses are important limitations? The cohort design may be most suitably applied to very lange cohorts with well- characterized exposures to agents of interest. The ongo- ing prospective follow-up study of nearly 100,000 North Carolina and lowa farmers for which past pesticide ex- posures are being assessed in detail!” might provide a useful template, Sufficiently large cohorts of this type are exceptional; hence, case-control studies are likely © continue as the most productive source of etiologic data, References 1 Pan |. Ana un the shang pal London: Seeman Nec ad Jones i817 1-86 Aad Panam dene pathephrniy Lancet 199,357: 120-187 Pats, Kolle WC. Detning Paks dese and ratknsn in Henry) Kaller WC, npn J, Eno Pathan Dh tone New Yk Mawel Dekker, 195.158 4 Darerom RU, Yar MU) Emcee ond parknim Asch Neat aan 5. Keke Ti Paki Seas edema respective fy Schenber Bsr el Adtince:m Soumlah sa 18, Sow York Raven Phew 155 Bia. Lane 1, Balan. Te |W, ren 1; Choe pakinena ours due fafa of mepeinealg then. Seence 10S es Tanner CM Paknsns dese In Goteck PB, Ate Mood. Handi st Neurcpaemlon New Yok Msc! Dekh, 4233-980 + Ren Slam Hor fina tem undencaning he case Psi: dene} Nev Netware Bchure Bash 4-16 © Galdire i Causespcie morality ndertanding wera if the ‘eter ) Epil Communsn Hea lis 49 MC Reccr WA. Anderin DX, Mein MO, Bact MMB Shantinore DAT 8 puis peop om Sage eran fr Bar. iim hene Newnhen IOEHCTT Ls) 1. Suite REG, Slr TR. Patknson’s decse eplemoly 1m the Nichanptig Doct, England Acts Neat Sand B9SI395 9048. e 12, Rok MC, ter MMB, Grscand GA, te A. Gree DE, sander Meche FCA, Homan & Presson of Pckinsats doewe i heer ‘he Reteadim Sade Newly 19RAT AUS TT4E 5 Tendle RE, Surah nab TR PARKINSON'S DISEASE EPIDEMIOLOGY 333 Tandberg FLasen JP Nese BU, Rise T, Au), The demi Prison’ dee’ 1o the County of Raysand, Norway Mow Dead Bos.10 341-50. TrenaieyG Schaaet .Gebad J Rand Dy Teka? Hee HEM: Genel WH. Suntey tol on spdemy 9 prises sl ype nthe eer Besalene of Puhitains dowel saa Sita seed bya etd sey of ss er tan 63 fears Arch Neu 1099321007 102 ipeus R Monies K, Cote, Dat |, Hemenesile N Mejia H. Tang Ma Langan R. Wilder O, Outind B Hauer A. The rency lope Prins dns by age chi op an en Newton Manharan, 1988-19. Arm | Epil 198-142820-309 eet TA, Becket LA, Maroy AN, Shan KM, Got? 0, in DAL Evans DA Preven prin ss an scat atly ‘nacommuney ppl of ce pele: N Engl | Med 106 3411-7 IPA Atelae O, Pelee M, Haro G, Linhll B. Oke J Grane: AK Aue stolen nd presence of Paki izes a Swed community. | Clin Elem! 199649697- 641 {Co Ar Magnan ©. Scher D. Prevalence of Paria he 8 Norhce alycomparton of oe ely sad inal sce then ase, Me Ded PRI 40008 Ben Shame ¥ Straar Kuh Pak ran’ doe: elem Incest ad management Be J Gen Pat 19954-61268 Marens DM, Das JW. Cannes A, Ross GW, gp], Whe LR Fpulerleernr sn akin’ Juche ry imapwnpetve stay fm med men Newly 1996461051050 anu My Nkathns Ky Hare Nakayama Takase Ende suo of aan’: date in Yonagy