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The basic elements of clinical science
J. chron. Dis. 1963, Vol. 16, pp. 1125-l 133. Pergamon Press Ltd. Printed in Great Britain
Editorial
THE BASIC ELEMENTS
(Received
OF CLINICAL
20 April
SCIENCE
1963)
IN MOST medical centers today, laboratories have become the major sites of research. Although the substances studied in the laboratory often come from patients, the bedside is used mainly for teaching and providing medical care. It is seldom used for investigations of clinical phenomena because most investigators believe such research cannot be scientific. Behind this belief lies the assumption that complex problems are best attacked by reduction to their basic components. and that the complications of multiple human variables should be avoided and replaced by experimental use of animals, microorganisms, tissues, cells, or infracellular and inanimate preparations. This type of fundamental scientific investigation in the laboratory is the best approach to many biologic problems, and the advances resulting from it have illuminated many areas in human disease. Yet, despite the progress achieved and anticipated from laboratory exploration of basic biologic mechanisms, scientific clinical studies of man at the bedside are also necessary in medical research for at least three reasons: (1) Many diseases cannot be adequately reproduced in nonhuman subjects. (2) Laboratory data, when derived from animals, cannot always be applied to man, and, when derived from man, lose much of their scientific quality if fused with unscientific clinical observations. (3) A complex clinical problem can rarely be solved merely by isolated investigations of its individual parts; its solution also requires separate study of the interaction of those parts in the integrated organism. These strictures pertain especially to chronic, degenerative and neoplastic diseases, now prime targets of investigation. The current concept that worthwhile research can be done only in the laboratory implies that an academic physician must function either as a nonclinical scientist or as a nonscientific clinician. An alternative activity, however, is available. He can do scientific clinical work with patients at the bedside. The prevalent belief that such work cannot be done arises because clinical investigators have generally failed to insist on the same standards for collection and organization of data at the bedside as in the laboratory. Absence of such standards has led to neglect of basic scientific requirements for reproducibility of clinical results. 1125
1126
ALVAN R. FEINSTEIN
The reproducibility of scientific work depends upon how well it is described by the methods used to acquire and classify the primary data. Statistical analysis is a secondary procedure, imposed on the main data for interpretation, reduction, or elaboration; it does not correct fundamental errors, insert omitted facts, or validate faulty reasoning. Although clinical investigators have greatly improved the methods used for statistical design and analysis, the primary data often remain defective. To increase the scientific potential of the bedside, investigators must also improve the methods for obtaining and organizing the basic data of human illness: symptoms, signs, and patterns of disease. CLASSIFICATION
OF
CLINICAL
DATA
The development of pathology and the subsequent correlation of clinical diagnosis with autopsy findings created a discipline of diagnostic accuracy in medicine, and led to the histopathologic system of disease classification. As a primary classification of diseases, this system is excellent, but its categories no longer provide enough details for the needs of modern medicine. Specific new diagnostic and therapeutic advances have enabled diseases to be recognized early, identified accurately, and treated effectively. This expansion of natural history gives clinicians a view of many aspects of disease that cannot be seen by pathologists. Histopathologic terminology is inadequate for the total clinical spectra of disease, and must be supplemented by additional classifications that describe not merely the names of diseases, but their clinical behavior. The new classifications, augmenting those that tell what a disease is, should add what it does, as determined from two major considerations. (1) Pattern of manifestations Clinicians see symptoms and signs, not histopathologic lesions. Clinicians cannot detect ‘myocardial infarction’, ‘rheumatic carditis’, or other tissue changes. They take histories, do physical examinations, order supplementary tests and then make inferences called ‘diagnoses’. These diagnostic inferences are important and necessary for doctor and patient in naming disease and planning treatment. When the inferences are used for additional scientific purposes, their single diagnostic titles are inadequate. Each disease must be subclassified by the patterns manifested in its symptoms and signs. For example, the outcome of recognizable acute rheumatic fever has recently become strikingly predictable by dividing patients, according to clinical manifestations, into groups with: (a) no significant murmurs, (b) significant apical systolic murmurs, (c) diastolic murmurs, or (d) significant cardiac enlargement or congestive heart failure. Correlation of subsequent clinical course with these initial classifications shows that the four groups have distinctly different cardiac prognoses but that the individual groups are reasonably homogeneous, and their prognoses are predictable with accuracy previously impossible. These clinical categories, when correlated with laboratory and therapeutic data, have also demonstrated how cardiac status may affect antibody response to streptococcal infections, and how confiicting results in studies of treatment have arisen because heterogeneous patients were combined indiscriminately into a single diagnostic entity of ‘acute rheumatic fever’. Because every disease has various patterns of manifestation, the subclassification
Editorial
1127
