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The “case-control” study: Valid selection of subjects
J Chron Dis Vol. 38, No. 7, pp. 553-555, 1985 Printedin Great Britain
0021.9681/85 $3.00 + 0.00 PergamonPress Ltd
Comment THE “CASE-CONTROL” STUDY: VALID SELECTION OF SUBJECTS OLAV
Department
of Occupational
Medicine,
AXELSON
University
Hospital,
581 85 Linkiiping,
Sweden
THE APPLICATION of a methodologic principle in an extreme situation might reveal its logic weaknesses. The “case-referent-story” on tequila and the other examples discussed by Dr Miettinen demonstrate that a new and more rigorous paradigm is needed for the design of case-referent studies. It seems as if the concept of a study base not only provides a new perspective, but also enables a deeper understanding of the nature of the case-referent approach. Having been exposed to these new ideas for some time [ 1,2], I have gradually adopted the study base concept along with its implications for study design. Its utilization in teaching has been very helpful, especially when applying an easily understandable pictorial representation [3], which makes the relationships of various study designs quite clear. Still, since the epidemiologic literature is full of the “old” duality of cohort and casecontrol studies, and probably will be so for quite some time, there is also a problem when such new ideas interfere with the traditional ones. In the resulting confused situation, it seems helpful to students at least, to point out that “cohort” usually refers to a study involving a census of a closed population, whereas the term “case-control” refers to a study of an open (dynamic) population involving a sample of the base. An exception is the nested case-control study or a case-control study in a cohort. This “nested case-control study” is also of interest from another point of view, namely that it would require a rare disease criterion, which has been associated with the “casecontrol” study in general for many years, until it relaxed in 1976 [4]. However, it follows from the idea of sampling the base, that the rare disease criterion need not necessarily be peculiar to “nested casecontrol studies”. This is particularly true if the sampling is done from the total base and not from among the individuals who remained healthy. The remark made by Dr Miettinen, that the reference series should be a representative sample of the base with regard to the distribution of the determinant is certainly welcome as pointing out a simple and direct consequence of the study base concept and the structure of the case-referent study, that is, not primarily concerned with comparing cases and non-cases. Not surprisingly, however, I recently found some case-referent data of ours regarding miners’ lung cancer, radon daughter exposure and a possible, relative protection of mucus, to be challenged in this journal [5] because of differences between cases and controls in distribution over age in spite of a stratification in this respect. Nothing was said about the representativeness of the referents with regard to the distribution of the exposure, even though that would have been more important to discuss; cf. also [6]. As a consequence of the generally held view that cases are to be compared to controls, matching as the happy solution of surmised problems of comparability in “case-control” 553
554
OLAV
AXELSON
studies is used very often. However, the result might easily be either over-matching or at least, the study base might not be properly represented in the reference series. Hence, when matching for some determinants extraneous to the illness is applied in studies the referents thereby selected tend to be drawn from those “case-control” particular sectors of the base, where the matching factors operate and cause concentration of cases. Consequently the base sample gets distorted in matched “case-control” data (a phenomenon that might be taken care of in the analysis if the consequences of matching are properly appreciated). A further and somewhat related aspect is that random variation might cause the base sample, the referents, to be less representative of the base with regard to the distribution of extraneous determinants. It tends to be helpful, however, if there is a reasonable size of the base sample (or number of referents) irrespective of the number of available cases with favourable power effects as well [7]. Another point, which I would like to comment on, relates to what is said in Dr Miettinen’s paper under valid selection of subjects, namely the problem of selecting proper disease entities for the reference series, i.e. diagnoses unrelated to the exposure. With the advancement of epidemiologic knowledge, an increasing number of conditions tend to become related to various determinants, e.g. the number of disease entities associated with smoking, usually positively but sometimes also negatively, has become so great that only few of the more frequent conditions remain acceptable for a reference series. The solution could be to do a study involving a primary base and to use a direct sample of it. If the case entity were of a less distinct character, e.g. like bronchitis or an undifferentiated syndrome usually not requiring hospitalization or registration, then the case-finding census procedure could become the obstacle. Furthermore, there is also the problem of evaluating multiple exposures. Hence, although the case-referent