University of North Carolina at Chapel Hill
                          School of Public Health
                         Department of Epidemiology
                   Fundamentals of Epidemiology (EPID 168)

                           Midterm Exam, Fall 1996
                             Answer Key - REVISED

Note:  this answer guide is especially detailed in order to provide thorough
explanations of the many concepts that exam touched on (including a few it
touched on unintentionally!).

   1.  The primary study question for this investigation concerns the
       relationship, suggested by previous studies, between exposure to
       pesticides and risk of birth anomalies in offspring.  The main exposure
       is pesticides (assessed by the surrogate measure of being licensed to
       apply certain pesticides).  The main outcome is birth anomalies in
       offspring, as recorded in birth records.

   2.  Classification of disease using manifestional criteria means grouping
       disorders on the basis of their having similar observable
       characteristics, e.g., symptoms, signs, behavior, laboratory findings,
       onset, course, prognosis, response to treatment.  Classification using
       causal criteria means grouping disorders on the basis of their having the
       same primary etiologic agent, which, of course, must have been previously
       identified.  The logic for analyzing the data in terms of organ systems
       (a manifestational criterion) is that anomalies occurring in the same
       organ system may be more likely to have the same (or closely related)
       etiology and therefore should exhibit stronger associations with the
       relevant exposure than would the more general category of all birth

   3.  The presentation of data concerning the occurrence of birth defects with
       regard to place (crop region) and time (seasons) is basic descriptive
       epidemiology.  The fact that the study was designed with a view to
       examining specific relationships of interest, which were then assessed
       with measures of association and statistical tests, derives from an
       analytic perspective.

   4.  C.  Passive surveillance

   5.  This study cannot really establish the temporal sequence of pesticide
       exposure and birth defects because a) half of births occurred before the
       data used for the pesticide certification (1991); and b) the time of
       actual exposure cannot be determined, since exposure is measured so
       indirectly and without the ability to establish when it occurred.

   6.  A. Any answer can be defended - the population attributable risk (PAR) is
       equal to the attributable risk multiplied by exposure prevalence or,
       equivalently, the crude incidence minus the incidence in unexposed
       persons.  When incidence is measured as a rate (i.e., ID), then the PAR
       is the difference of two rates.  When incidence is measured as a
       proportion (i.e., CI), then PAR is the difference of two proportions and
       therefore cannot exceed 1.0.  The resulting value is typically expressed
       as a rate or a proportion.  So this question is ambiguous -- apologies!

       B. Rate - by the definition of ID
       C. Proportion - by the definition of prevalence
       D. Ratio - relative risk is a ratio of independently-derived risks (or
       rates, if "relative risk" is interpreted as applying to the concept,
       rather than specifically to the risk ratio).

   7.  C.  prevalence - Although a birth with an anomaly is an "event", there is
       no way to establish the population at risk (denominator) for these
       events.  For example, would the denominator population be couples, fecund
       couples, fecund couples trying to conceive, embryos, recognized
       pregnancies?  Birth anomalies do not arise out of "live births", since
       the anomalies already exist in the fetus.  Therefore the "rate of
       anomalies per 1000 live births" is simply the proportion of live births
       in which a birth defect is present.

   8.  C.  Pesticide appliers had a greater proportion of births with anomalies
       as compared to the general population.

   9.  Assuming that prevalence of birth anomalies increases with increasing
       maternal age, an increase in the odds ratio due to age-adjustment
       indicates that the maternal age distribution in the general population is
       shifted toward older ages relative to that distribution in pesticide
       applier spouses.  The basis for this conclusion is the following.  Birth
       defect prevalence was greater for pesticide applier couples.  If some of
       that excess were due to greater age among pesticide applier mothers, then
       age-adjustment would diminish the excess, thereby decreasing the odds
       ratios.  Since instead, age-adjustment increased the odds ratios, then
       the older ages of general population mothers must have offset some of the
       excess risk due associated with pesticide exposure.

 10A.  Since the question does not specify absolute or relative impact, either
       attributable risk (AR) or attributable risk proportion (ARP) is correct
       (actually, attributable prevalence, but the term attributable risk is
       typically applied to rates and prevalences as well as risks).