Ci fp connate Stay eed nt 12 yas ago. Newrerpemlay 19961820107 Melm MO, Andenen DW, Vera RH, Roves WA. Pesknce of Paks’ uae Jun Baton Aes Pine, Argentina. Ma Di nt 1997 12 197-208, Sou A. Palen RS. Mende insti and Paki’ dese. Av] puerta 1988 1251017-103) Mavomine H, Sato M, Shee Mauboy S, Tanks H, shan Nakagws Hato Vokech Mi, Ketwyaty pes S. Taka SanpeKKoke MiP Koro, Moutn Y, Sealer AA, Ya {Y, alan S, Kuna ST, Maun, Locinton oa pene for an ates receive fom of rene paisa wo cheese (G252-27 Ar | Hum Gener 1878059880395 {in SM, Lia HP. ake ene ey one pate dene ty] New 19853 205-207 Cie Lt Yaungomer Paints dene: + cal review Newohiy Ioots ies Lana}. The sega debt of akin’ de met i the Uneed Stats) Neal Se 1ST 1508110. Kirke J. Murphy Pa The chang ters of Seth res patk foc, Newly IADADAD Fino JE Settee SS. Rane mocay oe to Parkinsons Shee ad fmsexgtic tcl cee arto ofthe omettie saae f eum tc) Ci Eade) 19298100110 Ballas PA, Larner! W. Permanent hungrier doe te EmethvetshemeL2 Setehwleryine IMPTPL sever ce Neslogy TAR 5048-956 “Tera JW, Levon 1, Cae , Rarenter Al. MIM phenom 0 runs cxf to Teme 1 per 23 ethadopmine (MPTP Nec 15019881987 Soule SH. Damato RY MPTP. no Chis Tere 4, Canmore. Metab of he uns tery tine, NTP by bra mensamne ane Buachem Bye Res Coe tam Bist c0574 505 Cite Chap M, Schau AV: neces ahi fe ial Compl Ibs netsh sn eslence he {petal olbement. | Neutshem 199238 78-9) W. Gone: Fl, Neh HR. ‘Neue csxhnome PARCHDY ulchenspanepaeme pc pote Iuitn of scree Fy ( Lewcure and raceonde ence erty Fam hepa: F430 gene CYPEDS. Ma Pharma FBLA AY FS {Ghar OF. Carn Pane Ml Sak SPD Rokene ACK. Wt (CR Meat lom e MPTP he cvecthnme P4520 a the eons {06 mRNA im human Ket ind lu ann bem Hobe Xembumes ber Iniss Bakenv A. Row M. Chaser T, Flas L, Pars § Ensnmetal and feta in th tly ot Pate Urene In Yabr St Bergmann Ra Nine Seo 145 New Nk Rinen res 1S hema D, Denon C, Daten F Pall P Jan-Aeu F, Aad Shar dkpumine defen Paks hee le ot An Neal (vo9se55-33¢ Calne DB, Meer E Even A, Spencer. Atte Paki ‘Seeue an] meaentn dee abutuphe mlercoon Beiween ae334 CHECKOWAY AND NELSON a " os 1. Chiko L Farell Dae Fs and ossnmet! Lan BEF 1OR agri Wt ice GA, No Lessin MurmasdTher 15 Ethane ABI Quan sve Paseo: Nou Apt Rambui Fat b Kins 4. Resse sagan pect ad he em aeaneraie Sane Rin Chm Lab sr E37 tS CUM Sate sry nl ens tos an nage ts Sout Neund RST, ‘Mocs Hy Mor Hy Miss ¥- Appin earadaynert Nes Nout Teen Sapp THES a Tis Rs Chat 2 Murky SP, Eho I, Jace DM Repu A pnnune mal pushin cetera of Spies ‘etre th pak cepts othe sat Tg He Neer them LE Stercnahdopymdins Pee Nal Acad Sor USA fostaoasae a8 Tarde ac. the i and Phin sense mikes torgoo TT ‘Som Ar J Walesa ME, bran A, Mant ee Glin tunes sata the once Twapnons) of evans ant my serve asi ter fevene cellar pers rahe | DOT [iene PM, Grn As Rood © haw Le Charts sing and fronton foam Padme Use: fae month otha ch? Nima, (945 04)“ 105 ek 1, Bunn BJ MK HE. meson HG, Tobe JA Nin