approach easily permits a formal examination of several potential determinants for an illness, there might be restrictions in this regard, since some of the disease entities in the reference series might have a relationship to some of the potential determinants but not to others [8]. In spite of the new guidelines now set out for the selection of referents, research practice remains treacherous, since one concern of validity might compete with another. For example, the suggestion to utilize a series of other malformations rather than healthy babies for the etiologic study of a particular birth defect is certainly attractive from the point of view of comparability of information, but, for example, recent experiences from Finland [9, lo] seem to suggest that solvent exposure might cause several types of birth defects. In the context of this type of exposure, it would have been less desirable therefore to have included some of these defects in the reference series when studying the other. But one could of course also suggest that problems concerning the comparability of information from mothers of healthy and defect babies were enough to explain the findings obtained. Other facts do not support the latter view, however, notably the lack of association with some other equally suspect and debated industrial exposures. Another example of concerns about the comparability of information stems from a set of Swedish studies on soft-tissue sarcomas and lymphomas putatively associated with exposure to chlorinated phenoxy acids and chlorophenols as the determinants [l 11. These studies utilized healthy individuals as well as deceased non-cancer cases as referents [9]. For comparability reasons it was decided to do an additional evaluation using colonic cancer cases as referents [ 121. However, it could not be excluded a priori, that there would not be some effect from the exposures at issue even with regard to colonic cancer. As a matter of fact the rate ratios for this cancer type with regard to the particular exposures under study were also slightly elevated when the exposure frequency of the colonic cancer cases was compared to the referents from the original sarcoma and lymphoma studies. Had the rate ratios been even higher, the judgements and conclusions would have been even more debatable concerning a true effect or a bias from incomparable information both in the original studies and in the colonic cancer study. So, to summarize, the elucidation of the nature of the “case-control” study as brought forward by Dr Miettinen along with the principles for subject selection will presumably
Valid Selection
of Subjects
555
lead to a more widespread understanding of central epidemiologic issues and to improvements in study designs. However, few, if any studies, have been ideal from a methodologic point of view, and even now, with better theoretical premises for study design, practical obstacles will continue to hamper the case-referent approach but also to make it challenging and stimulating for the researcher. A consequence of some new ideas emerging is usually that older material has to be reconsidered in the light of new knowledge. In so doing, probably most of the “case+ontrol” studies of the past will survive, but some studies might gain in credibility and others are likely to lose it. The traditional principles for study designs might work in most instances in the future, just as Newtonian physics is still useful in spite of a new paradigm. However, a new and more thorough understanding of matters would not only be desirable but also necessary in many situations for further development to take place.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
12.
Miettinen OS: Design options in epidemiologic research. An update. Sand J Work Environ Health 8 (Suppl. 1): 7-14, 1982 Miettinen OS: International Advanced Seminar in Epidemiologic Methods; lecture notes. Helsinki: Institute of Occupational Health, Aug 30-Sept 10, 1982 Axelson 0: Elucidation of some epidemiologic principles. Stand J Work Environ Health 9: 231-240, 1983 Miettinen OS: Estimability and estimation in case-referent studies. Am J Epid 102: 226-235, 1976 Higgins ITT: Commentary on “Possible effects on occupational lung cancer from smoking related to changes in the mucus content of the lung”. J Chron Dis 36: 677-680, 1983 Axelson 0: Room for a role for radon in lung cancer causation? Med Hypothesis 13: 51-61, 1984 Axelson 0, Johansson B, Axelson T: On the problem of controlling confounding in case-referent studies. Ann Acad Med (Singapore) 13 (Suppl.): 308-311, 1984 Axelson 0, Flodin U, Hardell L: A comment on the reference series with regard to multiple exposure evaluations in a case-referent study. Stand J Work Environ Health 8 (Suppl. 1): 15-19, 1982 Holmberg PC, Nurminen M: Congenital defects of the central nervous system and occupational factors during pregnancy. A case-referent-study. Am J Indust Med 1: 167-176, i980 Holmberg PC, Hernberg S, Kurppa K, Rantala K, Riala R: Oral clefts and organic solvent exposure during pregnancy. Int Arch Occup Environ Health 50: 371-376, 1982 Hardell L: Epidemiological studies on soft-tissue sarcoma and malignant lymphoma and their relation to phenoxy acid or chlorophenol exposure. Umeii University Medical Dissertations, New Series No 65, Umea 1981, 139 pp (cf. also References in [12]). Hardell L: Relation of soft-tissue sarcoma, malignant lymphoma and colon cancer to phenoxy acids, chlorophenols and other agents. Stand J Work Environ Health 7: 119-130, 1981
