of using the nomencla¬ he proposes: "toxoplasmosis mononucleosis" vs toxoplasmosis or "CMV mononucleosis" vs CMV dis¬ ease? Even if all of the diseases did resemble each other so closely as to permit grouping into syndromes (de¬ spite sérologie differences), his termi¬ nology would still be redundant and potentially confusing. Would we gain by changing the names of pneumococcal and streptococcal infections to pneumococcal and streptococcal
"advantage" ture
Letters, if clearly marked "For Publication," will be published
as space permits and at the discretion of the editor. They should be typewritten triple-spaced, with five or fewer references, should not exceed two pages in length, and will be subject to editing. Letters
are
not
acknowledged.
Nomenclature for Mononucleosis Syndromes To the Editor.\p=m-\DrJordan's "Nomenclature for Mononucleosis Syndromes" (p 45) contains a statement that his use of the term mononucleosis "pertains only to those cases that meet standard clinical and hematologic criteria for infectious mononucleosis." This passage refers to my work in which I have emphasized the need for three criteria\p=m-\clinical,hematologic, and serologic\p=m-\forvalid
diagnoses. However, two paragraphs later, Dr Jordan states that Klemola1 has shown that the cytomegaloviruses (CMV) can cause a form of mononucleosis that is always heterophil antibody-negative. Yet, the article by
Klemola et al2 concerns a disease that is not clinically similar to mononucleosis (and is, in fact, serologically different as well). Also, in another reference, Klemola et al reported on patients whose serologic and clinical manifestations were not those of infectious mononucleosis. Dr Jordan's statement: "In general, patients with CMV mononucleosis have less striking pharyngitis," is not accurate. An accurate statement would have been that patients with CMV disease—judging by the reports of Klemola et al—have very little or no pharyngitis. Dr Jordan admits that patients with "CMV mononucle¬ osis" have less lymphadenopathy than "their counterparts with EpsteinBarr virus infection," which is equated with what Dr Jordan terms "heterophil-positive mononucleosis." What I know about CMV disease is only what I have read, chiefly in Jor¬ dan's references, but what I know about infectious mononucleosis is based on personal experience extend¬ ing over a quarter of a century. Dur¬ ing this period I myself have ques¬ tioned and examined more than 500 patients and recorded the results. These patients all had clinical, héma¬ tologie, and sérologie evidence of mononucleosis. On the basis of care¬ fully and personally recorded data, I Edited
by John
D. Archer, MD, Senior Editor.
state emphatically that Dr Jor¬ dan is mistaken when he asserts that the "similarities between the two syndromes [CMV disease and 'heterophil-positive mononucleosis'] are far more compelling than their differ¬ ences." Furthermore, terming "heterophil-positive mononucleosis" a syn¬ drome rather than a disease entity is can
unwarranted. Dr Jordan states, "that a variety of different infectious agents can pro¬ duce identical clinical syndromes is
well known." This statement is mis¬ leading because CMV disease and in¬ fectious mononucleosis, as seen by me and many others, are far from clini¬ cally identical. It saddens me to see the great work of Paul-Bunnell-Davidson minimized by an inherent but unstated premise that the heterophil antibody test is not a decisive factor in diagnosis. Jor¬ dan thinks it "unreasonable" to dis¬ avow a diagnosis of infectious mono¬ nucleosis without heterophil antibody confirmation. Urging heterophil anti¬ body confirmation of clinical diag¬ noses of mononucleosis is not a per¬ sonal whim. Only after observing that hundreds of patients with typi¬ cal hématologie and sérologie find¬ ings had characteristic clinical mani¬ festations and that the patients with unusual or protean clinical manifesta¬ tions were those who had negative re¬ sults for heterophil antibody tests did I come to this not unreasonable con¬ clusion. Stated differently, I did not begin by setting up criteria for diag¬ nosis. They were generated by obser¬ vations and inductive reasoning. The fallacy in Dr Jordan's logic is called "begging the question": assum¬ ing the truth of a premise that has not been proved. In this case, Dr Jor¬ dan wishes us to believe that the clin¬ ical manifestations of CMV disease, and perhaps of other diseases, closely resemble those of mononucleosis. I have already stated why this premise is incorrect. Besides this critical point on which the decision between Dr Jordan's viewpoint and mine should be based, there is another point, namely, the
Downloaded From: http://jama.jamanetwork.com/ by a Simon Fraser University User on 06/05/2015
neutrophilia?
