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On the concept of the normal range
CORRESPONDENCE
thickness in melanoma should not be abandoned until a more reliable method is found. The estimation of the level of invasion is not such a method. ALEXA.NDER BRESLOW,
M.D.
George Washington University School of Medicine Washington, D.C. I. Breslow, A.: Tumor thickness, level of invasion and node
2. 3.
4.
5,
dissection in stage I cutaneous melanoma. Ann. Surg., 182:572. 1975. Hansen, M. G., and McCarten. A. B.: Tumor thickness and lymphocytic infiltration in malignant. melanoma of the head and neck. Am. J. Surg.. 128:557, 1974. Wanebo, H. j., Fortner, .l- G., Woodruff. J.. MacLean B.• and Binkowski. E.: Selection of the optimum surgical treatment. of stage I melanoma by depth of microinvasion: use of t.he combined mlcrostage technique (Clark-Breslow). Ann. Surg.. 182:302. 1975. Breslow, A.. Cascinelli, V.. van der Esch, E. P., and Marabito, A.: Stage I melanoma of the limbs: assessment of prognosis by levels of invasion and maximum thickness. (Submitted for publication.) Balch, C. M.• Murad, T., Soong, A., Griffin, A. L.. Hal· pern, N., and Maddox, W. A.: A multifactorial analysis of melanoma. I. Prognostic histopat.hologic features comparing Clark's and Breslow's st.aging methods. (Submitted for publication.)
ON THE CONCEPT OF THE NORMAL RANGE To
THE EDITOR;
The question of "normal values" has been labeled by Benson' as one of the most difficult and stubborn problems limiting the usefulness of clinical laboratory data. Sunderman" has attempted to eliminate the polysemy of the term "normal values" by introducing the concept of "reference values," which has a purely operational character and implies nothing in regard to an absolute definition of health. However, even within the framework of the concept of reference values, we cannot evade certain fundamental problems, which I should like to illustrate here with the example of the serum cholesterol level. Considerable confusion exists in defining reference or optimal serum cholesterol values." On the one hand, optimal values in cholesterolemia (based on the standard Abell- Kendall method) have been defined as being under 200 mg. per 100 ml., and higher cholesterol values are associated with an increased risk of coronary heart disease. On the other hand, application of the current statistical procedures used to determine the reference interval frequently means that values as high as 300 mg. per 100 ml. are considered acceptable. It is thus obviously necessary to draw a clear-cut distinction between the optimal cholesterol
level in relation to the increasing risk of coronary disease, and the reference interval of the cholesterol level in the common diagnostic sense. The underlying idea of reference values, though not stated explicitly, is the dichotomic (alternative) view of health and disease. The pathological state is here most frequently presumed to be produced by one prominent factor that affects a definite (usually small) part of the population. In a population a disease occurs alternatively and is not quantitatively graduated, and thus represents a state that is qualitatively different from health. The presence of a pathological condition will be expressed by a shift in the average value of a sign and in the corresponding frequency distribution by a certain positive or negative value. The philosophy of using the reference limits assumes in principle that the interval comprises only values that are equivalent from the viewpoint of a given disease, whereas outside the interval lie suspicious or pathological values. The eventual fate of the subjects constituting a reference sample is usually not investigated, and the possibility that certain values inside the reference interval may be associated with later pathologic change is not taken into account. Offer and Sabshin" called the pathological states in this concept "the diseases due to one gross cause" and discussed the historical roots of such a simplified view of health and disease. The traditional opinion, prevailing up to the second half of the nineteenth century. had been based on the physician's practical need to rid the patient of all major suffering or imminent danger to life. Health was conceived purely negatively, as a simple lack of apparent pathologic change, and as a homogeneous state characteristic of most of the human population. The term "reference cholesterol level" thus makes sense only when it relates to diseases for which the alternative model of occurrence may be adopted with a practical approximation, such as biliary obstruction, the nephrotic syndrome, or Addison's disease. The connection between the serum cholesterol level and coronary morbidity and mortality has been repeatedly studied from an epidemiological point of view, and a nearly linear relationship between the two factors has been demonstrated, starting with cholesterollevels as low as 130 mg. per 100 ml.5- 7 The distribution of serum cholesterol values in a population in general can be regarded as reflecting the simultaneous effect of a greater number of universally acting environmental factors, such as dietary habits, physical activity. sociometric status, effect of stress factors, and a number of hereditary factors chiefly of the polygenic type." Persuasive though as yet indirect evidence for the existence of a causal
239
HUMAN PATHOLOGY - VOLUME 9, NUtvIBER 2 i\!Iarch 1978
240