of patients by symptoms and signs is needed to avoid mixing different patients into a homogenate that is useless for comparative correlations. In the contemporary investigation of coronary heart disease, for example, the geographic, dietary, psychic, occupational, ethnic, biochemical, therapeutic and other features have been refined and studied with enormous care and effort, but the initial clinical classification of patients remains remarkably inconsistent and crude. Some reports merely put all patients together as ‘coronary heart disease’; in others, the patients are divided into groups, but only according to the presence or absence of angina, previous infarction, or a collection of ‘poor risk’ features. All these categories are too broad and must be further divided. In myocardial infarction, appropriate features for the divisions could be age, sex, previous coronary history, and associated clinical events such as shock, congestive failure, arrythmias, hypertension and various other factors. Similar subdivisions would apply to patients with angina or with asymptomatic coronary disease discovered accidentally. In such subdivisions. the many possible variables and subgroups may be distressing to both clinician and statistician. Nevertheless, even if each subgroup has a small number of patients, the initial divisions are necessary to prevent inadvertent consolidation of dissimilar groups. Later, after data are analyzed, the numbers can be made larger by combining appropriate subgroups when possible. Clinical, not statistical, significance is the object. Small amounts of consistent, homogeneous data will be clear and reproducible. Large melanges of unknown proportion and diverse content may yield numbers that are statistically significant, but the results will remain clinically meaningless no matter how elegant the imposed experiments and analyses. (2)
Pattern of discovery
The reason that a patient decides to see a doctor is a crucial feature of the natural history of a disease, and may be due to accident, to appearance of classical signs or symptoms, or to development of a ‘complication’. This reason must be determined and classified in order to evaluate the subsequent course and other relationships. For example, diabetes mellitus may sometimes be discovered unexpectedly as an incident of routine urinalysis; sometimes it is found during periodic testing of a patient with a family history of the disease. Some patients come to a doctor because of polydipsia and polyuria; in others, diabetes is found at a medical examination prompted by development of a foot ulcer or visual difficulty. In some patients, a ‘complication’ is the first manifestation of illness; in others, who are asymptomatic, the disease is found accidentally, if at all. Since the disease behaves differently with each of these modes of presentation and discovery, its clinical. laboratory, experimental and therapeutic data must be correlated accordingly. Similarly, in certain patients with neoplasia, length of survival may be related to how and why the disease was found. Some tumors look like cancer but do not have a rapidly lethal clinical course. The unequal malignancy of neoplasms is demonstrated by the occasional long survival of patients who refused treatment and by unsuspected tumors found at routine autopsy. By microscopic examination,
1128
ALVAN R. FEINSTEIN
pathologists can describe and categorize neoplasms but often cannot predict their clinical behavior. The predictability may be improved by studying the outcome of patients classified according to whether the neoplasm was found because specific symptoms or signs evoked medical aid, or whether the patient was asymptomatic and the neoplasm was discovered by accident. Neoplasms found unexpectedly have been present for unknown lengths of time; since each is usually treated when discovered, its natural course and lethal potential are also unknown. Conceivably, some or many ‘early’ tumors now being ‘cured’ by radical surgery or irradiation might have had equally long courses without drastic treatment. Existing clinical data could quickly prove or refute the hypothesis that asymptomatic patients found accidentally to have neoplasms or other diseases often have good prognoses regardless of the type of therapy. Many clinical records, however, cannot be used for this purpose. The records contain descriptions of chief complaints and other symptoms, pathologic and laboratory data, time and types of treatment, and therapeutic responses. The records often omit the specific exact details of how and why the patient decided to seek the examination that led to discovery of his disease. Patterns of presentation are important for understanding pathogenesis as well as prognosis. The realization that spectra of disease contain remarkably silent portions has recently unmasked several previously mysterious clinical entities. Hepatic cirrhosis in many nonalcoholic patients with no history of previous jaundice, and rheumatic heart disease in patients with no history of previous rheumatic fever, are now recognized as insidious effects of scar tissue begun during acute inflammation that was undetected in its asymptomatic acute stage. Clinicians do not study disease only as pathologists and should not classify it only by pathologic nomenclature. Behavioral classifications, based on the patterns by which diseases are discovered and manifested, will augment the value of histopathologic data in creating reproducible clinical substrates for subsequent investigation and correlation. The preparation of such classifications will frequently require analysis of hospital records of large numbers of patients whose data cannot all be obtained directly by a single investigator and must be used as recorded. The medical record of a patient’s hospitalization or clinic visit contains notes of the planned experiments performed in clinical management. The scientific value of this notebook rests upon the accuracy and thoroughness of the recorded observations. In the current emphasis on laboratory tests, the clinical content of many medical records has deteriorated. The records have sometimes become compendia of multiple, complex laboratory data accompanied by a smattering of admission notes and consultants’ opinions, with sparse description of the patient’s reactions before, during, and after hospitalization. The attention often given to maintenance of careful notes of laboratory experiments is seldom taught at the bedside and is not generally applied to the recording of clinical observations. For effective behavioral classification of diseases, the quality of medical records must be improved to include adequate descriptions of clinical patterns and subsequent events. The formation and analysis of classifications can be helped by recording data with mechanical devices, such as punch cards and computers, but no machinery, however ingenious, can replace the scientific clinician for deciding
1129
Editorial
what information to use, for ensuring that the requisite data are obtained recorded, and for establishing (as noted below) that the data are accurate. ACCURACY
