Evaluating Evaluating environmental/occupational environmental/occupational

“clusters” of disease“clusters” of disease

Robert J. McCunney, MDRobert J. McCunney, MD

Investigating Clusters of DiseaseInvestigating Clusters of Disease

Definition:Definition: "cluster" is an unusual "cluster" is an unusual aggregation, real or perceived, of health aggregation, real or perceived, of health events that are grouped together in time events that are grouped together in time and space and space

A cluster may be useful for generating A cluster may be useful for generating hypotheses but is not likely to be useful for hypotheses but is not likely to be useful for testing hypotheses testing hypotheses

Disease ClustersDisease Clusters

Focus: usually on increased rate or risk Focus: usually on increased rate or risk of diseaseof disease

Breast cancer and pesticidesBreast cancer and pesticides

Leukemia and contaminated waterLeukemia and contaminated water

Increased risk of lung cancer from Increased risk of lung cancer from hexavalent chromiumhexavalent chromium

Cancer Cluster Activities at the Cancer Cluster Activities at the CDCP CDCP

Cancer cluster investigations occasionally have led to the Cancer cluster investigations occasionally have led to the discovery of important pathways in the etiology of discovery of important pathways in the etiology of specific cancers, such as withspecific cancers, such as withangiosarcoma angiosarcoma lung cancer lung cancer Kaposi sarcomaKaposi sarcomavaginal clear-cell carcinomavaginal clear-cell carcinomabladder cancerbladder cancerscrotal cancerscrotal cancerNOTE: NOTE: The majority of studies that yielded etiologic The majority of studies that yielded etiologic information were of occupational, drug-induced, or information were of occupational, drug-induced, or infectious pathogenic exposure rather than studies infectious pathogenic exposure rather than studies of environmental exposure of environmental exposure

Media survey of cancer Media survey of cancer cluster reportscluster reports

For the period 1977 through 2001, mFor the period 1977 through 2001, media edia reports of 1,440 records of approximately reports of 1,440 records of approximately 175 175 suspected cancer cluster reports suspected cancer cluster reports These data reflect the breadth of popular These data reflect the breadth of popular concern and awareness regarding issues of concern and awareness regarding issues of exposure types, pollution sites, and specific exposure types, pollution sites, and specific environmental chemicals. environmental chemicals.

Clusters: case studyClusters: case study

7 cases of kidney cancer at a 7 cases of kidney cancer at a manufacturing plantmanufacturing plant

Is there a cluster?Is there a cluster?

Criteria to determine whether to Criteria to determine whether to proceed to investigate a clusterproceed to investigate a cluster

identification of a identification of a single cancer type;single cancer type; biological plausibility biological plausibility adequate adequate latencylatency political pressure; political pressure; identification of a common cancer in an unusual identification of a common cancer in an unusual age group; age group; identification of a rare cancer; identification of a rare cancer; identification of exposure to a carcinogenic identification of exposure to a carcinogenic substance; substance; elevated ratio of observed/expected confirmed elevated ratio of observed/expected confirmed cancer cases cancer cases

Guidelines for Investigating Guidelines for Investigating Clusters of Health Events Clusters of Health Events

CDCCDC

GUIDELINES FOR A GUIDELINES FOR A SYSTEMATIC APPROACH SYSTEMATIC APPROACH

The issue of The issue of increased frequencyincreased frequency of occurrence of occurrence should be separated from the issue of potential should be separated from the issue of potential etiologiesetiologies

Stage 1. Collect information. Stage 1. Collect information.

A variety of diagnoses speaks against a A variety of diagnoses speaks against a common origin common origin

Stage 2. Assessment Stage 2. Assessment

Separate two concurrent issues: Separate two concurrent issues: 1. whether an excess has occurred and 1. whether an excess has occurred and 2. whether the excess can be linked 2. whether the excess can be linked etiologically to some exposure etiologically to some exposure

Stage 3. Feasibility Study Stage 3. Feasibility Study

Conduct Conduct detailed literaturedetailed literature search with search with particular attention to known and putative particular attention to known and putative causes of the health effect of concern. causes of the health effect of concern. Consider an Consider an appropriate studyappropriate study design designDetermine Determine what data should be collectedwhat data should be collected on on cases and controls, including laboratory cases and controls, including laboratory measurements. Determine the nature, extent, measurements. Determine the nature, extent, and frequency of methods used for and frequency of methods used for environmental measurementsenvironmental measurements. . Determine Determine hypotheseshypotheses to be tested and to be tested and powerpower to detect differencesto detect differences

Stage 4. Etiologic Investigation Stage 4. Etiologic Investigation

PurposePurpose: Perform an etiologic investigation of a : Perform an etiologic investigation of a potential disease- exposure relationship.potential disease- exposure relationship.