          AR  =  P1 - P0 = [125 / (125 + 4456)] - [3666 / (3666 + 179,265)]
              =  0.02728 - 0.02004  =  0.0072466  =  0.0072, or
                                               7.2 per 1000 total live births

          Meaning:  7.2 births with anomalies per 1000 live births fathered by
          pesticide appliers are attributable to pesticide exposure.

          Attributable Risk proportion (ARP) = (RR-1) / RR  (using OR for RR)
              =  (OR - 1) / OR  =  (1.37 - 1) / 1.37  =  0.270  =  27%
          ARP  =  AR / P1  =  (0.027283 - 0.02004)/0.027283 = 0.26548  =  27%

          Meaning:  27% of the prevalence of births with anomalies among all
          live births fathered by pesticide appliers are attributable to
          pesticide exposure.

       To attribute cases to exposure requires the assumption of a causal
       relationship between pesticides exposure and birth defects.  

 10B.  Again, either population attributable risk (PAR) or population
       attributable risk proportion (PARP) provide an answer.

       Prevalence of paternal exposure among all live births is:

          Pe  =  4456 / (4456 + 179,265)  =  0.02425  =  2.4% of live births

       So PAR = AR x Pe  =  0.0072466 x 0.02425  =  0.0655  =  0.000176
                                               =  1.8 per 10,000 live births.

          or PCrude - P0  =  0.020217 - 0.02004  =  0.000177  =  1.8 / 10,000

       Meaning:  1.8 births with anomalies per 10,000 live births to the general
       (married) population are attributable to pesticide exposure in pesticide

       PARP  =  [Pe (RR-1) ] / [1 + Pe (RR-1)]     (using OR for RR)
                     =  [(0.02425) (1.37-1)] / [1+0.02425(1.37)]  =  0.0089
                    =  1% (approximately)

       Or, using the case-control formulation, 

          Pe|d  =  125 / ( 125 + 3666 ) = .032973

       PARP  =  Pe|d (OR-1) / OR  = (.032973) (1.37-1) / 1.37  =  0.008905
                                  =  1% (approximately)

       Or, PARP  = Pe x ARP  =  0.02425 x 0.26548  =  0.00644, using the ARP
       from part a.

       Meaning:  Approximately 1% of all Minnesota live births with anomalies
       are attributable to pesticide exposure in pesticide appliers.

       (Note:  small differences among the results from the various methods are
       primarily due to the fact that the OR of 1.37 has been rounded to fewer
       significant digits than are the prevalences computed above.

  11.  OR = 1.04  (Derivation:
       "Corrected" cases in exposed = 127 - (19 + 12) = 96
       Proportion in exposed = 96 / (4456 + 96)  =  0.0211
       "Corrected" cases in control = 3666 + 31 =  3697;  
       Proportion in control = 3697 / (3697 + 179,265)  =  0.0202
          0.0211 / 0.0202  =  1.04  =  new odds ratio)

       Thus, incorrectly classifying those anomalies into the exposed group
       overestimates the strength of association.

  12.  A. False - there is no basis for assuming that all births would be
       affected equally.

       B. True - The total proportion of harm, including fetal loss, is:

                     (lost fetuses + birth anomalies)
            (lost fetuses + birth anomalies + normal live births)

       This proportion exceeds the prevalence of birth anomalies among live
       births, potentially by a substantial amount.

  13.  A. ecologic study - exposure is assessed at the community (region) level,
       and exposure of persons is inferred based on residence in a geographic
       region where pesticides are heavily used.

  14.  1) Strength of association, estimated using odds ratios, is modest, and
          therefore does not provide strong evidence on which to infer causal

       2) Biological plausibility - various laboratory studies and a clinical
          epidemiologic study show that active ingredients and contaminants in
          pesticides can be teratogenic and/or spermatotoxic.  Also, several
          compounds in the pesticides are endocrine disrupters.

       3) Consistency (the authors cite epidemiologic studies [in Iowa,
          Nebraska, Colorado] that have found similar relationships).