txpvare an Parkin Uoene. in) Epa 191 101-20, iin Mk. Plney ECiar SR Ce fBeacn Mi Hates H ekanp 5S Suey Phe epuemiley vf Prknas sae aes ‘SE swuncomat and lon purse Ach Nowe 199S8903 90 Hime omen Fl, Me { Cinees Rell 3 Frome ski sad sotumy,sdwf drkng a Pics Ics Cincom tay Mw Ded IME 810344 revield Pt, Vaan BU Syever PS, Lineman CA, Nur 0 fener anecen of panomer Paka dae Now ounshise-1i3s Magers R, Tag MX, Mane inv dnane Mow Dao 1934520 Mange CN, Quad Ps ea Wed} Neon Se 1ISASDOT Ie Te Mitac Gills A Vdgy G De Man ¥, Canon A, Abe Canon B Caselane AE Carpal. Eastsemenea and weet tk oun in Pakinrs dee a onsoaie titer Tale Moe Teed Bat 17-3 Helena We Sehr A, Rates BE Virsa P Oxted WH, Jo Nechun fs SciecerF Ulm (i Smeking abd Fakir dese: 9 econ rim Cerin ot) paeal 1997.26 28-98, icin 18. The fhen tal searing admit ame US. eters Femi andi yrs of hrs Na Cancers Mm 19 Behe MIU age Heath Elation in Wel 1906 1-27 Sn Als Palrbaer RS Sicha Pinos cine Ezek milo Ise a60-4, Grandin Ay Mens DM, Rood D, Mach Presi ea ‘eaten ier asvelpin lupus Parse dae Sn} Epo 1941991129108 ees DM, Gr A, Dae J, Ran CAV, Wie UB, Red Exaince ania the stitch meray sn explain she procs feemn chose ating nd reed vecrence 1s fe Paks Sse Am Eri 98 A 8. atom CM: Daimebr Nf thre poner perma yal Parkins dee? Newtloe 19L Aloo 2073-78 Risk P Kea Hehe (oma MBM. Neath pe Freche to the once of mami snide Acta New Serb asad 4 Feel J Vote ND, Wane (5), Pape Ni La J Mace Auf, Shes Shyer D. Wold AP Warmer Ze es i tohbtion sf musa swine Bw the Mans ser Nau oe ie ‘Wer Q, Yeune Mf, Juma OP, Ande JK Gant vation fm sie dsc vel ipminenss PUI? cll toe tee fe eal damage ad ety MOTE. | Nees Res HARE 6. Thani Kant A Ad Ys Hh Ec: Decrease pe 8 sors nm sgominge sen sll n Paka cn Ss Ielgy 9964613621209 ‘Fanner Mien J, Sumer dene An Ned IS I¥ I apa a fe preacuse snes factor in Pakimenve dcne. Mes Based 1905 66-70. Hellontand We Bing H. Rega BP, Seer & Vin P;Noxhan [eer] Okra WH, Schnee E, Un (Dian Tees ds 2 pote le fe the pe inks pe wane Reale Fe En Sim Y, Ski and Parkin ta Vitamin we nd Phomen's 7 Re May 1999, Volume Id Number 3 logy sradumotens teddy estate an sinew sh Shonti 1atagae es mae Moss frdech HI Lankan taster a a Is m Pucker dnc a J Near 1 BSTC TTS, Monts OM Cerne 4, Was CL, Path CR: Res GW, Whe ER Circsonta stn tsp Paha doe abl dtr ann E take Neorg ome 27-1278 Sijoust WL, Fetus LA, Hela! T. Mtl JR, Fale Detan antler dy tacts he cee Pa Ahecoe New Dred B97 100-198 LGromine Mane, Gc) Frost. Skok V gue wel, Mays Reta om al tl Pre ts on nd RNa Ie Anke (: Checks H, Frain OM. Resid S, Sth: Weller T Stina PU Drea tsa Pk de let bl ap nd oi Gees he Dred 142 Geen GC. Nomen math abs Pye Res I5SISSO lan EC Ch dala sine Mar BIL 1 Tanner CM, Occitan ue Ca T Hosa RES, Noun )S Kale WU: Bok fe Trnmoe she Newly 19918 183-167 Hernan © Wine M, Se Boke S Calne DA easel th Pains Unese 9 hifi of Pn Columb Nh Dont bq 00-7 Svat EM, Line Bh Lee RG. Parkins dace and