Robert J. Hoagland, MD Warrenton, Va
1. Klemola E, K\l=a"\\l=a"\ri\l=a"\inenL: Cytomegalovirus as a possible cause of a disease resembling infectious mononucleosis. Br Med J 2:1099-1102, 1965. 2. Klemola E, von Essen R, Henle G, et al: Infectious mononucleosis-like disease with negative heterophil agglutination test: Clinical features in relation to Epstein\x=req-\ Barr virus and cytomegalovirus antibodies. J Infect Dis 121:608-614, 1970.
Coronary Drug Project To the Editor.\p=m-\As a statistician, I object to the manner in which statistical hypothesis testing has been used to support negative conclusions in the report on the Coronary Drug Project (231:360, 1975). For example, we are told that "there is no evidence of significant efficacy of clofibrate with regard to total mortality or cause-specific mortality." It is difficult to object to the literal meaning of this circumspect language, but as I shall show, it is very misleading, for one might equally well say that there is no evidence against an important degree of efficacy. The authors seem to have made the common mistake of confusing statistical and practical significance. Specifically, they appear to believe that failure to obtain a statistically significant difference between drug and placebo implies that any true drug effect is likely to be small in practical terms. This is a gross delusion, even in studies such as this with a "large" number of patients. Consider, for example, the unad¬ justed five-year rates of death from coronary heart disease. The incidence was 16.2% on a regimen of placebo and 14.1% on a regimen of clofibrate. Expressed in terms of the number must
who would die on a regimen of pla¬ cebo, this amounts to an observed re¬ duction of 13%. Of course, sampling variation is a fact of life, and, hence, the authors subject this 13%-figure to a hypothesis test. The result is that the reduction is not "statistically sig¬ nificant" according to their criterion. This means that the data are con-
Five-Year Rates of Events*
Event
Niacin-Placebo i % of Patients Clofibrate-Placebo f With Event-*-, ,-*-, % 95% Confidence % Confidence 95% ,_«_, Limits Limits Difference Miacin Placebo Difference Clofibrate
Mortality
All causes All cardiovascular Coronary heart disease Combined mortality-morbidity Coronary death or definite, nonfatal myocardial infarction
+1
-12 -15 —18
+15 +13 +14
20.0 17.3 14.1
21.2 18.8 15.9
20.9 18.9 16.2
-4 -9 -13
-18 -23 -28
+9 +6 +3
23.8
22.8
26.2
—9
—21
+3_—13_—25_—2
'Unadjusted for baseline characteristics. tDifference in rate and confidence limits for difference, expressed
sistent with the celebrated "null hy¬ pothesis" of zero effect. But data will always be consistent with a whole range of hypotheses, if by "hypothe¬ sis" is meant an assumption of the size of true effect. Before concluding that the study demonstrates practical insignificance, one must look at the limits of this range, or "confidence in¬ terval," as it is called. In the present case, it can be calcu¬ lated that at the 95% confidence level, this interval runs from a true reduc¬ tion in coronary heart disease mortal¬ ity of 28% to an increase of 3%. The point is that at the stated level of confidence, each and every value in this range is consistent with the ex¬ perimental data. Few would dispute the clinical importance of a 28% true reduction. Thus, while we cannot con¬ clude that there is a practical benefi¬ cial effect on the basis of this study, we also cannot conclude that there is not. The data are simply consistent with both alternatives. Nor does changing the level of confidence make much difference, at least as far as the optimistic limit is concerned: 80% and 99% confidence limits run 23% reduction-3% reduction and 33% reduction-8% increase, respectively. Confidence limits for certain other events are given in the Table. For clofibrate therapy, they show that re¬ ductions of about 20% are consistent with the data, as are 0 reductions or some degree of increase. For the fatal events occurring during niacin ther¬ apy the optimistic limits are smaller and the pessimistic larger, but in ei¬ ther case, the extremes would repre¬ sent a drug effect (good or bad) of practical importance. Note also that the combination of coronary heart disease death or a nonfatal infarct might be reduced as much as 25% by niacin therapy. Thus, the appropriate conclusion concerning total or coronary heart disease mortality would appear to
-1 -2
percentages of placebo rate. be that the data cannot be used to limits is as
distinguish between important and small or zero effect. This represents a failure of this aspect of the project and should be recognized as such. As for a statement of inability to dis¬ criminate and a misleading state¬ ment of "no evidence" of effect, there is a difference. Those familiar with the statistical variability of count data will recognize this variability as the underlying problem. Finally, I should say that I do not challenge the increased incidence of nonfatal dele¬ terious effects, but wish to caution against attempting to assess the benefit-risk ratio in the absence of knowledge of the existence or degree of benefit. Daniel J. Gans, MS Pfizer Inc
