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Cohort studieshv
 

Cohort studieshv

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  • Author profile :-After medical graduation, worked for 17 years in the field as primary care physician in primary health centres, area hospitals, mobile medical units, cholera combat team, filarial control project, casualty department, divisional secondary care hospitals Then completed post graduation in public health medicine/preventive &social medicine &epidemiology and teaching medical graduates and post graduates, nursing students, physiotherapy students, primary care personnel for the last 15 years. At present ,working as Professor & Head of the department of Community medicine & Epidemiology contributing to the cause of epidemiological spread and growth in India as Indian super course epidemiology developer . Other TWELVE super course lectures of mine can be accessed at www. pitt.edu/~super1/faculty/lecturers/htm
  • But not the true experimental studies (as they lack randomization and intervention or manipulation).
  • The choice of analytical design depends upon the feasibility, the setting and the requirements of the study . Both the case control and cohort designs are having their own merits and demerits. While the bias is the main problem with the former, follow up , attrition and ethical problems are the hurdles for the latter. Some believe that case control study is the initial step for establishing causality later to be followed by cohort study. But case control technique will be uniquely useful in certain circumstances.
  • The follow up period depends on the incubation period of disease. To improve the validity, a comparative cohort without the suspected exposure is also observed and followed for the incidence and risks. The results are compared with those of study cohort and analyzed in a similar manner.
  • IF A/A+B > C/ C+D, AND THE RELATIVE RISK IS HIGH, THE ASSOCIATION MAY BE A CAUSAL ONE
  • RATES are calculated which are appropriate and feasible to a particular study. When calculated for specific time intervals, caution is observed with regard to time factor and particularly to the exact population involved under study. Time-person years will be a better denominator not only in those instances but also most of the times as there is an imminent danger of loss of the cohort subjects at any time. Cumulative incidence speaks better than crude incidence in studies of longer duration.
  • COMPARISON COHORT GROUP OF PERSONS WHO ARE NOT EXPOSED TO THE SUSPECTED CAUSE BUT HAS A CHANCE OF GETTING THE DISEASE IN QUESTION e.g. NON-SMOKERS COHORT.
  • FOR SHORT PERIOD STUDIES:- Incidence rate (number of new cases / population at risk) Instantaneous incidence rate (new cases per unit time relative to disease-free population at risk at time t.) FOR LONGER STUDIES:- Cumulative incidence (disease risk during a specific interval/length of that interval) Cumulative incidence rate (summing the products of incidence rate and interval length over a series of intervals)
  • Standardized morbidity rate (number of the cases observed /number of cases expected/ from the standard rates as applied to the age/time specific person-years of observation )
  • If incidence rates are higher in the exposed cohort when compared to non-exposed cohort with high Relative risk, the association may be a causal one.
  • Cohort design commences from the suspected factor and not from the disease as in case control study. It proceeds prospectively in a forward direction from the cause towards the occurrence of the expected diseasedisease
  • It is called follow-up study as cohort, which is exposed to a suspected factor but not yet developed the disease, is observed and followed over time, Follow up study may be misleading and should be very carefully used as follow up carried out for disease outcomes or treatment outcomes is not a cohort study. For example, if a tuberculosis patient is followed up during his treatment for its outcome, it is not a cohort study.
  • It can be commenced in the past or present, can be carried onto the present or extended into the future according to the needs of the study. Sometimes, case control design may also be nested in a cohort design. Cohort design is flexible enough to suit the needs of both the study question and the investigator’s time and resources.
  • Study cohort or the exposure cohort is a group of persons exposed to the cause and in whom we are expecting the development of the disease in question e.g. smokers cohort.
  • It is essential, before commencing the study, to exclude from among the study Group of exposed persons, Those persons already having the disease in question in any form, either in an incipient stage at cellular or biochemical level or in its early unrecognizable stages
  • Study cohort can be a homogeneous with regard to its exposure e.g. all are smoking 2 packets of cigarettes per day or heterogeneous like some people smoking 2 packets, some smoking 3 packets and some smoking 4 packets per day. When heterogeneous, the exposure in the subgroups has to be carefully assessed and analyzed to protect the internal validity. .
  • Special population groups (doctors) or exposure groups (occupational groups) are taken for the study, as these are easily available and follow up will be easier. But they may reduce the external validity (generalization) to a certain extent, as these groups may not represent the general population.