IN
MEASUREMENT
OF
CRITICAL
and
VARIABLES
Classifying clinical data poses one set of problems; determining the basic accuracy of the data poses another. Data from laboratory tests or biopsy can usually be easily standardized. In certain diseases, however, critical variables cannot be measured by laboratory tests or biopsy and require evaluation of symptoms and signs. This is true when diagnoses depend mainly on history, as in coronary heart disease, on physical examination, as in rheumatic heart disease, or on both, as in cerebrovascular disease. It also applies when the significant therapeutic variables are in clinical events such as cardiac, neurologic, or vascular deterioration. When the crucial parameters are clinical, the laboratory measurements of intricate biochemical, physiologic or immunologic phenomena will provide adjuncts that, although impressive and interesting, have only secondary significance. The primary data in such diseases must come directly from the patient and are collected by an apparatus called a physician. Accurate function of this apparatus is essential in providing care for patients and is equally important in compiling scientific data. Although physicians are irreplaceable as the apparatus that performs clinical examination, they are rarely tested by the confirmatory inspections and calibration given equipment in the laboratory. The absence of better methods for objectivity and accuracy at the bedside is a critical defect of clinical science. A few approaches to ‘calibration’ of the physician are considered below. History-taking
In history-taking, physicians may make several kinds of error. They may miss important information by failing to permit the patient to express himself thoroughly. In addition to such errors of omission, errors of commission occur when physicians allow their attitude, manner of questioning, and interpretation of replies to be influenced by their own conscious or subconscious preconceptions. Consequently, the patient’s perception of certain symptoms may be altered, or the description recorded in the chart may be distorted. The frequency and magnitude of these and other errors in history-taking are generally unknown. Variability in physical examination is occasionally studied, but discrepancies in history-taking are rarely investigated. Taught to students at a time in medical training when they can least comprehend clinical subtleties, history-taking usually remains untaught thereafter and its techniques unexplored. The cautious examinations of data in the laboratory, and the long hours spent in establishing accuracy of equipment and of the technicians who use it, are not often duplicated at bedside rounds, where the examinations of attending physicians may be credulous and brief. The physicians may accept histories as presented and check only those physical findings reported to be abnormal. This approach saves time for discussing the clinical data but fails to teach how to acquire or to verify the data. By watching a rapid physical examination, students learn little save its motions because they cannot, as individuals, simultaneously feel or hear the same things as the attending physician. By listening to him take a salient history, they
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would learn much because what he asks and hears in reply is audible to all. History-taking is the most subtle and complex function of clinical apparatus, and can be learned well only from direct observation of that function. If history-taking is not demonstrated at the bedside, young physicians are deprived of instruction in their most important skill. If crucial historical data are not checked directly with patients, inaccuracies may pass unchallenged. Some errors of history-taking might be prevented by use of a fixed set of written questions. This objective approach can improve certain kinds of data but it will usually fail to allow patients thorough expression and it cannot evaluate nuances and reliability of answers. In specific studies that use historical data as a critica variable, calibration or standardization can be obtained by using special forms, supplemented by a review of important symptoms with each patient directly by a responsible, alert investigator. Physical examination This procedure can be divided into functions that are descriptive, interpretive and diagnostic. (By description, a blanching red area is observed on the skin, with a nonblanching darker red center. By interpretation, it is called a petechia surrounded by erythema. By diagnosis, it is attributed to meningococcemia.) The records of physical examination should always contain full descriptions. Certain interpretations can be used when the terms are clear and beyond dispute. (Thus, the term ‘murmur’ is generally permissible as an interpretation to replace the descriptive term ‘noise’.) Diagnosis, however, is not part of the description of physical findings, and should be reserved for the concluding ‘impression’. Failure to recognize these components in physical examination may lead to serious errors of omission and commission: (1) The description may be inadequate for later interpretation. (2) Instead of describing, the examiner may interpret or make diagnoses, using stated or unstated criteria that are erroneous or nonstandard. (3) The interpretations may be biased by knowledge of other clinical data. These errors are illustrated as follows : (1) An examiner may describe the intensity, radiation, pitch and quality of an apical systolic murmur, and omit such properties as duration, site of maximum intensity and response to deep inspiration. Absence of the latter data may then impede differentiation of the murmur as physiologic or organic in a young patient with rheumatic fever. (2) When examiners describe cardiac auscultation only in phrases such as ‘mitral regurgitation murmur’, ‘pericardial friction rub’, or ‘opening snap of mitra1 valve’, they use acoustic gestalts that cannot be verified and that close the examiner’s mind to other possibilities. (3) White spots in the fundus of a patient with diabetes or hypertension may be called ‘retinopathy’ by a physician who knows the clinical diagnosis and ‘drusen’ by a more objective ophthalmoscopist. The interpretation of X-ray films, an adjunct to physical examination, is also often biased by clinical data. The same film can sometimes receive a dramatically different reading when it is reviewed ‘blindly’ by the same radiologist supplied with different clinical data.