Groton, Conn
Reply.\p=m-\Theprimary objective of the Coronary Drug Project, as described in its design monograph,1 was to detect with high probability any study drug that reduced five-year mortality from all causes by as much as 25%. We concluded, on the basis of the results, as does Mr Gans on the basis of his calculated confidence limits, that an effect of this magnitude can be excluded for either clofibrate or niacin. To have sought to detect smaller differences, which would obviously have been desirable, would have required at the outset more than the 8,341 patients that we studied. To be able to detect a reduction half as large (12.5%) would have required four times as many patients. It is for this reason logically impossible to establish that an agent has no effect, and we did not claim this. It is possible to agree with Mr Gans that there is a range of possible effects relative to five-year mortality and other end points as well that can¬ not be excluded. However, it is not acceptable to imply that "each and every value" within the confidence In
Downloaded From: http://jama.jamanetwork.com/ by a Simon Fraser University User on 06/05/2015
equally consistent with the experimental data. The observed five-year mortality in the Coronary Drug Project was 20.0% for clofi¬
brate, 21.2% for niacin, and 20.9% for
placebo. Clearly, the
true
population
values most consistent with the ob¬ served findings are, as Mr Gans indi¬ cates in his table, a 4% reduction in five-year mortality in the clofibrate group and a 1% increase in five-year mortality in the niacin group. As in¬ dicated in the same table, the 95% confidence limits for the clofibrateplacebo difference in five-year mortal¬ ity include all values between an 18% reduction and a 9% increase. But while all of the values within the con¬ fidence interval are in some sense "consistent" with the observed data, the degree of consistency with the ob¬ served data of the value 0 (no differ¬ ence) is 5.7 times that of the values -18% and +9%. (This is based on computation of likelihoods given no actual treatment effects and given an 18% reduction or a 9% increase in five-year mortality in the clofibrate
group.) To give a bit more balance to Mr Gans' presentation, it should be pointed out that if total follow-up ex¬ perience—ranging from 5 to 8lÁ years per patient—is considered, the mor¬ tality is 25.48% for clofibrate, 24.40% for niacin, and 25.42% for placebo. The true population values most con¬ sistent with these findings are a 0.2% increase in total mortality in the
clofibrate group and a 4% reduction in total mortality in the niacin group. We suggest that in addition to the distinction between statistical and practical significance, with which we are familiar, there is also a dis¬ tinction between data analysis and decision. At any given time, physi¬ cians must use the best information available to decide which, if any, of several therapies should be used for a particular class of patients; this is al-
"advantage" ture
Letters, if clearly marked "For Publication," will be published
as space permits and at the discretion of the editor. They should be typewritten triple-spaced, with five or fewer references, should not exceed two pages in length, and will be subject to editing. Letters
are
not
acknowledged.
Nomenclature for Mononucleosis Syndromes To the Editor.\p=m-\DrJordan's "Nomenclature for Mononucleosis Syndromes" (p 45) contains a statement that his use of the term mononucleosis "pertains only to those cases that meet standard clinical and hematologic criteria for infectious mononucleosis." This passage refers to my work in which I have emphasized the need for three criteria\p=m-\clinical,hematologic, and serologic\p=m-\forvalid
diagnoses. However, two paragraphs later, Dr Jordan states that Klemola1 has shown that the cytomegaloviruses (CMV) can cause a form of mononucleosis that is always heterophil antibody-negative. Yet, the article by
Klemola et al2 concerns a disease that is not clinically similar to mononucleosis (and is, in fact, serologically different as well). Also, in another reference, Klemola et al reported on patients whose serologic and clinical manifestations were not those of infectious mononucleosis. Dr Jordan's statement: "In general, patients with CMV mononucleosis have less striking pharyngitis," is not accurate. An accurate statement would have been that patients with CMV disease—judging by the reports of Klemola et al—have very little or no pharyngitis. Dr Jordan admits that patients with "CMV mononucle¬ osis" have less lymphadenopathy than "their counterparts with EpsteinBarr virus infection," which is equated with what Dr Jordan terms "heterophil-positive mononucleosis." What I know about CMV disease is only what I have read, chiefly in Jor¬ dan's references, but what I know about infectious mononucleosis is based on personal experience extend¬ ing over a quarter of a century. Dur¬ ing this period I myself have ques¬ tioned and examined more than 500 patients and recorded the results. These patients all had clinical, héma¬ tologie, and sérologie evidence of mononucleosis. On the basis of care¬ fully and personally recorded data, I Edited