relationship between the cholesterol level and the development of coronary disease implies that this disease is, if only from the viewpoint of cholesterol participation, multifactorially conditioned. Thus a population cannot be strictly divided into coronary patients and completely healthy people, The differences in the cholesterol level among individuals signal different degrees of proneness to develop coronary disease, regardless of the fact that these people at present are healthy. In considering the relationship between the serum cholesterol level and coronary artery disease, the concept of the reference interval "from-to" loses meaning completely. Here no limits can be set within which there would be no risk of developing a disease and outside of which a disease would be much more probable. Neither is there any "break" in the dangerous effect of an increasing cholesterol level. Moreover, the most frequent variants around the middle of a population do not in this case represent any optimum, away from which in either direction the biological fitness of an individual would diminish. We may conclude that the concept of the reference interval is of practical use or necessary only when the underlying pathological state can be regarded as a "gross" factor, disturbing the homogeneity of a population and leading to polyrnodality of a sign. The traditional concept of the "normal range" led to a disregard of the significance of interindividual variability among the "healthy" population. Sunderman's proposal' of a "reference interval" is purposely differentiated from that concept in that it set out to consider numerous factors that exert an influence on a given sign, regardless of the characteristics of the reference population, environmental or physiological conditions, or other circumstances under which the specimens were obtained, However, this view is difficult to realize in practice, because the reference populations would have to be divided according to too many criteria. It will still be possible to find the reference intervals (or discrimination values) only by simultaneously considering three to four other factors at the most, and it follows from the very principle of reference intervals that even in the future t.hey will not emerge from the framework of an alternative model. The continuity of the transition between health and disease and the polycausal explanation of both have, however, been accepted more and more widely," and coronary sclerosis is only one example of many (e.g., essential hypertension, diabetes). It may thus be anticipated that the diagnostic and prognostic significance of the signs associated with morbidity and mortality in the sense of a continuous functional relationship will grow. Within
the framework of this concept, we can no longer ask about the limits of the "reference interval"; rather we have to attempt to find the shape of the particular relationship as well as its maxima and minima. Jill.! VA.cJ·lA, M.D., PH.D. Institute of Biophysics Czechoslovak Academy of Science Brno , Czechoslovakia J. Benson. E. S.: The wncept of the normal range. Human Path .. 3: 152, 1972. 2. Sunderman. F. W" Jr.: Current concepts of "normal values," "reference values," and "discrimination values" in clinical chemistry, Clin. Chern., 21 :1873. 1975, 3. Wright. 1. S.: Correct levels of serum cholesterol. Average vs. normal vs. optimal, J.A.M.A.. 236:261, 1976, 4, Offer. D .. and Sabshin, M.: Normality. Theoretical and Clinical Concepts of Mental Health. New York. Basic Books. Inc. Publishers. 1966. 5. Blackburn. H,. and Parlin, R. W.: Antecedents of disease. Insurance mortality experience. Ann. N.Y. Acad. Sci., 134:265. 1966. 6. Kannel, W. E .. Dawber, T. R.. Friedman. G. D" Glennon. W. E., and Mclvamara, P. M.: Risk factors in coronary heart disease. An evaluation of several serum lipids as predictors of coronary heart disease. The Framingham Study, Arm. Int. Med., 6/:888, 1964. 7. Page, 1. H" Berrettoni. J. N.• Butkus. A.. and Mason Sones, F" Jr.: Prediction of coronary heart disease based on dinical suspicion. age. total cholesterol. and triglyceride. Circulation, 42:625, 1970. 8, Jensen. J.. and Blankenhorn. D. H.: The inheritance of familial hypercholesterolemia, Am . .J. Med .• 52:499, 1972. 9. Murphy, E. A.: A scientific viewpoint on normalcy, Persp. BioI. Med .• 9:333, 1966.
COMMENT In extending his concept of the normal range to accomodate the transit.ion between health and disease, Dr. Vacha succinctly reviews the serious shortcomings of "normal" and "reference" values. While recognizing the continuous functional relationship between a risk factor, such as cholesterol, and a disease entity, coronary heart disease, Dr. Vacha stops short of asking the critical question, "What happens if we lower the serum cholesterol in an individual patient?" He stops at an "operational analysis" of a laboratory test. We submit that he extend his thinking to the level of "medical decision making." There is quite a difference between a risk factor and a useful laboratory test. Although some risk factors may indeed be useful laboratory tests, there are many risk factors that are not. I The serum cholesterol level is assayed routinely on the assumpt.ion that it. is an important risk factor, and that its measurement is useful in predicting the possible occurrence of coronary atherosclerosis. But how good a risk factor is it? If it were possible to lower everyone's serum cholesterol to a level t.hat
thickness in melanoma should not be abandoned until a more reliable method is found. The estimation of the level of invasion is not such a method. ALEXA.NDER BRESLOW,
M.D.