0021.9681/85 $3.00 + 0.00 PergamonPress Ltd
Comment THE “CASE-CONTROL” STUDY: VALID SELECTION OF SUBJECTS OLAV
Department
of Occupational
Medicine,
AXELSON
University
Hospital,
581 85 Linkiiping,
Sweden
THE APPLICATION of a methodologic principle in an extreme situation might reveal its logic weaknesses. The “case-referent-story” on tequila and the other examples discussed by Dr Miettinen demonstrate that a new and more rigorous paradigm is needed for the design of case-referent studies. It seems as if the concept of a study base not only provides a new perspective, but also enables a deeper understanding of the nature of the case-referent approach. Having been exposed to these new ideas for some time [ 1,2], I have gradually adopted the study base concept along with its implications for study design. Its utilization in teaching has been very helpful, especially when applying an easily understandable pictorial representation [3], which makes the relationships of various study designs quite clear. Still, since the epidemiologic literature is full of the “old” duality of cohort and casecontrol studies, and probably will be so for quite some time, there is also a problem when such new ideas interfere with the traditional ones. In the resulting confused situation, it seems helpful to students at least, to point out that “cohort” usually refers to a study involving a census of a closed population, whereas the term “case-control” refers to a study of an open (dynamic) population involving a sample of the base. An exception is the nested case-control study or a case-control study in a cohort. This “nested case-control study” is also of interest from another point of view, namely that it would require a rare disease criterion, which has been associated with the “casecontrol” study in general for many years, until it relaxed in 1976 [4]. However, it follows from the idea of sampling the base, that the rare disease criterion need not necessarily be peculiar to “nested casecontrol studies”. This is particularly true if the sampling is done from the total base and not from among the individuals who remained healthy. The remark made by Dr Miettinen, that the reference series should be a representative sample of the base with regard to the distribution of the determinant is certainly welcome as pointing out a simple and direct consequence of the study base concept and the structure of the case-referent study, that is, not primarily concerned with comparing cases and non-cases. Not surprisingly, however, I recently found some case-referent data of ours regarding miners’ lung cancer, radon daughter exposure and a possible, relative protection of mucus, to be challenged in this journal [5] because of differences between cases and controls in distribution over age in spite of a stratification in this respect. Nothing was said about the representativeness of the referents with regard to the distribution of the exposure, even though that would have been more important to discuss; cf. also [6]. As a consequence of the generally held view that cases are to be compared to controls, matching as the happy solution of surmised problems of comparability in “case-control” 553
554
OLAV
AXELSON
studies is used very often. However, the result might easily be either over-matching or at least, the study base might not be properly represented in the reference series. Hence, when matching for some determinants extraneous to the illness is applied in studies the referents thereby selected tend to be drawn from those “case-control” particular sectors of the base, where the matching factors operate and cause concentration of cases. Consequently the base sample gets distorted in matched “case-control” data (a phenomenon that might be taken care of in the analysis if the consequences of matching are properly appreciated). A further and somewhat related aspect is that random variation might cause the base sample, the referents, to be less representative of the base with regard to the distribution of extraneous determinants. It tends to be helpful, however, if there is a reasonable size of the base sample (or number of referents) irrespective of the number of available cases with favourable power effects as well [7]. Another point, which I would like to comment on, relates to what is said in Dr Miettinen’s paper under valid selection of subjects, namely the problem of selecting proper disease entities for the reference series, i.e. diagnoses unrelated to the exposure. With the advancement of epidemiologic knowledge, an increasing number of conditions tend to become related to various determinants, e.g. the number of disease entities associated with smoking, usually positively but sometimes also negatively, has become so great that only few of the more frequent conditions remain acceptable for a reference series. The solution could be to do a study involving a primary base and to use a direct sample of it. If the case entity were of a less distinct character, e.g. like bronchitis or an undifferentiated syndrome usually not requiring hospitalization or registration, then the case-finding census procedure could become the obstacle. Furthermore, there is also the problem of evaluating multiple exposures. Hence, although the case-referent approach easily permits a formal examination of several potential determinants for an