Types of studiesTypes of studies: : Retrospective cohort Retrospective cohort mortalitymortality-most common-most commonCase/control-good for rare diseasesCase/control-good for rare diseasesCross sectional-good for Cross sectional-good for morbiditymorbidity assessments assessments

Cluster InvestigationsCluster Investigations

A number of problems are encountered in A number of problems are encountered in the study of clusters. the study of clusters. The health events being investigated The health events being investigated (often morbidity or mortality) are usually (often morbidity or mortality) are usually rare, and increases of these events tend to rare, and increases of these events tend to be small and may occur over a long be small and may occur over a long period. period. A major complication is that A major complication is that most clusters most clusters are chance events are chance events

CDCCDC

aa) provides a centralized, coordinated response ) provides a centralized, coordinated response system for cancer cluster inquiries, system for cancer cluster inquiries,

bb) supports an electronic cancer cluster list ) supports an electronic cancer cluster list server, server,

cc) maintains an informative web page, and) maintains an informative web page, and

dd) provides support to states, ranging from ) provides support to states, ranging from laboratory analysis to epidemiologic assistance laboratory analysis to epidemiologic assistance and expertise and expertise

Occupational/Environmental Occupational/Environmental epidemiologyepidemiology

Goal: Evaluate Goal: Evaluate exposure- diseaseexposure- disease relationshipsrelationships

Strengths: risks in humans –no need to Strengths: risks in humans –no need to extrapolate from animal studiesextrapolate from animal studies

Evaluate consequences of exposure in Evaluate consequences of exposure in which it actually occurswhich it actually occurs

Occupational epidemiologyOccupational epidemiology

Limitations:Limitations:

Low level risks difficult to identifyLow level risks difficult to identify

Small increases in risk may be affected Small increases in risk may be affected by bias, confounding and chanceby bias, confounding and chance

Long latency with cancerLong latency with cancer

Inadequate exposure categorizationInadequate exposure categorization

Measures of effectMeasures of effect

RATESRATES are the central metric used to assess disease are the central metric used to assess disease occurrence in occupational cohort studiesoccurrence in occupational cohort studiesComparison of a study group to a reference group- Comparison of a study group to a reference group- usually done by assessing the ratio of their respective usually done by assessing the ratio of their respective standardizedstandardized rates ratesone frequently used outcome measure is the one frequently used outcome measure is the Standardized Mortality Ratio (SMR)Standardized Mortality Ratio (SMR)SMRSMR: ratio of the sum of the observed events in the : ratio of the sum of the observed events in the study group to the sum of the expected numbers in the study group to the sum of the expected numbers in the study group; expected numbers are based on study group; expected numbers are based on standardizedstandardized rates in the reference group rates in the reference group

Example of use of Standardized Example of use of Standardized Mortality Ratio (SMR)Mortality Ratio (SMR)

Null hypothesis (HNull hypothesis (H00): no effect of exposure): no effect of exposure

SMR for lung cancer of 1.8SMR for lung cancer of 1.8

80% excess compared to reference 80% excess compared to reference populationpopulation

P<.05; 95 % Confidence Intervals; (1.2-P<.05; 95 % Confidence Intervals; (1.2-2.3); thus, statistically significant2.3); thus, statistically significant

? Role of confounding and bias? Role of confounding and bias

Interpreting SMR resultsInterpreting SMR results

Chance: P values; p<.05 and 95% Chance: P values; p<.05 and 95% confidence intervals (reflect uncertainty to confidence intervals (reflect uncertainty to random error-not confoundingrandom error-not confounding

Bias: selection, recallBias: selection, recall

Confounding (understates the uncertainty Confounding (understates the uncertainty about a true “effect”: smoking and lung about a true “effect”: smoking and lung cancer (biases SMR upward); alcohol and cancer (biases SMR upward); alcohol and liver disease, diabetes and neuropathyliver disease, diabetes and neuropathy

Occupational epidemiologyOccupational epidemiology

Reference population – of paramount Reference population – of paramount importance-importance- ideally should match study group in ideally should match study group in all important demographics characteristics aside all important demographics characteristics aside from “exposure” of interestfrom “exposure” of interestType of reference populations: General Type of reference populations: General (national, state, county) population disease rates (national, state, county) population disease rates categorized by age, gender, race, geographical categorized by age, gender, race, geographical area, calendar timearea, calendar timeKey point: reference and study populations Key point: reference and study populations should be identical as much as possible should be identical as much as possible aside from the exposure of interestaside from the exposure of interest

Reference populationReference population

Lung cancer and carbon black: German Lung cancer and carbon black: German studystudy

SMR: 2.2 (national rates)SMR: 2.2 (national rates)

SMR: 1.8 (local rates)SMR: 1.8 (local rates)

PRINCIPLES IN EVALUATING WHETHER A PRINCIPLES IN EVALUATING WHETHER A DISEASE IS ENVIRONMENTALLY RELATED*DISEASE IS ENVIRONMENTALLY RELATED*

Strength of associationStrength of associationConsistency of results; does the Consistency of results; does the association hold in different settings and association hold in different settings and among different study groups?among different study groups?Specificity: How closely are the exposure Specificity: How closely are the exposure factors and health outcome associated?factors and health outcome associated?Temporality: Does exposure precede Temporality: Does exposure precede disease outcome. Is latency involved?disease outcome. Is latency involved?