  • If the study cohort is heterogeneous in its exposure status and possessing different subgroups with different levels of exposure , these subgroups can be compared with each other regarding their extent of exposure and contributions (risks) to cause the disease. For example, number of cases occurred in people smoking 2- packets /day can be compared with those developed in people smoking 4-packets/ day.
  • A separate non –exposed cohort is taken from the same special group as study cohort or from the general population and then compared with the study cohort. It is preferable to choose the external comparison cohort from the same population from which the study cohort is drawn as it enhances the elimination and neutralization of the different variables present in both the groups and increases the validity.
  • When internal or external comparison is not possible or feasible to some reasons the rates are compared with the general population rates . In case of urgency, when the external comparison cohorts cannot be formed or not available for comparison, the comparison with the existing population incidence and risks will be useful
  • Study and comparison cohorts can be chosen from special groups, exposure groups, hospital registers, medical records, and death certificates etc. When choosing the special groups like doctors or occupation groups, special care to be taken regarding their representative ness When registers and records were used for selecting a cohort e.g. historical cohort, relevant and complete records if available are to be used. Naturally, selection bias will creep in, as there is no randomization.
  • Both the study and comparison cohorts are to be selected from the same population to which the results are to be extrapolated to enhance the generalizability or external validity. In a cohort design, usually exposed groups are chosen and followed for the incidence of expected For exposure groups, degree and nature of exposure are to be considered.
  • To be collected in a similar fashion from both the groups regarding their exposure status and vulnerability to the disease or expected outcome This base-line information serves as a benchmark for future analysis and other considerations. Sources of information vary according to the availability and feasibility. They may be records and registers, medical examinations and investigations , interviews and environmental influence or contributions. Time, duration and extent of collection of data not only determine the design of cohort study but also influence the validity of the study.
  • Collection through medical records and registers are to be carefully carried out considering the period of recording, quality and applicability. This is truer when information about investigations or tests is gathered for the study as their methodology and significance may change with the time. Study subjects may like the investigator or interested in the study and hence may give false or exaggerated information. Collection of information about dose-response relationship is vital and unless it is collected meticulously, study looses its validity.
  • While gathering information, it is imperative to select the sources of good or high quality. If the technique employed is interviewing, either direct or indirect, equal time and same questions (usually open-ended) should be applied for both the groups. Bias may creep in if interviewer is not careful about the details of the collection of data.
  • To minimize loss, not only taking the informed consent but also enlisting the commitment to continue and cooperate in the study is to be given maximum consideration at the commencement of study itself. If lost during follow up, every effort must be made to trace and include them. The information of the lost persons either from registers (e.g. death registers) or from the neighbors and relatives is also to be considered at the time of analysis. It is always tried to keep the non-response at a low level to improve the validity.
  • Cohort study is an incidence study. Hence the exposed and unexposed groups have to be followed for the occurrence of new cases or expected outcomes or end-points. . These end-points have to be standardized even before the follow-up is initiated. Any difference in endpoints will result in loss of validity The end points or outcomes expected are to be defined clearly for observation during follow up. These should be the same for both the cohorts otherwise analysis and inference will be false. Both the cohorts have to be followed up in similar fashion without any difference. The duration for follow up depends upon both the induction (initiation or onset of disease) and incubation periods (period when clinically appears) of the disease in question. It may be longer as in cancers, usually years. .
  • GOOD FOLLOW-UP INCREASES THE INTERNAL VALIDITY OF THE STUDY AS IT MINIMIZES ATTRITION. FOLLOW-UP TECHNIQUES AND THEIR DURATION OF APPLICATION SHOULD BE SIMILAR TO BOTH THE COHORTS Cohort subjects can be followed in several ways either through direct personal interviews or examinations or indirectly through mailed questionnaires, videoconference, neighbors, friends and relatives etc. Lost persons can be traced through the letters, from their relatives and friends. Attrition should be restricted to minimum possible extent. Migrated cohort subjects can also be traced through travel and immigration authorities. Information about the dead persons regarding the cause of death can be obtained either from local or regional mortality registers or death certificates. Follow-up through the periodical medical examinations and mailed questionnaires is usually practiced. Follow-up techniques and their duration of application should be similar to both the cohorts. Good follow-up increases the internal validity of the study as it minimizes attrition.