Editorial
1131
Increased accuracy in physical examination requires that examiners first describe, and then interpret, using criteria that are based on adequately detailed descriptions of important parameters. At bedside rounds, the attending physician should examine selected areas before he is told what his colleagues have found there. Occasional or even frequent differences between his observations and theirs will be not deplorable, but desirable, since they will illustrate the range of variation in the examining apparatus and teach precision in its use. In specific scientific studies, calibration can be obtained by having crucial physical findings confirmed by objective, independent examiners unaware of previous opinions. For example, the latter approach has been used with remarkable success for long-term periodic examinations of patients who have had rheumatic fever. By ‘blind’ auscultation, the physician examines the patient at each clinic visit before looking at the chart, forms his tentative auscultatory impressions, and then compares his opinion with those previously recorded. In this way his first reactions are unaffected by prior comments and he can detect his own inconsistencies, errors, and differences in criteria. The process inevitably develops auscultatory skill, precision, and standardization. Calibration of multiple examiners
When many examining physicians are used in a scientific clinical study, they should be assembled beforehand to calibrate examination of critical areas in a selected group of ‘unknown’ patients. This procedure cannot adequately be replaced by uniform oral or written agreement on details of examining criteria and techniques. Examiners must check and compare results in the same patients in order to be certain that the actual examinations are not performed with subtle individual differences that may create otherwise unexplainable deviations in data. For example, a recent study of treatment in acute rheumatic fever, performed cooperatively by investigators at 12 different centers, was designed with careful written criteria for interpretation of cardiac auscultation, but the actual performance of auscultation was not calibrated. Although the types of patient initially selected for examination at the 12 centers did not seem significantly different, basal diastolic murmurs were reported in 80 per cent of the patients at one institution but in only about 10 per cent of patients at the other 11 centers. The inconsistency, discovered after the study was completed, could not be rectified or explained. It might have arisen from subtle differences either in the patient population or in the way the examining physicians interpreted the noises heard on auscultation. Without calibration, the physicians could not be excluded as the cause of the inconsistency. Consequently, the divergent data were excluded from the analysis of total results. In that circumstance, the statistical appraisals of cooperatively obtained data could make proviso for the disparity. In other clinical trials, however, when the ‘same’ study is performed by many separate investigators, no common appraisal of the data is possible. If the isolated results disagree, they cannot be reconciled. This situation is prevalent in current studies of anticoagulant therapy in coronary heart disease. The methods used by different investigators for assessing the critical variables of symptoms and signs (and also electrocardiographic tracings) are often dissimilar, despite apparent agreement in written descriptions of the procedures. The direct calibration of a group of examiners may seem strange and may be
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ALVAN R. FEINSTEIN
inconvenient when the examiners must come long distances. In scientific medicine, however, this type of calibration cannot be omitted. Without it, investigators cannot discern the sources of conflict in clinical studies that reach contradictory conclusions_ Great effort is often expended in repeating the studies, but the results seldom bring the desired distinctions because the basic, hidden discrepancies remain unaltered. CONCLUSIONS
These illustrations have shown how clinicians seeking ‘science’ often neglect the scientific importance of data from patients at the bedside. Lack of reproducibility in primary clinical data creates fundamental deficiencies that cannot be remedied by the experiments or analyses imposed subsequently. Many clinical experiments cannot be confirmed or refuted because they cannot be duplicated; hence erroneous conclusions can remain undetected and can be perpetuated. The deficiencies in clinical data prevent advantageous correlation of magnificent new biologic, biochemical, and biophysical methods. These problems impede the effective application and evaluation of advances in medical and surgical therapy. The problems will not be solved by modern techniques for experimental design and data analysis, and may even be aggravated thereby. Nor can they be solved by greater use of computers, massive clinical trials, or increasingly complex laboratory and statistical maneuvers. As long as the basic clinical data remain defective, no amount of subsequent processing can improve them. To improve classification and accuracy of clinical data requires no special equipment. The simple techniques described here for history-taking and physical examination can be helpful and should be used when possible. The improvement will not occur, however, without a renaissance of attention to the three observational disciplines that are the primary and unique skills of the clinician: history-taking, physical examination and maintenance of a record of human illness. These skills: appear to be atrophying at many academic centers where clinical science has been caught in the arc of a vicious circle. Some investigators assume that research can be done only in the laboratory, not at the bedside. The bedside therefore remains scientifically barren because its science is not taught or practised. The subsequent absence of scientific clinical work then confirms and continues the original assumption. Clearly, medicine needs good research at the bedside as well as in the laboratory. If one area becomes exclusive or suppressive of the other, neither can achieve maximum growth or fruition, since they are interdependent and complementary. Perceptive scientific experiments can be done in the ward or examining room as well as in the cage or test tube, but human subjects must be managed by abilities, skills and techniques completely different from those of the laboratory. The clinician who is not a scientist cannot perform an accurate examination. The scientist who does not care for patients may be unable to cope well with human beings as his experimental subjects, and may fail to develop the rapport and understanding that produce a complete and accurate history and that help sustain the patient’s continued experimental participation. A good relationship between physician and
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1133
patient is thus important, not merely as an honorable and traditional part of good medical practice, but as a necessary tool for acquiring scientific data. These concepts may seem trivial and obvious to investigators who are unaware that a major distinction between laboratory and clinical science is the ease with which experimental material can be reproduced. To attain reproducibility for intricate clinical data is extraordinarily difficult and requires careful attention to improving the techniques for recording and classifying symptoms, signs, and clinical patterns. Some investigators may feel that these observational activities of ‘clinical taxonomy’ do not offer the experimental excitement of the laboratory. Without an effective, accurate, descriptive taxonomy, however, biologic investigation has no order or logic for its data or its concepts. Human illness is too complex for its research to be confined to laboratory techniques and laboratory data. The observation and classification of diseased patients must begin. scientifically as well as medically, by realizing their individual distinctions as sick patients and not merely as diseased tissues. Investigation at the bedside will never attain the exact precision achieved in the laboratory. Nevertheless, scientific advances depend not upon where but upon how the work is done. Science comes from the intelligence, imagination, perseverance and insight of the investigator. whether the basic elements of his data are obtained from molecules or man. Unless the basic elements of clinical medicine-symptoms, signs and patterns-are studied and used scientifically, the continued clinical application of isolated advances from the laboratory may bring only scientific dignity without scientific clarity. Without science at the bedside, modem medical research may yield an intricately designed, expensively produced, doubly-blind controlled. statistically significant chaos.