expan 19 oteleal work penle shemale Newndoge 92213261338, SLUSH idetend W Rebs Bf Vier Necn Pen) eel ‘WH. Ulm, G. Schider © Posie cseonmen, seca sd cher sty factor fo" Pike Jee cect al (Germany Newly 546 12751288 Lor HBL Tun Cz Chen Ch Jen S, Chane YC, Chen SY, Chen RC. Enmnmeral rk tke Pinus Ince: act a i ‘Taya Neurogy 10974 1983- 1588 GrrlIM, jnaen OC: Rook BA, etre EL, Racha 8). Ther Sifakis news with epee pestis ing el eS faa tng, Neu TOMES 1750. Hartman (2 Wier A Bonenng 0. Sm B, Calne Pawn’ doce: 2 cnetwonind sy of scoped an econ mak as ae fndad iment Kile, Ver Oneal B, Gey, Alnandr C. Chin T, Dale J res Ry Tanne Event tk ctor Daten doce evry 190A 1218-1221 Wong GF Gray, Hasan BS, Keller WC Enema rk fs tn ching wh Paks dene, Avch Nevel 99148287298 Rusea A, Rey M. Bemice G, Cannel G, Pare S. Eset of Pinson’ deca previews an ennental npects fl se Cin Neunt seria AH, Ui Ry Stern W, Laverty W, ODunoell K, Dame Your WK, Dut 8, Cunt, dating ter cbemieny poets ed Tefen amd tho cndegy od Prk nee Can ) Neat Set osriaaieeats ‘Simhs KM, Line EJ: Loe RG. Pains dei on apse tu ovnmmenel rs pain ned onecotr tay Can} Natl Slips Roxcs WA, Anienon DW. Menchiny F. Gre, Mont by eget A, Seater Ds Pere xcopy cdi, nd Pah (iso onc i man Tan plane, Me Deed 196 wind Mer Lyrmcine ©, Al B, Maja H. Hlim A, Loa E, Cte L Mins Envinmentl ra attr Paks cn an Pita somnnny, Newey HOSOI 81 Tesmim RC The genres uf Paks deme Ade Newel IH: weois Ge LL Th genes of Prk cs 4 emule, Newly Tosti 3h Stoo DM. Hiding AE Misa CD. clin an ane {Fal Pass dscns Maw Dvd ODI 820-2U iain AM Mer RH, Zomeun TR, Mik ME, Coie Li, Sa [cba WU, Panonan RA cla geet tf Pree ‘Galen tren rami Nena 199506 Baajmerenn MH Higa Cibo Lomi WG, he SED ho {G,Nge.Stpna ES Ph LT, aor AA, Lain AM, Num RL Thou RCL opp 3 gee for kiss cn och foe aidleg2) Sone 198274 1197-199 Shen MF. Len Len E, MeSE; Debug A, Du A, kB ean HRulerotn | Bue By Senne ES Chast S.A fei A Puen T, jee, WO. Lares AM Pash RC By tee Gy Galle LL Neckean RL Mision inthe ayacn one ‘tao iis wh Pots een, Seance I99/27630152087 sosmenu fictce Be ad samen ces of pki,Epidemiology May 1999, Volume 10 Number 5 wm. 1, Grout T Male Mgdk ALSO Ze A, Vian J Pie Moon, Bons 8 kina Re Ap ¥ Be Ar Weed Net Simian! Torte dans, Scene Hcy Famer M Wheel Vows thnk R Boe Tepe Tah Hh Ishin WL Sal) Mrgans )nam KLan TL goes Stacynackin murine fal Prhinee denen Newt Chin, Tanner CM Jan Ligne ond he ye ‘ene mere tan CAT iL ate wth emer Pa Enotshuone Stay DaSSOS1 318 SELIM Chas Tanner (M, Gan Pan Esk SK. Asse rsync ee me mutt (2O8A anf patent a amy Raton Raktmsnsdocne Neg, 9965p AIST Gover Mati hed fe Woh 2K, hl Blinc DR Bo Veta Pe Reeemun Ki¥ A cwepebs some p18 Nw et 9% Taso RU Fe SE, Not J, ds, ale Pa sts ens 68 pan sane ad fsa, Novy sian koh Bree Roe SE, The cons tt bo Patan’ sie feu Neudagy WELSH Marien CD Paves dns tas) Nou Taner CM, Oren Lewin JW: Ptr an in i Lm 54, Ekaberg J. Chan P, Mt ist JAMA 18, ances Pakinwn