by John
D. Archer, MD, Senior Editor.
state emphatically that Dr Jor¬ dan is mistaken when he asserts that the "similarities between the two syndromes [CMV disease and 'heterophil-positive mononucleosis'] are far more compelling than their differ¬ ences." Furthermore, terming "heterophil-positive mononucleosis" a syn¬ drome rather than a disease entity is can
unwarranted. Dr Jordan states, "that a variety of different infectious agents can pro¬ duce identical clinical syndromes is
well known." This statement is mis¬ leading because CMV disease and in¬ fectious mononucleosis, as seen by me and many others, are far from clini¬ cally identical. It saddens me to see the great work of Paul-Bunnell-Davidson minimized by an inherent but unstated premise that the heterophil antibody test is not a decisive factor in diagnosis. Jor¬ dan thinks it "unreasonable" to dis¬ avow a diagnosis of infectious mono¬ nucleosis without heterophil antibody confirmation. Urging heterophil anti¬ body confirmation of clinical diag¬ noses of mononucleosis is not a per¬ sonal whim. Only after observing that hundreds of patients with typi¬ cal hématologie and sérologie find¬ ings had characteristic clinical mani¬ festations and that the patients with unusual or protean clinical manifesta¬ tions were those who had negative re¬ sults for heterophil antibody tests did I come to this not unreasonable con¬ clusion. Stated differently, I did not begin by setting up criteria for diag¬ nosis. They were generated by obser¬ vations and inductive reasoning. The fallacy in Dr Jordan's logic is called "begging the question": assum¬ ing the truth of a premise that has not been proved. In this case, Dr Jor¬ dan wishes us to believe that the clin¬ ical manifestations of CMV disease, and perhaps of other diseases, closely resemble those of mononucleosis. I have already stated why this premise is incorrect. Besides this critical point on which the decision between Dr Jordan's viewpoint and mine should be based, there is another point, namely, the
Downloaded From: http://jama.jamanetwork.com/ by a Simon Fraser University User on 06/05/2015
neutrophilia?
Robert J. Hoagland, MD Warrenton, Va
1. Klemola E, K\l=a"\\l=a"\ri\l=a"\inenL: Cytomegalovirus as a possible cause of a disease resembling infectious mononucleosis. Br Med J 2:1099-1102, 1965. 2. Klemola E, von Essen R, Henle G, et al: Infectious mononucleosis-like disease with negative heterophil agglutination test: Clinical features in relation to Epstein\x=req-\ Barr virus and cytomegalovirus antibodies. J Infect Dis 121:608-614, 1970.
Coronary Drug Project To the Editor.\p=m-\As a statistician, I object to the manner in which statistical hypothesis testing has been used to support negative conclusions in the report on the Coronary Drug Project (231:360, 1975). For example, we are told that "there is no evidence of significant efficacy of clofibrate with regard to total mortality or cause-specific mortality." It is difficult to object to the literal meaning of this circumspect language, but as I shall show, it is very misleading, for one might equally well say that there is no evidence against an important degree of efficacy. The authors seem to have made the common mistake of confusing statistical and practical significance. Specifically, they appear to believe that failure to obtain a statistically significant difference between drug and placebo implies that any true drug effect is likely to be small in practical terms. This is a gross delusion, even in studies such as this with a "large" number of patients. Consider, for example, the unad¬ justed five-year rates of death from coronary heart disease. The incidence was 16.2% on a regimen of placebo and 14.1% on a regimen of clofibrate. Expressed in terms of the number must
who would die on a regimen of pla¬ cebo, this amounts to an observed re¬ duction of 13%. Of course, sampling variation is a fact of life, and, hence, the authors subject this 13%-figure to a hypothesis test. The result is that the reduction is not "statistically sig¬ nificant" according to their criterion. This means that the data are con-
Five-Year Rates of Events*
Event
Niacin-Placebo i % of Patients Clofibrate-Placebo f With Event-*-, ,-*-, % 95% Confidence % Confidence 95% ,_«_, Limits Limits Difference Miacin Placebo Difference Clofibrate
Mortality
All causes All cardiovascular Coronary heart disease Combined mortality-morbidity Coronary death or definite, nonfatal myocardial infarction
+1
-12 -15 —18
+15 +13 +14
20.0 17.3 14.1
21.2 18.8 15.9
20.9 18.9 16.2
-4 -9 -13
-18 -23 -28
+9 +6 +3
23.8
22.8
26.2
—9
—21
+3_—13_—25_—2
'Unadjusted for baseline characteristics. tDifference in rate and confidence limits for difference, expressed