  • Diseases with high incidence, we choose for this study and the study needs large group of people. The follow-up of large group (usual in cohort study) over a longer period of time is difficult. Several problems, like resource crunch, time scarcity, paucity of trained personnel can occur or even the investigator may die. Hence, unless these requirements are adequately met, the cohort study should not be chosen. Moreover, the attrition , loss on follow up (due to deaths, change in addresses, non-cooperation and withdrawal) is another major draw back with this design. If this loss on follow-up is significant, the internal validity suffers.
  • THE FOUR STEPS OF CONDUCTING THESE STUDIES CAN BE SEEN COHORT FORMATION COLLECTION OF BASE LINE OINFORMATION FOLLOW UP ANALYSIS
  • STUDY COHORT includes those women with: - 1) Natural menopause (1479)2) Hysterectomy +bilateral oopherectomy (3241) CONTROL COHORT : -includes those women with :-1) Hysterectomy +unilateral 2) X-ray &irradiation group EXCLUDED: - 1) Prior mastectomy2) Prior breast cancer3) Treated for Pelvic malignancy4) Natural menopause <405) Premature removal of ovaries
  • III STEP:- FOLLOW-UP For 21-42 years, cohorts were followed through various sources like health records, death certificates and tumor registry. IV STEP:- ANALYSIS Incidence is measured directly from the number of new cases occurred out of the total number in the cohort. Risk is measured by calculating Relative risk, cumulative risk, estimated cumulative risk and aetiological fraction
  • Doctors are chosen, as they will be ---- more interested in health matters, cooperate well, give accurate information easily accessible for follow-up.
  • III STEP:- FOLLOW-UP Further mailed questionnaires were sent twice to the women and thrice to the male doctors. Information about death was obtained from Registrar General of U.K, General medical register, British Medical association and from the underlying condition noted in the death certificates. IV STEP:- ANALYSIS Age specific rates (35-74 years)= 17.4% in non-smokers versus 24.9% in smokers RR =1.4% A.R=6.4%
  • PROSPECTIVE STUDY Conducted at Framingham town, Messachusets, to find out the association between the coronary artery disease and the risk factors like high serum cholesterol, hypertension, smoking etc. Framingham town was selected as it is compact, economically stable, more cooperative and represents U.S. population to a larger extent. (though sample is only 68%) In 1948, a Cardiovascular demonstration programme was carried out in Framingham town. Later, in the year 1951, it was converted into a cohort study. The volunteers who have attended for initial demonstration programme were also included in the study.
  • III STEP:- FOLLOW-UP Cohorts were followed for 20 years by means of repeated bi –annual examinations. Loss of cohort was more during the first 14 years (85%) due to incapacitation and migration. Indirectly, follow-up was carried through the secondary sources i.e. from the Framingham hospital records and town regional mortality registers . IV STEP:- ANALYSIS Average annual incidence= 0.0125 R.R. with high cholesterol= 1.81-3.43
  • LARGE SIZE IOF COHORTS WILL BE DIFFICULT TO FOLLOW WITHOUT LOSS. LOSS OF MORE THAN 10% WILL REDUCE THE VALIDITY, THOUGH ATTRITION IS UNAVOIDABLE . ETHICALLY AS IT IS NOT ADVISABLE AND HUMANE TO LEAVE THE THE PATIENTS TO GET THE DISEASE WITHOUT PREVENTION IS NOT CORRECT. HENCE,NECESSARY PERMISSIONS FROM ETHICAL COMMITTEE IS ESSENTIAL

Cohort studieshv Cohort studieshv Presentation Transcript

  • COHORT STUDIES Dr. A. K. AVASARALA MBBS, M.D. PROFESSOR & HEAD DEPT OF COMMUNITY MEDICINE & EPIDEMIOLOGY PRATHIMA INSTITUTE OF MEDICAL SCIENCES, KARIMNAGAR, A.P. INDIA: +91505417 avasarala@yahoo.com
  • LEARNING OBJECTIVES LEARNER SHOULD BE ABLE TO KNOW AT THE END OF THIS LECTURE • WHAT IS A COHORT STUDY? • WHEN TO CONDUCT A COHORT STUDY? • WHAT TYPES OF COHORT STUDIES ARE AVAILABLE? • HOW TO TEST THE HYPOTHESIS BY MEANS OF A COHORT STUDY?