ALVAN R. FEINSTEIN
Assistant Professor of Medicine, Yde University School of Medicine and Chief, Clinical Pharmacology. West Haven Veterans Administration Hospital
Editorial
THE BASIC ELEMENTS
(Received
OF CLINICAL
20 April
SCIENCE
1963)
IN MOST medical centers today, laboratories have become the major sites of research. Although the substances studied in the laboratory often come from patients, the bedside is used mainly for teaching and providing medical care. It is seldom used for investigations of clinical phenomena because most investigators believe such research cannot be scientific. Behind this belief lies the assumption that complex problems are best attacked by reduction to their basic components. and that the complications of multiple human variables should be avoided and replaced by experimental use of animals, microorganisms, tissues, cells, or infracellular and inanimate preparations. This type of fundamental scientific investigation in the laboratory is the best approach to many biologic problems, and the advances resulting from it have illuminated many areas in human disease. Yet, despite the progress achieved and anticipated from laboratory exploration of basic biologic mechanisms, scientific clinical studies of man at the bedside are also necessary in medical research for at least three reasons: (1) Many diseases cannot be adequately reproduced in nonhuman subjects. (2) Laboratory data, when derived from animals, cannot always be applied to man, and, when derived from man, lose much of their scientific quality if fused with unscientific clinical observations. (3) A complex clinical problem can rarely be solved merely by isolated investigations of its individual parts; its solution also requires separate study of the interaction of those parts in the integrated organism. These strictures pertain especially to chronic, degenerative and neoplastic diseases, now prime targets of investigation. The current concept that worthwhile research can be done only in the laboratory implies that an academic physician must function either as a nonclinical scientist or as a nonscientific clinician. An alternative activity, however, is available. He can do scientific clinical work with patients at the bedside. The prevalent belief that such work cannot be done arises because clinical investigators have generally failed to insist on the same standards for collection and organization of data at the bedside as in the laboratory. Absence of such standards has led to neglect of basic scientific requirements for reproducibility of clinical results. 1125
1126
ALVAN R. FEINSTEIN
The reproducibility of scientific work depends upon how well it is described by the methods used to acquire and classify the primary data. Statistical analysis is a secondary procedure, imposed on the main data for interpretation, reduction, or elaboration; it does not correct fundamental errors, insert omitted facts, or validate faulty reasoning. Although clinical investigators have greatly improved the methods used for statistical design and analysis, the primary data often remain defective. To increase the scientific potential of the bedside, investigators must also improve the methods for obtaining and organizing the basic data of human illness: symptoms, signs, and patterns of disease. CLASSIFICATION
OF
CLINICAL
DATA
The development of pathology and the subsequent correlation of clinical diagnosis with autopsy findings created a discipline of diagnostic accuracy in medicine, and led to the histopathologic system of disease classification. As a primary classification of diseases, this system is excellent, but its categories no longer provide enough details for the needs of modern medicine. Specific new diagnostic and therapeutic advances have enabled diseases to be recognized early, identified accurately, and treated effectively. This expansion of natural history gives clinicians a view of many aspects of disease that cannot be seen by pathologists. Histopathologic terminology is inadequate for the total clinical spectra of disease, and must be supplemented by additional classifications that describe not merely the names of diseases, but their clinical behavior. The new classifications, augmenting those that tell what a disease is, should add what it does, as determined from two major considerations. (1) Pattern of manifestations Clinicians see symptoms and signs, not histopathologic lesions. Clinicians cannot detect ‘myocardial infarction’, ‘rheumatic carditis’, or other tissue changes. They take histories, do physical examinations, order supplementary tests and then make inferences called ‘diagnoses’. These diagnostic inferences are important and necessary for doctor and patient in naming disease and planning treatment. When the inferences are used for additional scientific purposes, their single diagnostic titles are inadequate. Each disease must be subclassified by the patterns manifested in its symptoms and signs. For example, the outcome of recognizable acute rheumatic fever has recently become strikingly predictable by dividing patients, according to clinical manifestations, into groups with: (a) no significant murmurs, (b) significant apical systolic murmurs, (c) diastolic murmurs, or (d) significant cardiac enlargement or congestive heart failure. Correlation of subsequent clinical course with these initial classifications shows that the four groups have distinctly different cardiac prognoses but that the individual groups are reasonably homogeneous, and their prognoses are predictable with accuracy previously impossible. These clinical categories, when correlated with laboratory and therapeutic data, have also demonstrated how cardiac status may affect antibody response to streptococcal infections, and how confiicting results in studies of treatment have arisen because heterogeneous patients were combined indiscriminately into a single diagnostic entity of ‘acute rheumatic fever’. Because every disease has various patterns of manifestation, the subclassification
Editorial
1127