sistent with the celebrated "null hy¬ pothesis" of zero effect. But data will always be consistent with a whole range of hypotheses, if by "hypothe¬ sis" is meant an assumption of the size of true effect. Before concluding that the study demonstrates practical insignificance, one must look at the limits of this range, or "confidence in¬ terval," as it is called. In the present case, it can be calcu¬ lated that at the 95% confidence level, this interval runs from a true reduc¬ tion in coronary heart disease mortal¬ ity of 28% to an increase of 3%. The point is that at the stated level of confidence, each and every value in this range is consistent with the ex¬ perimental data. Few would dispute the clinical importance of a 28% true reduction. Thus, while we cannot con¬ clude that there is a practical benefi¬ cial effect on the basis of this study, we also cannot conclude that there is not. The data are simply consistent with both alternatives. Nor does changing the level of confidence make much difference, at least as far as the optimistic limit is concerned: 80% and 99% confidence limits run 23% reduction-3% reduction and 33% reduction-8% increase, respectively. Confidence limits for certain other events are given in the Table. For clofibrate therapy, they show that re¬ ductions of about 20% are consistent with the data, as are 0 reductions or some degree of increase. For the fatal events occurring during niacin ther¬ apy the optimistic limits are smaller and the pessimistic larger, but in ei¬ ther case, the extremes would repre¬ sent a drug effect (good or bad) of practical importance. Note also that the combination of coronary heart disease death or a nonfatal infarct might be reduced as much as 25% by niacin therapy. Thus, the appropriate conclusion concerning total or coronary heart disease mortality would appear to
-1 -2
percentages of placebo rate. be that the data cannot be used to limits is as
distinguish between important and small or zero effect. This represents a failure of this aspect of the project and should be recognized as such. As for a statement of inability to dis¬ criminate and a misleading state¬ ment of "no evidence" of effect, there is a difference. Those familiar with the statistical variability of count data will recognize this variability as the underlying problem. Finally, I should say that I do not challenge the increased incidence of nonfatal dele¬ terious effects, but wish to caution against attempting to assess the benefit-risk ratio in the absence of knowledge of the existence or degree of benefit. Daniel J. Gans, MS Pfizer Inc
Groton, Conn
Reply.\p=m-\Theprimary objective of the Coronary Drug Project, as described in its design monograph,1 was to detect with high probability any study drug that reduced five-year mortality from all causes by as much as 25%. We concluded, on the basis of the results, as does Mr Gans on the basis of his calculated confidence limits, that an effect of this magnitude can be excluded for either clofibrate or niacin. To have sought to detect smaller differences, which would obviously have been desirable, would have required at the outset more than the 8,341 patients that we studied. To be able to detect a reduction half as large (12.5%) would have required four times as many patients. It is for this reason logically impossible to establish that an agent has no effect, and we did not claim this. It is possible to agree with Mr Gans that there is a range of possible effects relative to five-year mortality and other end points as well that can¬ not be excluded. However, it is not acceptable to imply that "each and every value" within the confidence In
Downloaded From: http://jama.jamanetwork.com/ by a Simon Fraser University User on 06/05/2015
equally consistent with the experimental data. The observed five-year mortality in the Coronary Drug Project was 20.0% for clofi¬
brate, 21.2% for niacin, and 20.9% for
placebo. Clearly, the
true
population
values most consistent with the ob¬ served findings are, as Mr Gans indi¬ cates in his table, a 4% reduction in five-year mortality in the clofibrate group and a 1% increase in five-year mortality in the niacin group. As in¬ dicated in the same table, the 95% confidence limits for the clofibrateplacebo difference in five-year mortal¬ ity include all values between an 18% reduction and a 9% increase. But while all of the values within the con¬ fidence interval are in some sense "consistent" with the observed data, the degree of consistency with the ob¬ served data of the value 0 (no differ¬ ence) is 5.7 times that of the values -18% and +9%. (This is based on computation of likelihoods given no actual treatment effects and given an 18% reduction or a 9% increase in five-year mortality in the clofibrate
group.) To give a bit more balance to Mr Gans' presentation, it should be pointed out that if total follow-up ex¬ perience—ranging from 5 to 8lÁ years per patient—is considered, the mor¬ tality is 25.48% for clofibrate, 24.40% for niacin, and 25.42% for placebo. The true population values most con¬ sistent with these findings are a 0.2% increase in total mortality in the
clofibrate group and a 4% reduction in total mortality in the niacin group. We suggest that in addition to the distinction between statistical and practical significance, with which we are familiar, there is also a dis¬ tinction between data analysis and decision. At any given time, physi¬ cians must use the best information available to decide which, if any, of several therapies should be used for a particular class of patients; this is al-