  • PERFORMANCE OBJECTIVES LEARNER SHOULD BE ABLE TO • CONDUCT THE COHORT STUDY FOR ANY NEW HYPOTHESIS WHICH HE IS THINKING CAUSALLY RELATED • APPLY THIS ANALYTICAL METHOD WHEN SITUATION DEMANDS
  • COHORT STUDIES • ANALYTICAL OBSERVATIONAL STUDIES • ALMOST SIMILAR TO THE EXPERIMENTAL STUDIES
  • WHAT IS A COHORT? • COHORT IS A GROUP HAVING A COMMON CHARACTERISTIC • e.g. A SMOKER’S COHORT MEANS ALL ARE SMOKERS IN THAT GROUP
  • PURPOSE • THEY TRY TO PROVE THE CAUSAL INFLUENCE ON THE DISEASE OUTCOME IN A FORWARD DIRECTION FROM CAUSE TO THE EFFECT AND IN A COMPARATIVE FASHION
  • INDICATIONS • FOR FURTHER CONFIRMATION OF CAUSAL HYPOTHESIS ALREADY SUGGESTED BY CASE CONTROL DESIGN • COHORT METHOD IS DIRECTLY CARRIED OUT WHEN INDEX OF CAUSAL SUSPICION OF HYPOTHESIS IS VERY GREAT
  • COHORT STUDY DESIGN • A COHORT, WHICH IS EXPOSED TO A SUSPECTED FACTOR BUT NOT YET DEVELOPED THE DISEASE, IS OBSERVED AND FOLLOWED OVER TIME • THEN, THE INCIDENCE OF THE DISEASE, THE EXPOSURE RISK, THE DISEASE RISK AND THE POPULATION RISKS ARE MEASURED DIRECTLY
  • COHORT STUDY DESIGN EXPOSURE / SUSP- ECTED FACTOR (SMOKING) DISEASE DEVELOPED (LUNG CANCER PRESENT) DISEASE NOT DEVELOPED (LUNG CANCER ABSENT) TOTAL PRESENT a b a+b ABSENT c a+c d b +d c+d a+b+c+d
  • ANALYSIS • IN A SIMILAR MANNER BOTH FOR THE STUDY COHORT AND COMPARISON COHORT • DUE CONSIDERATION TO • THE LOSS ON FOLLOW-UP • THE SECONDARY INFORMATION OBTAINED FROM OTHER SOURCES (FAMILY MEMBERS AND NEIGHBORS) WITH REGARD TO ATTRITION
  • COMPARISON COHORT THE COMPARISON CAN BE DONE 1. INTERNALLY, 2. EXTERNALLY OR 3. WITH GENERAL POPULATION RATES.
  • INCIDENCE RATES • INCIDENCE AMONG THE EXPOSED (NEW CASES AMONG THE SMOKERS) = (A/ A+B) • INCIDENCE AMONG THE NON-EXPOSED (NEW CASES AMONG THE NON- SMOKERS) = (C/ C+D )
  • RISKS • EXCESS RISK (ER) = (A /A+B) – (C / C+D) • RELATIVE RISK OR RISK RATIO (RR) = [A / (A+B)] / [C / C +D)] (incidence in the exposed (smokers) / incidence in the non-exposed (non- smokers) • Attributable risk (AR = excess risk/ incidence among the exposed (AETIOLOGICAL FRACTION) • Population attributable risk (PAR) = incidence in the total population minus incidence among the non-exposed.