  15.  This question underwent a revision to simplify it, but unfortunately some
       parts of the previous version remained.  The columns labelled
       "# live births" should have included the qualifier "Normal", and the
       rates for Minnesota needed to be re-computed accordingly.  Due to this
       problem, two alternate solutions are completely acceptable, one in which
       the denominators are the numbers in the "# live births" column and one in
       which the denominators equal the sum of these numbers plus the numbers of
       births with anomalies.  In addition, full credit is given if the rates
       for Minnesota were recomputed.   Here is the version in which the stated
       rates were used and the # of live births column was treated as if it
       meant "Total live births":

       Birth anomaly prevalences for Illinois, by water type:
          Well water:  2/100  =  20.0 per 1000 live births
          City water:  6/200  =  30.0 per 1000 live births
          Bottled water:  145/7293 = 19.9 per 1000 live births
          Overall (crude):  153/7593  =  20.2 per 1000 live births
       Thus, the crude prevalence is higher in Minnesota than in Illinois.

             Number of live births (both states combined)
                 Well water                        3479
                 City water                        1074
                 Bottled water                     7499
                 Total                           12,052

        Standardized prevalence for MN:

           3479 x 26.8 + 1074 x 30.0 + 7499 x 23.7
           ----------------------------------------  =  25.2 per 1,000
                   12,052 x 1000

        Standardized prevalence for IL:

           3479 x 20.0 + 1074 x 30.0 + 7499 x 19.9
           ----------------------------------------  =  20.8 per 1,000
                   12,052 x 1000

        The standardized prevalence for Minnesota also exceeds that for
        Illinois, though by a smaller amount than the difference in the crude
        prevalences.  The difference has been slightly reduced because the
        standardized prevalence for Minnesota gives somewhat greater weight to
        the prevalence for bottled water (23.7/1000) and less to the
        prevalence for well water (26.8/1000) than did the crude prevalence.

   16.  Yes - it is not clear from these data whether birth anomalies occurred
        in people with or without exposure because exposure information was
        based on group data.

   17.  A. False - subjects were selected from birth records for live births
        B. False
        C. True
        D. False
        E  False
        F. True - (however, a correlation coefficient indicates the extent of
           association in the sense of two variables moving in tandem; it does
           not indicate the strength of association in the epidemiologic sense
           of how great a change occurs in the response variable for a change
           of a given size in the exposure variable)
        G. True

   18.  [Question removed, 10/7/97]

   19.  Points in favor of action at this time are the evidence that the
        relationship is causal (biological plausibility, consistency between
        results of ecologic [by crop-region] and individual-based [pesticide
        applier] analyses, pattern of findings (season of conception),
        consistency across several epidemiologic studies, and the high
        attributable risk percent (27%) among babies with birth anomalies born
        to pesticide applier couples.  In addition, the substantially
        increased prevalences of birth anomalies among all live births in
        county clusters with high use of chlorophenoxy herbicides/fungicides
        (Table 4), consistent across the four regions, suggest that anomalies
        due to pesticides (assuming that the relationship is causal) occur
        throughout areas where these pesticides are used.  Even though the
        population attributable risk proportion is very small (about 1%) for
        exposure due to being a pesticide applier, the proportion of all
        Minnesota birth anomalies potentially attributable to residence in a
        county cluster with high pesticide use is 27% [overall prevalence of
        birth anomalies for all Minnesota in-wedlock births was 3791 / 183,721
        = 20.63 per 1000 live births (Table 1), prevalence of birth anomalies
        in low-pesticide county clusters ("unexposed") was 15 per 1000 (Table
        4), so PARP = (PCrude - P0) / PCrude  =  (20.63 - 15) / 20.63 = .27).
        The effects seem to be strongest for chlorophenoxy pesticides,
        suggesting that at least this category should be restricted.
        Moreover, there are powerful arguments for reducing pesticide use for
        environmental reasons as well.

        Against taking action other than continuing research are that the
        evidence is still not very strong (biological mechanisms not yet
        elucidated, relationship is not highly specific, epidemiologic studies
        limited and not entirely consistent, experimental evidence not
        available), the potential impact on agriculture and therefore food
        prices is considerable, and the costs to industry and commerce from
        restrictions on a major product are substantial.  Moreover, the
        relative weakness of the odds ratios (below 2.0) indicates a
        significant possibility that other factors could be responsible for
        the increase in birth anomaly prevalence seen in association with
        pesticide exposure, a possibility whose investigation requires better
        data on exposure and other factors that may lead to birth anomalies.

        Grading of this question is based on the clarity and support for your
        evaluation and recommendation.

10/21/96, 10/7/97 - wr:eml/vs \ mepid168\ exams 1996 Midterm exam - answers rev.