1. Basic Ideas and Terminology Ettore Beghi Institute for Pharmacological Research Mario Negri, Milano, Italy

2. EPIDEMIOLOGY Discipline which studies the frequency and the determinants of a given disease in a well-defined population

3. PRINCIPAL AIMS OF EPIDEMIOLOGY Calculation of the distribution of a disease in a given populationCalculation of the distribution of a disease in a given population Definition of risk factors and etiological factorsDefinition of risk factors and etiological factors Development of strategies for disease preventionDevelopment of strategies for disease prevention Planning of health assistancePlanning of health assistance

4. RELEVANT ISSUES IN EPIDEMIOLOGICAL STUDIES Representativeness of the study population Sources of cases Diagnosis (disease definition) Criteria for the assessment of causality Criteria for the assessment of disease course and impact of treatments

5. CLASSIFICATION OF EPIDEMIOLOGICAL STUDIES DESCRIPTIVE (Population Survey)DESCRIPTIVE (Population Survey) In populationsIn populations Frequency of diseaseFrequency of disease Distribution of disease - time - place - personDistribution of disease - time - place - person ANALYTIC (Case-control & Cohort Studies)ANALYTIC (Case-control & Cohort Studies) In individualsIn individuals Test casual hypothesesTest casual hypotheses Uncontrolled assignmentUncontrolled assignment

6. SAMPLING AND BIAS Targetpopulation Intendedsample Actualsample MeasurementsHypothesistesting Samplingbiases

7. BIAS Any systematic error in the design, conduct, or analysis of a study that results in a mistaken estimate of an exposure’s effect on the risk of disease” Schlesselman, 1982 “ Any systematic error in the design, conduct, or analysis of a study that results in a mistaken estimate of an exposure’s effect on the risk of disease” Schlesselman, 1982

8. DIAGRAM OF THE IDENTIFICATION OF A DISEASE IN THE GENERAL POPULATION Kurtzke, 1978

9. SOURCES OF NEUROLOGICAL DISEASES IN EPIDEMIOLOGICAL STUDIES Hospital records Ambulatory records Electrophysiological (EMG) records General practitioners’ files Disability records Lay associations Tertiary centers Death certificates Diagnosis related groups (DRGs) Disease registries

10. MEASURES OF DISEASE FREQUENCY INCIDENCE: Number of individuals in a population that become ill in a stated period of timeINCIDENCE: Number of individuals in a population that become ill in a stated period of time CUMULATIVE INCIDENCE: Proportion of a fixed population that becomes ill in a stated period of timeCUMULATIVE INCIDENCE: Proportion of a fixed population that becomes ill in a stated period of time PREVALENCE: Proportion of a population affected by a disease at a given point of timePREVALENCE: Proportion of a population affected by a disease at a given point of time MORTALITY: Number of individuals in a population died for a disease in a stated period of timeMORTALITY: Number of individuals in a population died for a disease in a stated period of time

11. PREVALENCE AND INCIDENCE Migratingin Migratingout Recovery Death Incidence Prevalence Prevalence = Incidence x average duration

12. DIAGNOSIS In the presence of diagnostic markers, the diagnostic process is simplified In the absence of diagnostic markers, the diagnosis is based on criteria implying a validation process and consensus among caring physicians

13. VALIDITY & RELIABILITY OF A DIAGNOSTIC TEST VALIDITY: capability to identify as positive those affected by the disease and as negative those not affected by the disease RELIABILITY: capability to obtain the same results in different occasions (1. Assessment of the same patient at different times; 2. Assessment of the same patient by different investigators)

14. VALIDITY OR ACCURACY True positives (a) False positives (b) False negatives (c) True negatives (d) Test Disease Positive Negative Positive Negative Sensitivity = True positives___ a__ PPV = True positives__ a__ Total with dis a+c Total tested pos a+b Total with dis a+c Total tested pos a+b Specificity = Total negatives__ d NPV = True negatives_ d__ Total without dis b+d Total tested neg c+d Total without dis b+d Total tested neg c+d

15. EPILEPTIFORM ABNORMALITIES General Population (n=1000) 53 40 955 Goodin & Aminoff, 1984 Sens = 60% Spec = 96% PPV = 7% NPV = 99%

16. EPILEPTIFORM ABNORMALITIES Epilepsy Center (n=1000) Goodin & Aminoff, 1984 260 240 20 480 Sens = 52% Spec = 96% VPP = 93% VPN = 67%

17. RELIABILITY RepeatabilityorAgreement Interobserver Intraobserver ObserverInstrumentObject

18. RELIABILITY True positives (a) False positives (b) False negatives (c) True negatives (d) Observer 1 Observer 2 Positive Negative Positive Negative Percent = Positive + negative agreements x 100 = a+d x 100 Agreement All observations N Kappa = Observed % agreement – Expected % agreement 100% - expected % agreement 100% - expected % agreement

19. KAPPA STATISTIC Parameter quantifying inter-rater agreement adjusting for chance agreement Its value ranges from 0 (chance agreement) to 1 (perfect agreement) As measured by kappa, agreement is poor ( 0.75)

20. INTER-OBSERVER AGREEMENT ON EEG CONCLUSIONS (Dichotomous Scale)(*) Report Observed agreement Expected agreement K (SE) Normal Standard EEG Sleep-depr EEG 0.730.730.500.54.47 (12).42 (13) Epileptiform Standard EEG Sleep-depr EEG 0.840.730.610.55.59 (13).41 (13) Van Donselaar et al, 1992 (*) Epileptiform = yes/no

21. OBSERVATIONAL CRITERIA FOR CAUSATION Temporal sequence Consistency of association Strength of association Biological gradient Specificity of association Biological plausibility Bradford-Hill, modified

22. DESIGN OF STUDIES ASSESSING DISEASE ETIOLOGY Schoenberg, 1983

23. ODDS RATIO (OR) Is a measure of association closely related to the relative risk (RR) Approximates the RR for rare diseases In the 2 x 2 tableDisease ExposureYes No YesAB NoCD Odds of exposure A/C among the cases and B/D in the controls; the ratio of the odds of exposure is:OR = (A/C) : (B/D) = AD / BC

24. RELATIVE RISK (RR) The relative risk is the ratio between the rate (risk) of disease in those with the exposure factor and the rate (risk) of disease in those without the factor RR = R (exp) / R (nexp)The relative risk is the ratio between the rate (risk) of disease in those with the exposure factor and the rate (risk) of disease in those without the factor RR = R (exp) / R (nexp)

25. RELEVANCE OF CAUSAL ASSOCIATION Relative Risk or Odds Ratio - Definite> 10 - Highly probable4-10 - Probable2.5-3.9 - Possible1.1-2.4Relative Risk or Odds Ratio - Definite> 10 - Highly probable4-10 - Probable2.5-3.9 - Possible1.1-2.4

26. Considerations When Studying Mortality Death among people with the conditionDeath among people with the condition Death due to the conditionDeath due to the condition Courtesy of Giancarlo Logroscino

27. STANDARDIZED MORTALITY RATIO The standardized mortality ratio or SMR, is a quantity, expressed as either a ratio or percentage quantifying the increase or decrease in mortality of a study cohort with respect to the general populationmortality

28. WHY TO CALCULATE THE STUDY POWER A study should be sufficiently large to avoid two important statistical errors: - Assuming that a difference between groups is real while it is a chance finding (alpha error) - Assuming that there are no differences between groups when a difference is actually present (beta error)A study should be sufficiently large to avoid two important statistical errors: - Assuming that a difference between groups is real while it is a chance finding (alpha error) - Assuming that there are no differences between groups when a difference is actually present (beta error)