  • SPECIAL GROUPS GENERAL POPULATION STUDY COHORT (EXPOSED GROUP) COMPARISON COHORT (NOT EXPOSED) INTERNAL OR EXTERNAL COMPARISON OR WITH THE GENERAL POPULATION RATES FOLLOW UP FOR INCIDENCE OF NEW CASES INCIDENCE & RISK MEASUREMENT IN BOTH GROUPS RR, EXCESS RISK, AR AND PAR METHODOLOGY
  • PROSPECTIVE OR FORWARD LOOKING STUDY SUSPECTED CAUSE EFFECT/ DISEASE FORWARD
  • FOLLOW UP STUDY • COHORTS ARE FOLLOWED TILL NEW CASES ARE OBSERVED HENCE THE NAME
  • TYPES 1. CURRENT COHORT OR PRESENT COHORT (USUAL COHORT) 2. HISTORICAL COHORT (STUDY COMMENCED AT A POINT OF TIME IN THE PAST UNTO THE PRESENT) 3. RETROSPECTIVE – PROSPECTIVE COHORT (COMMENCED IN THE PAST AND EXTENDED INTO THE FUTURE)
  • STEPS IN CONDUCTING COHORT STUDY 1. FORMATION OF STUDY AND COMPARISON COHORTS 2. COLLECTING BASELINE INFORMATION 3. FOLLOW-UP 4. ANALYSIS FOR INCIDENCE AND RISK MEASUREMENT IN BOTH THE GROUPS AND COMPARISON
  • FORMATION OF STUDY COHORT EXCLUDE FROM THE STUDY • DISEASED PERSONS • EXPOSED PERSONS
  • EXPOSURE CONSIDERATIONS • HOMOGENEOUS COHORT • HETEROGENEOUS COHORT
  • SOURCES OF STUDY COHORT 1. GENERAL POPULATION 2. SOME SELECTED GROUPS LIKE DOCTORS, LAWYERS, etc 3. SPECIAL EXPOSURE GROUPS LIKE ASBESTOS WORKERS, MINERS, etc.
  • INTERNAL COMPARISON DIFFERENT SUBGROUPS OF SAME HETEROGENEOUS COHORT ARE COMPARED
  • EXTERNAL COMPARISON • STUDY COHORT COMPARED WITH A SEPARATE NON- EXPOSED COHORT
  • COMPARISON WITH THE GENERAL POPULATION RATES
  • IDEAL COHORT WHILE SELECTING THE COHORT, • A STABLE COHORT, • A COOPERATIVE COHORT, • A COMMITTED COHORT AND • A WELL-INFORMED COHORT IS TO BE USUALLY SELECTED.
  • COHORT SELECTION TECHNIQUES • SPECIAL GROUPS, • EXPOSURE GROUPS, • HOSPITAL REGISTERS, • MEDICAL RECORDS, AND •DEATH CERTIFICATES, ETC.
  • COHORT SELECTION TECHNIQUES • SELECT BOTH COHORTS FROM SAME POPULATION • SELECT THE EXPOSED GROUPS • MEASURE THE DEGREE AND DURATION OF EXPOSURE • DO FOLLOW UP FOR INCIDENCE OF OUTCOMES.
  • COLLECTION OF BASE LINECOLLECTION OF BASE LINE INFORMATIONINFORMATION • COLLECTED IN A SIMILAR FASHION FROM BOTH THE GROUPS • SERVES AS A BENCHMARK FOR FUTURE ANALYSIS • TIME, DURATION AND EXTENT OF COLLECTION OF DATA TO BE CONSIDERED.
  • DATA COLLECTION TECHNIQUES • THE PERIOD OF RECORDING, QUALITY AND APPLICABILITY OF RECORDS • DOSE-RESPONSE RELATIONSHIP
  • DATA COLLECTION TECHNIQUES-2 • SOURCES OF GOOD OR HIGH QUALITY • QUESTIONS OF EITHER DIRECT OR INDIRECT, EQUAL TIME AND SAME QUESTIONS (USUALLY OPEN-ENDED) • INTERVIEWER BIAS
  • ATTRITION REDUCTION • BY TAKING THE INFORMED CONSENT • BY ENLISTING THE COMMITMENT TO CONTINUE AND COOPERATE IN THE STUDY • BY TRACING THE LOST ONES AND INCLUDE THEM • BY CONSIDERING THE INFORMATION OF THE LOST PERSONS AT THE TIME OF ANALYSIS • BY KEEPING THE NON-RESPONSE AT A LOW LEVEL TO IMPROVE THE VALIDITY
  • FOLLOW UP • WELLDEFINED AND STANDARDIZED END POINTS FOR PROPER FOLLOW UP • SIMILAR END POINTS FOR BOTH COHORTS • DURATION OF FOLLOW UP