* * From Hill AB. The environment and disease: From Hill AB. The environment and disease: association or causation? association or causation? Proc R Soc Med 1965: Proc R Soc Med 1965: 58: 295-30058: 295-300

PRINCIPLES IN EVALUATING WHETHER PRINCIPLES IN EVALUATING WHETHER A DISEASE IS WORK RELATEDA DISEASE IS WORK RELATED

Biological gradient: does a dose- response Biological gradient: does a dose- response relationship exist?relationship exist?Plausibility: Does the association make Plausibility: Does the association make sense biologically?sense biologically?Coherence: Is the association consistent Coherence: Is the association consistent with the natural history and biology of the with the natural history and biology of the disease?disease?Experimental Evidence: Does experimental Experimental Evidence: Does experimental evidence support the hypothesis of an evidence support the hypothesis of an association?association?Analogy: Are there other examples with Analogy: Are there other examples with similar risk factors and outcome?similar risk factors and outcome?

Interpreting occupational Interpreting occupational epidemiological literatureepidemiological literature

Study design-Study design- is the hypothesis clearly defined? is the hypothesis clearly defined?MethodsMethods: are they adequate to evaluate the hypothesis?: are they adequate to evaluate the hypothesis?

How was exposure assessed?How was exposure assessed?How was the cohort defined? Is there adequate How was the cohort defined? Is there adequate ascertainment of vital status?ascertainment of vital status?What is the reference population? Is it an appropriate What is the reference population? Is it an appropriate comparison group for the cohort being studied?comparison group for the cohort being studied?

ResultsResultsWhat statistical methods were used?What statistical methods were used?How was chance assessed?How was chance assessed?How was confounding controlled?How was confounding controlled?How were potential biases addressed in the analysis, such as How were potential biases addressed in the analysis, such as selection bias and confounding?selection bias and confounding?

Interpreting occupational Interpreting occupational epidemiological literatureepidemiological literature

DiscussionDiscussionHave the authors contrasted their results with Have the authors contrasted their results with previous scientific literature?previous scientific literature?Have the authors discussed the limitations of their Have the authors discussed the limitations of their study?study?What further work can be done to more fully define What further work can be done to more fully define the results?the results?

ConclusionConclusionHave the authors properly assessed the results Have the authors properly assessed the results based on their own analysis ands limitations in based on their own analysis ands limitations in light of previous literature?light of previous literature?

Renal cell carcinoma Renal cell carcinoma

Renal cell carcinomaRenal cell carcinoma

Incidence: increased diagnostic Incidence: increased diagnostic accuracy :CT, ultrasound, MRIaccuracy :CT, ultrasound, MRI

Obesity, hypertension, smoking: Obesity, hypertension, smoking: established risk factorsestablished risk factors

Occupational: ? TCE, solventsOccupational: ? TCE, solvents

PlantPlant

1200 employees1200 employees

Produces plastics, TDI, benzene, Produces plastics, TDI, benzene, phosgenephosgene

Built in 1950sBuilt in 1950s

Product manufacturing and researchProduct manufacturing and research

Is there an excess ?Is there an excess ?

Expected rate of renal cancer: 12/100,000Expected rate of renal cancer: 12/100,000

Preliminary analysis:Preliminary analysis:

From 1990-2006: 1200 employees for 16 From 1990-2006: 1200 employees for 16 years :~20,000 person years: 7 observedyears :~20,000 person years: 7 observed

35 observed over 100,000 person years35 observed over 100,000 person years

12 expected 12 expected

Thus: ~ 3 fold excess???Thus: ~ 3 fold excess???

Disease clusters and studentsDisease clusters and students

Be critical of media reportsBe critical of media reports

Systematic approach to evaluationsSystematic approach to evaluations

Recognize role of health departmentsRecognize role of health departments

Most clusters are statistical artifactsMost clusters are statistical artifacts

Interpret epidemiology studies cautiouslyInterpret epidemiology studies cautiously

Be attentive to possible new links between Be attentive to possible new links between exposure and disease ) eg. nanoparticles, exposure and disease ) eg. nanoparticles, new materials etcnew materials etc

DiscussionDiscussion

Next step?Next step?