illness, there might be restrictions in this regard, since some of the disease entities in the reference series might have a relationship to some of the potential determinants but not to others [8]. In spite of the new guidelines now set out for the selection of referents, research practice remains treacherous, since one concern of validity might compete with another. For example, the suggestion to utilize a series of other malformations rather than healthy babies for the etiologic study of a particular birth defect is certainly attractive from the point of view of comparability of information, but, for example, recent experiences from Finland [9, lo] seem to suggest that solvent exposure might cause several types of birth defects. In the context of this type of exposure, it would have been less desirable therefore to have included some of these defects in the reference series when studying the other. But one could of course also suggest that problems concerning the comparability of information from mothers of healthy and defect babies were enough to explain the findings obtained. Other facts do not support the latter view, however, notably the lack of association with some other equally suspect and debated industrial exposures. Another example of concerns about the comparability of information stems from a set of Swedish studies on soft-tissue sarcomas and lymphomas putatively associated with exposure to chlorinated phenoxy acids and chlorophenols as the determinants [l 11. These studies utilized healthy individuals as well as deceased non-cancer cases as referents [9]. For comparability reasons it was decided to do an additional evaluation using colonic cancer cases as referents [ 121. However, it could not be excluded a priori, that there would not be some effect from the exposures at issue even with regard to colonic cancer. As a matter of fact the rate ratios for this cancer type with regard to the particular exposures under study were also slightly elevated when the exposure frequency of the colonic cancer cases was compared to the referents from the original sarcoma and lymphoma studies. Had the rate ratios been even higher, the judgements and conclusions would have been even more debatable concerning a true effect or a bias from incomparable information both in the original studies and in the colonic cancer study. So, to summarize, the elucidation of the nature of the “case-control” study as brought forward by Dr Miettinen along with the principles for subject selection will presumably
Valid Selection
of Subjects
555
lead to a more widespread understanding of central epidemiologic issues and to improvements in study designs. However, few, if any studies, have been ideal from a methodologic point of view, and even now, with better theoretical premises for study design, practical obstacles will continue to hamper the case-referent approach but also to make it challenging and stimulating for the researcher. A consequence of some new ideas emerging is usually that older material has to be reconsidered in the light of new knowledge. In so doing, probably most of the “case+ontrol” studies of the past will survive, but some studies might gain in credibility and others are likely to lose it. The traditional principles for study designs might work in most instances in the future, just as Newtonian physics is still useful in spite of a new paradigm. However, a new and more thorough understanding of matters would not only be desirable but also necessary in many situations for further development to take place.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
12.
Miettinen OS: Design options in epidemiologic research. An update. Sand J Work Environ Health 8 (Suppl. 1): 7-14, 1982 Miettinen OS: International Advanced Seminar in Epidemiologic Methods; lecture notes. Helsinki: Institute of Occupational Health, Aug 30-Sept 10, 1982 Axelson 0: Elucidation of some epidemiologic principles. Stand J Work Environ Health 9: 231-240, 1983 Miettinen OS: Estimability and estimation in case-referent studies. Am J Epid 102: 226-235, 1976 Higgins ITT: Commentary on “Possible effects on occupational lung cancer from smoking related to changes in the mucus content of the lung”. J Chron Dis 36: 677-680, 1983 Axelson 0: Room for a role for radon in lung cancer causation? Med Hypothesis 13: 51-61, 1984 Axelson 0, Johansson B, Axelson T: On the problem of controlling confounding in case-referent studies. Ann Acad Med (Singapore) 13 (Suppl.): 308-311, 1984 Axelson 0, Flodin U, Hardell L: A comment on the reference series with regard to multiple exposure evaluations in a case-referent study. Stand J Work Environ Health 8 (Suppl. 1): 15-19, 1982 Holmberg PC, Nurminen M: Congenital defects of the central nervous system and occupational factors during pregnancy. A case-referent-study. Am J Indust Med 1: 167-176, i980 Holmberg PC, Hernberg S, Kurppa K, Rantala K, Riala R: Oral clefts and organic solvent exposure during pregnancy. Int Arch Occup Environ Health 50: 371-376, 1982 Hardell L: Epidemiological studies on soft-tissue sarcoma and malignant lymphoma and their relation to phenoxy acid or chlorophenol exposure. Umeii University Medical Dissertations, New Series No 65, Umea 1981, 139 pp (cf. also References in [12]). Hardell L: Relation of soft-tissue sarcoma, malignant lymphoma and colon cancer to phenoxy acids, chlorophenols and other agents. Stand J Work Environ Health 7: 119-130, 1981