doen feature and inst pacts Art Neal BOSE? el WAIN. Gene and parson} Newtl News Phe 197 peed Chetomay H, Fan FM, Cost Min P her M, Gnt UG: Ge tee pore Pakanonibete Nearly OVO oi Koh JH. Kerth MC, Padus SE. Schesnthan JD. Anau fmemamine nee Blk nah Fah dveie An No Ho SL, Kopah AL, Ramakn DP, Wilms AC. Aa al awesti fru mmm vidoe Bin Paki seine Ant Neal 193 sree Nanko 8 Uc A Hatt M. Ne cin Rete Parkas de el memuumine aude Aan! Bene plemaphons. Net Lt ipanch 51 Gots Ps Check Hoey B.S We T, Fain GM, Sanson DhiCine 1, Avene a ei tn 13 he ie Ive aides Beane wih anon desi, Am} Med Gant B34 ise Pane: Bakreane V. Trin Thana F. Sl, Waal NW, Mir Tv funline AE Eoskutnan of ur cn gene einer the rnc pathy fal al ore Parken’ dee Ruse oe nastnin0 1 RE oe Noung POF. 1 ‘Gnnes DE, Canes , Nudictn Dy De Shab BT [NRE Kec Brumearten Kross BC, Lory DU, sth Fan RL. Baar i, Wn O% Micha Tok 8, Sond Chom liga SI The dopamine Te cee xe = aon eo Dounpenhtre dono BAMA HS ACIS SIMLE'S Cabs 8 Hosnar Sh ig XY, Twokne sabi B HK mca H, Noahs scant Btwcen Parts dan a ‘humane M2 Di and o recgporsane pstmeephor AM Md tet Eo Genoa Nis Louhton PW S&C SI. an SME Aon fbtbaume ma sheskune tons cee nth Pi (reheat eee Rabson Chae Ts Rov Sk Mla LP Pot Eisen ot Padinea see budeaahnewot Scbrecune Lanse eh nt rie ‘Serunnn UR, Heal MTE, Sumas $6, Wane Eliehm [ Derennve neuracl drone and debs Shenson sap Ml Ss Bee 117 Te le Renee 1 als Ist lmenesimanes Fe Sle: ©. Paws AM. SilsoStLitene estate} aus Cuutnge pln ‘akbwenqune Paden dite. | New Newbeare Poskain acer Witham A¢ snes Gress Sh Re Rate S Ura St Zant UME Net OC Ganon BN. Hardon [PMenw U8 Charsercan fone dat an buat dent im ckbragane rth dem Sau Hom 4 Sksgr A. Gensasing ot pe Ine ernie Alnk-peste FUR ait 7 mee tees Bik 3k hememne AU Strbnun S0_8e ME Ke IR Gamat and rts eta the asin st brengs hea ohne PsiCe pepe Phage: DM ba 2 Rease DR she T Paton (YB PARKINSON'S DISEASE EPIDEMIOLOGY 335 Aone My Pay AK, Chas Sasa DN, lle JR. Soran Seager asm Pans, La 199258 Sieh A, Guagh AC, Leah PN, Suter A, Hike AF Matsa [DM Seaman SC Shore AH, Withane AC: Rurancanee DAT Femajine Rrdntne aoe ltpem ad ssepele to Pik Satie: Laney IWATE Rihin MC Ken HL Vanot sth C482 OVP2D alk og fim Pking she A) ed Can HAS ee ‘nck Veo tr teach Ke Takeah Heies Y. 8 med ‘stan Pci eset Bako do Be Unsere Tune -: Gatid Nata Sista amoahs R Matan Frogs the cshnme CPE we tn Eke ors Akon S). fund SM, James KM. Le Gancr DG The ames ews pon tne BSG ov an Pr eevee hotness} Sot 1 1 KTS Lnhing 8, EssopereeB Aehuaci P itsko MB. Ms ral NADILRhsdeane nf CYPIe geste ih hen at Sate J Nemes os FS 174188, Wine sta AN Las Ms Blame 1D, C2 and cebu CID tains Chew: Phamaconts MASS SS, Reda 8 ok Estacwe As Libr Laie I enol lt Btwn feet plbmiin af cjchaome P3010 eloped eb Frown’ acne Cho Seuearaced 1981971323 Per 8 ge (2 ets. Kos M, ents F. Vito Met Gone caning the CYP 20 gene sma bce opr kwon Ann Nore TSR S686 5 Realmun Vaan Hedman, Morden