of patients by symptoms and signs is needed to avoid mixing different patients into a homogenate that is useless for comparative correlations. In the contemporary investigation of coronary heart disease, for example, the geographic, dietary, psychic, occupational, ethnic, biochemical, therapeutic and other features have been refined and studied with enormous care and effort, but the initial clinical classification of patients remains remarkably inconsistent and crude. Some reports merely put all patients together as ‘coronary heart disease’; in others, the patients are divided into groups, but only according to the presence or absence of angina, previous infarction, or a collection of ‘poor risk’ features. All these categories are too broad and must be further divided. In myocardial infarction, appropriate features for the divisions could be age, sex, previous coronary history, and associated clinical events such as shock, congestive failure, arrythmias, hypertension and various other factors. Similar subdivisions would apply to patients with angina or with asymptomatic coronary disease discovered accidentally. In such subdivisions. the many possible variables and subgroups may be distressing to both clinician and statistician. Nevertheless, even if each subgroup has a small number of patients, the initial divisions are necessary to prevent inadvertent consolidation of dissimilar groups. Later, after data are analyzed, the numbers can be made larger by combining appropriate subgroups when possible. Clinical, not statistical, significance is the object. Small amounts of consistent, homogeneous data will be clear and reproducible. Large melanges of unknown proportion and diverse content may yield numbers that are statistically significant, but the results will remain clinically meaningless no matter how elegant the imposed experiments and analyses. (2)
Pattern of discovery
The reason that a patient decides to see a doctor is a crucial feature of the natural history of a disease, and may be due to accident, to appearance of classical signs or symptoms, or to development of a ‘complication’. This reason must be determined and classified in order to evaluate the subsequent course and other relationships. For example, diabetes mellitus may sometimes be discovered unexpectedly as an incident of routine urinalysis; sometimes it is found during periodic testing of a patient with a family history of the disease. Some patients come to a doctor because of polydipsia and polyuria; in others, diabetes is found at a medical examination prompted by development of a foot ulcer or visual difficulty. In some patients, a ‘complication’ is the first manifestation of illness; in others, who are asymptomatic, the disease is found accidentally, if at all. Since the disease behaves differently with each of these modes of presentation and discovery, its clinical. laboratory, experimental and therapeutic data must be correlated accordingly. Similarly, in certain patients with neoplasia, length of survival may be related to how and why the disease was found. Some tumors look like cancer but do not have a rapidly lethal clinical course. The unequal malignancy of neoplasms is demonstrated by the occasional long survival of patients who refused treatment and by unsuspected tumors found at routine autopsy. By microscopic examination,
1128
ALVAN R. FEINSTEIN
pathologists can describe and categorize neoplasms but often cannot predict their clinical behavior. The predictability may be improved by studying the outcome of patients classified according to whether the neoplasm was found because specific symptoms or signs evoked medical aid, or whether the patient was asymptomatic and the neoplasm was discovered by accident. Neoplasms found unexpectedly have been present for unknown lengths of time; since each is usually treated when discovered, its natural course and lethal potential are also unknown. Conceivably, some or many ‘early’ tumors now being ‘cured’ by radical surgery or irradiation might have had equally long courses without drastic treatment. Existing clinical data could quickly prove or refute the hypothesis that asymptomatic patients found accidentally to have neoplasms or other diseases often have good prognoses regardless of the type of therapy. Many clinical records, however, cannot be used for this purpose. The records contain descriptions of chief complaints and other symptoms, pathologic and laboratory data, time and types of treatment, and therapeutic responses. The records often omit the specific exact details of how and why the patient decided to seek the examination that led to discovery of his disease. Patterns of presentation are important for understanding pathogenesis as well as prognosis. The realization that spectra of disease contain remarkably silent portions has recently unmasked several previously mysterious clinical entities. Hepatic cirrhosis in many nonalcoholic patients with no history of previous jaundice, and rheumatic heart disease in patients with no history of previous rheumatic fever, are now recognized as insidious effects of scar tissue begun during acute inflammation that was undetected in its asymptomatic acute stage. Clinicians do not study disease only as pathologists and should not classify it only by pathologic nomenclature. Behavioral classifications, based on the patterns by which diseases are discovered and manifested, will augment the value of histopathologic data in creating reproducible clinical substrates for subsequent investigation and correlation. The preparation of such classifications will frequently require analysis of hospital records of large numbers of patients whose data cannot all be obtained directly by a single investigator and must be used as recorded. The medical record of a patient’s hospitalization or clinic visit contains notes of the planned experiments performed in clinical management. The scientific value of this notebook rests upon the accuracy and thoroughness of the recorded observations. In the current emphasis on laboratory tests, the clinical content of many medical records has deteriorated. The records have sometimes become compendia of multiple, complex laboratory data accompanied by a smattering of admission notes and consultants’ opinions, with sparse description of the patient’s reactions before, during, and after hospitalization. The attention often given to maintenance of careful notes of laboratory experiments is seldom taught at the bedside and is not generally applied to the recording of clinical observations. For effective behavioral classification of diseases, the quality of medical records must be improved to include adequate descriptions of clinical patterns and subsequent events. The formation and analysis of classifications can be helped by recording data with mechanical devices, such as punch cards and computers, but no machinery, however ingenious, can replace the scientific clinician for deciding
1129
Editorial
what information to use, for ensuring that the requisite data are obtained recorded, and for establishing (as noted below) that the data are accurate. ACCURACY