  • FOLLOW-UP TECHNIQUES 1. PERIODICAL MEDICAL EXAMINATIONS AND MAILED QUESTIONNAIRES 2. DIRECT PERSONAL INTERVIEWS OR EXAMINATIONS 3. VIDEOCONFERENCE, NEIGHBORS, FRIENDS AND RELATIVES, ETC 4. LOST PERSONS CAN BE TRACED THROUGH THE LETTERS, FROM THEIR RELATIVES AND FRIENDS 5. MIGRATED COHORT SUBJECTS CAN ALSO BE TRACED THROUGH TRAVEL AND IMMIGRATION AUTHORITIES 1. DEAD PERSONS - LOCAL OR REGIONAL MORTALITY REGISTERS OR DEATH CERTIFICATES
  • PROBLEMS FOR FOLLOW UP • THE FOLLOW-UP OF LARGE GROUP (USUAL IN COHORT STUDY) • RESOURCE CRUNCH • TIME SCARCITY • PAUCITY OF TRAINED PERSONNEL • ATTRITION, LOSS ON FOLLOW UP
  • EXAMPLES 1.HISTORICAL COHORT STUDY ON ARTIFICIAL MENOPAUSE AND BREAST CANCER IN BOSTON AREA (1940) 2.PROSPECTIVE STUDY ON SMOKING AND MORTALITY IN BRITISH DOCTORS (1951) 3. FRAMINGHAM HEART STUDY (1951)
  • ARTIFICIAL MENOPAUSE AND BREAST CANCER IN BOSTON AREA (1940) 1ST STEP - FORMATION OF COHORTS • WOMEN AGED 55 YEARS AND YOUNGER AND TREATED IN TWO BOSTON HOSPITALS BETWEEN 1920 AND 1940 ARE SELECTED FOR THE STUDY. DETAILS WERE COLLECTED FROM THE PATHOLOGICAL RECORDS AND DEATH CERTIFICATES.
  • II STEP - COLLECTING INFORMATION • FROM THE AVAILABLE SURGICAL & PATHOLOGICAL RECORDS OF HIGH QUALITY • INFORMATION IS ALSO AVAILABLE ABOUT THE CO-VARIABLES ARTIFICIAL MENOPAUSE AND BREAST CANCER IN BOSTON AREA (1940)
  • PROSPECTIVE STUDY ON SMOKING AND MORTALITY IN BRITISH DOCTORS (1951) 1ST STEP - FORMATION OF COHORTS 40637 BRITISH DOCTORS WERE SELECTED FROM BRITISH MEDICAL REGISTER.
  • PROSPECTIVE STUDY ON SMOKING AND MORTALITY IN BRITISH DOCTORS (1951) II STEP- COLLECTING INFORMATION • MAILED QUESTIONNAIRES WERE USED FOR OBTAINING INFORMATION. • ADDITIONAL QUESTIONNAIRES WERE SENT TO KNOW MORE ABOUT A) SMOKING, AGE WHEN SMOKING STARTED, NATURE, DURATION, CURRENT STATUS B) IF STOPPED, THE
  • FRAMINGHAM HEART STUDY (1951) • 1ST STEP - FORMATION OF COHORTS • TOTALLY, 5209 INDIVIDUALS WERE REGISTERED FOR THE STUDY.
  • FRAMINGHAM HEART STUDY (1951) II STEP - COLLECTING INFORMATION • BY INITIAL EXAMINATION AND DETAILED INTERVIEWS, THE DATA WAS GATHERED. • 82 PERSONS WHO HAD CARDIOVASCULAR EVENT AT THE INITIAL EXAMINATION WERE EXCLUDED OUT OF 5209 SUBJECTS. • THE REMAINING 5127 SUBJECTS WERE CLASSIFIED ACCORDING TO THE RISK FACTORS LIKE HIGH SERUM CHOLESTEROL, SMOKING, HYPERTENSION, BODY MASS INDEX AND THE PRESENCE OF OTHER DISEASES.
  • HURDLES IN COHORT STUDIES • FOLLOW UP • ATTRITION • ETHICAL PROBLEMS
  • SUMMARY THOUGH COHORT STUDY IS • TIME CONSUMING • EXPENSIVE • LESS BIASED IT IS BETTER ANALYTICAL METHOD TO PROVE CAUSAL HYPOTHESIS AND DIRECT RISK MEASURE MENT • •
  • REFERENCES • Brian Mac Mahan - Epidemiology -principles & methods • Roger Detels, James Mc Even -Oxford Text Book of Public Health • Maxcy-Rosenau-Last, Public Health & Preventive medicine