CP, Mowe NW, Assan ecb monlowe sume be Sac lnsie2 wh aml Para wea dacne Lane 19 801136-1159 Blam Redanene V. Dave My Marc DM, Mara CD, Hane AE. Defennne halon ene pokey nfl Psa scone J Nout Newmans Pychiy 194HTS11-91 [Rec A,r ene Lora A, Bera ML, Mal A. Ai EIssn Faure Cana Avseuto Renoen thea {Résmetm hect ave sé Parkins dee hn Ther ssrA, Sandy As, Armee, Taner OM. Day AK. Dv Moon 18, Lange IMO Ue JR CATE ale spans on fone Parke Lino Whine nanprsctive tery in Paka dee Cenaje and cumencses Neuthes ORCAe Shol“ oh Willams ‘A, Stove Gi, Souman Wanna By Xenon ene Pres nal Fars Sans Neuro) 100 Hap 120-82 eckoniy HsCrss 1G, Wea JS ssh AF Land PO Saar PD, enshual Hho al wise of tewsm evs Pa upc BtmaetnPakins ens | Rol Tran Fk Des 1S ‘Mowicn mY. Muravama N; Kian, Kon L Varusha ; Mica Y rks nce wha Jape fulton, Aw} Sed Cinet BOS (Cpechnat H, Fuakiy GM, Conte Sou Welle, Selnum F1,Cone {42 get petom ot SAKE ae te het “ i ne A Say Ho meer 2, ths J Reva JP Eng HX Rahimi 2. rea NiRenge beck [a Cabanas Gen SAL Rone RTs RE Ha trun ican Bank Book chine WY PT. Une: Shr i SC Sotine Teal Vins SI Has Resin (FA, Uns Hoc Hi Pewen RH Je Suttos 28 ‘Sperone demure ne aveunod woh aml svat al teow Niue Pears Sums WI ude NL SshmsalP Perks M4. Enid Sheer GS, Rese AD. Apigcen E histins ine [bambi wer vedere teed alg sp ase Aisne fiste Fre Sul Ned stra ieee Ween FRndvan U. Dew MB Manin U1 Hating AE. Sane the meen came 1 S01 Tsuen tad Paros dnc KolesQe UlersL HufbeIf Pell A Toone AL Hauler IS Hero RE Mint Sh K Kins Aikinmin EMC Yu CE Soha GU. Appncen € myer in Fahirrns doses wknd weer Iemenn nn Quis He Saas {Niue oS. Rend > Finn F Baler A Sth Re hl V Emenee apelpepeswn Enfsba 4 ikiern secede ut wer Palins Servi Mound Seavnay Fovtian be336 | CHECKOWAY AND NELSON 147, Hashes A, Re Shlomo, Dane SE, Lees: What eas moe the ‘Xeumcy occa Jogi Pakinens dsc 2 chmxopboby St Neu or 19242 142-1148, 14s, Calne DB, Siow Bf. Lie C-Crters fe dagmsane Paris's does Ann Neal 1258157 149, Mamden CO. Pakanons de. Lancet 1BAD835048952 112. Langton J Preise Potnons dues Newlogy 13S 'S Sherman DT, MeLayghlin JK, Mand! JS. Section of orl in case conta tes I Types of contol. Am ] Epes 9n1029 104 152, Wile WC Nominal Epidemiology, nd ed New Yk: Oxfnd Us: sem Fren, 1998 158. McGaw V, Nebr LM. Keeell TD. Checkoway H, Lanasteth WT Je. 16, 156 Epidemiology May 1999, Volume 10 Number 3 Acumen of acipatonal apie: commun tue studs Ame Rev Pt Heath 19819 93. Senters Ke Sinden KC. Ou Chin ¥, Hansa WH, MeQulln GM Simeon £) ENA tanking epueriolopc aes Endemol Ret 197 Wise 162 Linde ES. Schigk NJ. Genetic Sneson f complex tnt. Science Toskde5 2057-048 iang Beaty TH, Ling KY, Covet) boat 4. Migs sample for emma, fo det pene envitment inert sn exe ool ‘Kea Aim Edn 1994 1461009107 ‘avanje MCR. Sandler DP, MeMase SB Zshn SH, McDonell). iynch CF, Peanghacker M Rotman N. Desemect My Bond AE. Bat {A "The agcaltarat heath stay Eneton Heath Peespect 986:104 Seas See