IN
MEASUREMENT
OF
CRITICAL
and
VARIABLES
Classifying clinical data poses one set of problems; determining the basic accuracy of the data poses another. Data from laboratory tests or biopsy can usually be easily standardized. In certain diseases, however, critical variables cannot be measured by laboratory tests or biopsy and require evaluation of symptoms and signs. This is true when diagnoses depend mainly on history, as in coronary heart disease, on physical examination, as in rheumatic heart disease, or on both, as in cerebrovascular disease. It also applies when the significant therapeutic variables are in clinical events such as cardiac, neurologic, or vascular deterioration. When the crucial parameters are clinical, the laboratory measurements of intricate biochemical, physiologic or immunologic phenomena will provide adjuncts that, although impressive and interesting, have only secondary significance. The primary data in such diseases must come directly from the patient and are collected by an apparatus called a physician. Accurate function of this apparatus is essential in providing care for patients and is equally important in compiling scientific data. Although physicians are irreplaceable as the apparatus that performs clinical examination, they are rarely tested by the confirmatory inspections and calibration given equipment in the laboratory. The absence of better methods for objectivity and accuracy at the bedside is a critical defect of clinical science. A few approaches to ‘calibration’ of the physician are considered below. History-taking
In history-taking, physicians may make several kinds of error. They may miss important information by failing to permit the patient to express himself thoroughly. In addition to such errors of omission, errors of commission occur when physicians allow their attitude, manner of questioning, and interpretation of replies to be influenced by their own conscious or subconscious preconceptions. Consequently, the patient’s perception of certain symptoms may be altered, or the description recorded in the chart may be distorted. The frequency and magnitude of these and other errors in history-taking are generally unknown. Variability in physical examination is occasionally studied, but discrepancies in history-taking are rarely investigated. Taught to students at a time in medical training when they can least comprehend clinical subtleties, history-taking usually remains untaught thereafter and its techniques unexplored. The cautious examinations of data in the laboratory, and the long hours spent in establishing accuracy of equipment and of the technicians who use it, are not often duplicated at bedside rounds, where the examinations of attending physicians may be credulous and brief. The physicians may accept histories as presented and check only those physical findings reported to be abnormal. This approach saves time for discussing the clinical data but fails to teach how to acquire or to verify the data. By watching a rapid physical examination, students learn little save its motions because they cannot, as individuals, simultaneously feel or hear the same things as the attending physician. By listening to him take a salient history, they
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would learn much because what he asks and hears in reply is audible to all. History-taking is the most subtle and complex function of clinical apparatus, and can be learned well only from direct observation of that function. If history-taking is not demonstrated at the bedside, young physicians are deprived of instruction in their most important skill. If crucial historical data are not checked directly with patients, inaccuracies may pass unchallenged. Some errors of history-taking might be prevented by use of a fixed set of written questions. This objective approach can improve certain kinds of data but it will usually fail to allow patients thorough expression and it cannot evaluate nuances and reliability of answers. In specific studies that use historical data as a critica variable, calibration or standardization can be obtained by using special forms, supplemented by a review of important symptoms with each patient directly by a responsible, alert investigator. Physical examination This procedure can be divided into functions that are descriptive, interpretive and diagnostic. (By description, a blanching red area is observed on the skin, with a nonblanching darker red center. By interpretation, it is called a petechia surrounded by erythema. By diagnosis, it is attributed to meningococcemia.) The records of physical examination should always contain full descriptions. Certain interpretations can be used when the terms are clear and beyond dispute. (Thus, the term ‘murmur’ is generally permissible as an interpretation to replace the descriptive term ‘noise’.) Diagnosis, however, is not part of the description of physical findings, and should be reserved for the concluding ‘impression’. Failure to recognize these components in physical examination may lead to serious errors of omission and commission: (1) The description may be inadequate for later interpretation. (2) Instead of describing, the examiner may interpret or make diagnoses, using stated or unstated criteria that are erroneous or nonstandard. (3) The interpretations may be biased by knowledge of other clinical data. These errors are illustrated as follows : (1) An examiner may describe the intensity, radiation, pitch and quality of an apical systolic murmur, and omit such properties as duration, site of maximum intensity and response to deep inspiration. Absence of the latter data may then impede differentiation of the murmur as physiologic or organic in a young patient with rheumatic fever. (2) When examiners describe cardiac auscultation only in phrases such as ‘mitral regurgitation murmur’, ‘pericardial friction rub’, or ‘opening snap of mitra1 valve’, they use acoustic gestalts that cannot be verified and that close the examiner’s mind to other possibilities. (3) White spots in the fundus of a patient with diabetes or hypertension may be called ‘retinopathy’ by a physician who knows the clinical diagnosis and ‘drusen’ by a more objective ophthalmoscopist. The interpretation of X-ray films, an adjunct to physical examination, is also often biased by clinical data. The same film can sometimes receive a dramatically different reading when it is reviewed ‘blindly’ by the same radiologist supplied with different clinical data.