George Washington University School of Medicine Washington, D.C. I. Breslow, A.: Tumor thickness, level of invasion and node
2. 3.
4.
5,
dissection in stage I cutaneous melanoma. Ann. Surg., 182:572. 1975. Hansen, M. G., and McCarten. A. B.: Tumor thickness and lymphocytic infiltration in malignant. melanoma of the head and neck. Am. J. Surg.. 128:557, 1974. Wanebo, H. j., Fortner, .l- G., Woodruff. J.. MacLean B.• and Binkowski. E.: Selection of the optimum surgical treatment. of stage I melanoma by depth of microinvasion: use of t.he combined mlcrostage technique (Clark-Breslow). Ann. Surg.. 182:302. 1975. Breslow, A.. Cascinelli, V.. van der Esch, E. P., and Marabito, A.: Stage I melanoma of the limbs: assessment of prognosis by levels of invasion and maximum thickness. (Submitted for publication.) Balch, C. M.• Murad, T., Soong, A., Griffin, A. L.. Hal· pern, N., and Maddox, W. A.: A multifactorial analysis of melanoma. I. Prognostic histopat.hologic features comparing Clark's and Breslow's st.aging methods. (Submitted for publication.)
ON THE CONCEPT OF THE NORMAL RANGE To
THE EDITOR;
The question of "normal values" has been labeled by Benson' as one of the most difficult and stubborn problems limiting the usefulness of clinical laboratory data. Sunderman" has attempted to eliminate the polysemy of the term "normal values" by introducing the concept of "reference values," which has a purely operational character and implies nothing in regard to an absolute definition of health. However, even within the framework of the concept of reference values, we cannot evade certain fundamental problems, which I should like to illustrate here with the example of the serum cholesterol level. Considerable confusion exists in defining reference or optimal serum cholesterol values." On the one hand, optimal values in cholesterolemia (based on the standard Abell- Kendall method) have been defined as being under 200 mg. per 100 ml., and higher cholesterol values are associated with an increased risk of coronary heart disease. On the other hand, application of the current statistical procedures used to determine the reference interval frequently means that values as high as 300 mg. per 100 ml. are considered acceptable. It is thus obviously necessary to draw a clear-cut distinction between the optimal cholesterol
level in relation to the increasing risk of coronary disease, and the reference interval of the cholesterol level in the common diagnostic sense. The underlying idea of reference values, though not stated explicitly, is the dichotomic (alternative) view of health and disease. The pathological state is here most frequently presumed to be produced by one prominent factor that affects a definite (usually small) part of the population. In a population a disease occurs alternatively and is not quantitatively graduated, and thus represents a state that is qualitatively different from health. The presence of a pathological condition will be expressed by a shift in the average value of a sign and in the corresponding frequency distribution by a certain positive or negative value. The philosophy of using the reference limits assumes in principle that the interval comprises only values that are equivalent from the viewpoint of a given disease, whereas outside the interval lie suspicious or pathological values. The eventual fate of the subjects constituting a reference sample is usually not investigated, and the possibility that certain values inside the reference interval may be associated with later pathologic change is not taken into account. Offer and Sabshin" called the pathological states in this concept "the diseases due to one gross cause" and discussed the historical roots of such a simplified view of health and disease. The traditional opinion, prevailing up to the second half of the nineteenth century. had been based on the physician's practical need to rid the patient of all major suffering or imminent danger to life. Health was conceived purely negatively, as a simple lack of apparent pathologic change, and as a homogeneous state characteristic of most of the human population. The term "reference cholesterol level" thus makes sense only when it relates to diseases for which the alternative model of occurrence may be adopted with a practical approximation, such as biliary obstruction, the nephrotic syndrome, or Addison's disease. The connection between the serum cholesterol level and coronary morbidity and mortality has been repeatedly studied from an epidemiological point of view, and a nearly linear relationship between the two factors has been demonstrated, starting with cholesterollevels as low as 130 mg. per 100 ml.5- 7 The distribution of serum cholesterol values in a population in general can be regarded as reflecting the simultaneous effect of a greater number of universally acting environmental factors, such as dietary habits, physical activity. sociometric status, effect of stress factors, and a number of hereditary factors chiefly of the polygenic type." Persuasive though as yet indirect evidence for the existence of a causal
239
HUMAN PATHOLOGY - VOLUME 9, NUtvIBER 2 i\!Iarch 1978
240
relationship between the cholesterol level and the development of coronary disease implies that this disease is, if only from the viewpoint of cholesterol participation, multifactorially conditioned. Thus a population cannot be strictly divided into coronary patients and completely healthy people, The differences in the cholesterol level among individuals signal different degrees of proneness to develop coronary disease, regardless of the fact that these people at present are healthy. In considering the relationship between the serum cholesterol level and coronary artery disease, the concept of the reference interval "from-to" loses meaning completely. Here no limits can be set within which there would be no risk of developing a disease and outside of which a disease would be much more probable. Neither is there any "break" in the dangerous effect of an increasing cholesterol level. Moreover, the most frequent variants around the middle of a population do not in this case represent any optimum, away from which in either direction the biological fitness of an individual would diminish. We may conclude that the concept of the reference interval is of practical use or necessary only when the underlying pathological state can be regarded as a "gross" factor, disturbing the homogeneity of a population and leading to polyrnodality of a sign. The traditional concept of the "normal range" led to a disregard of the significance of interindividual variability among the "healthy" population. Sunderman's proposal' of a "reference interval" is purposely differentiated from that concept in that it set out to consider numerous factors that exert an influence on a given sign, regardless of the characteristics of the reference population, environmental or physiological conditions, or other circumstances under which the specimens were obtained, However, this view is difficult to realize in practice, because the reference populations would have to be divided according to too many criteria. It will still be possible to find the reference intervals (or discrimination values) only by simultaneously considering three to four other factors at the most, and it follows from the very principle of reference intervals that even in the future t.hey will not emerge from the framework of an alternative model. The continuity of the transition between health and disease and the polycausal explanation of both have, however, been accepted more and more widely," and coronary sclerosis is only one example of many (e.g., essential hypertension, diabetes). It may thus be anticipated that the diagnostic and prognostic significance of the signs associated with morbidity and mortality in the sense of a continuous functional relationship will grow. Within
the framework of this concept, we can no longer ask about the limits of the "reference interval"; rather we have to attempt to find the shape of the particular relationship as well as its maxima and minima. Jill.! VA.cJ·lA, M.D., PH.D. Institute of Biophysics Czechoslovak Academy of Science Brno , Czechoslovakia J. Benson. E. S.: The wncept of the normal range. Human Path .. 3: 152, 1972. 2. Sunderman. F. W" Jr.: Current concepts of "normal values," "reference values," and "discrimination values" in clinical chemistry, Clin. Chern., 21 :1873. 1975, 3. Wright. 1. S.: Correct levels of serum cholesterol. Average vs. normal vs. optimal, J.A.M.A.. 236:261, 1976, 4, Offer. D .. and Sabshin, M.: Normality. Theoretical and Clinical Concepts of Mental Health. New York. Basic Books. Inc. Publishers. 1966. 5. Blackburn. H,. and Parlin, R. W.: Antecedents of disease. Insurance mortality experience. Ann. N.Y. Acad. Sci., 134:265. 1966. 6. Kannel, W. E .. Dawber, T. R.. Friedman. G. D" Glennon. W. E., and Mclvamara, P. M.: Risk factors in coronary heart disease. An evaluation of several serum lipids as predictors of coronary heart disease. The Framingham Study, Arm. Int. Med., 6/:888, 1964. 7. Page, 1. H" Berrettoni. J. N.• Butkus. A.. and Mason Sones, F" Jr.: Prediction of coronary heart disease based on dinical suspicion. age. total cholesterol. and triglyceride. Circulation, 42:625, 1970. 8, Jensen. J.. and Blankenhorn. D. H.: The inheritance of familial hypercholesterolemia, Am . .J. Med .• 52:499, 1972. 9. Murphy, E. A.: A scientific viewpoint on normalcy, Persp. BioI. Med .• 9:333, 1966.
COMMENT In extending his concept of the normal range to accomodate the transit.ion between health and disease, Dr. Vacha succinctly reviews the serious shortcomings of "normal" and "reference" values. While recognizing the continuous functional relationship between a risk factor, such as cholesterol, and a disease entity, coronary heart disease, Dr. Vacha stops short of asking the critical question, "What happens if we lower the serum cholesterol in an individual patient?" He stops at an "operational analysis" of a laboratory test. We submit that he extend his thinking to the level of "medical decision making." There is quite a difference between a risk factor and a useful laboratory test. Although some risk factors may indeed be useful laboratory tests, there are many risk factors that are not. I The serum cholesterol level is assayed routinely on the assumpt.ion that it. is an important risk factor, and that its measurement is useful in predicting the possible occurrence of coronary atherosclerosis. But how good a risk factor is it? If it were possible to lower everyone's serum cholesterol to a level t.hat