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Increased accuracy in physical examination requires that examiners first describe, and then interpret, using criteria that are based on adequately detailed descriptions of important parameters. At bedside rounds, the attending physician should examine selected areas before he is told what his colleagues have found there. Occasional or even frequent differences between his observations and theirs will be not deplorable, but desirable, since they will illustrate the range of variation in the examining apparatus and teach precision in its use. In specific scientific studies, calibration can be obtained by having crucial physical findings confirmed by objective, independent examiners unaware of previous opinions. For example, the latter approach has been used with remarkable success for long-term periodic examinations of patients who have had rheumatic fever. By ‘blind’ auscultation, the physician examines the patient at each clinic visit before looking at the chart, forms his tentative auscultatory impressions, and then compares his opinion with those previously recorded. In this way his first reactions are unaffected by prior comments and he can detect his own inconsistencies, errors, and differences in criteria. The process inevitably develops auscultatory skill, precision, and standardization. Calibration of multiple examiners
When many examining physicians are used in a scientific clinical study, they should be assembled beforehand to calibrate examination of critical areas in a selected group of ‘unknown’ patients. This procedure cannot adequately be replaced by uniform oral or written agreement on details of examining criteria and techniques. Examiners must check and compare results in the same patients in order to be certain that the actual examinations are not performed with subtle individual differences that may create otherwise unexplainable deviations in data. For example, a recent study of treatment in acute rheumatic fever, performed cooperatively by investigators at 12 different centers, was designed with careful written criteria for interpretation of cardiac auscultation, but the actual performance of auscultation was not calibrated. Although the types of patient initially selected for examination at the 12 centers did not seem significantly different, basal diastolic murmurs were reported in 80 per cent of the patients at one institution but in only about 10 per cent of patients at the other 11 centers. The inconsistency, discovered after the study was completed, could not be rectified or explained. It might have arisen from subtle differences either in the patient population or in the way the examining physicians interpreted the noises heard on auscultation. Without calibration, the physicians could not be excluded as the cause of the inconsistency. Consequently, the divergent data were excluded from the analysis of total results. In that circumstance, the statistical appraisals of cooperatively obtained data could make proviso for the disparity. In other clinical trials, however, when the ‘same’ study is performed by many separate investigators, no common appraisal of the data is possible. If the isolated results disagree, they cannot be reconciled. This situation is prevalent in current studies of anticoagulant therapy in coronary heart disease. The methods used by different investigators for assessing the critical variables of symptoms and signs (and also electrocardiographic tracings) are often dissimilar, despite apparent agreement in written descriptions of the procedures. The direct calibration of a group of examiners may seem strange and may be
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inconvenient when the examiners must come long distances. In scientific medicine, however, this type of calibration cannot be omitted. Without it, investigators cannot discern the sources of conflict in clinical studies that reach contradictory conclusions_ Great effort is often expended in repeating the studies, but the results seldom bring the desired distinctions because the basic, hidden discrepancies remain unaltered. CONCLUSIONS
These illustrations have shown how clinicians seeking ‘science’ often neglect the scientific importance of data from patients at the bedside. Lack of reproducibility in primary clinical data creates fundamental deficiencies that cannot be remedied by the experiments or analyses imposed subsequently. Many clinical experiments cannot be confirmed or refuted because they cannot be duplicated; hence erroneous conclusions can remain undetected and can be perpetuated. The deficiencies in clinical data prevent advantageous correlation of magnificent new biologic, biochemical, and biophysical methods. These problems impede the effective application and evaluation of advances in medical and surgical therapy. The problems will not be solved by modern techniques for experimental design and data analysis, and may even be aggravated thereby. Nor can they be solved by greater use of computers, massive clinical trials, or increasingly complex laboratory and statistical maneuvers. As long as the basic clinical data remain defective, no amount of subsequent processing can improve them. To improve classification and accuracy of clinical data requires no special equipment. The simple techniques described here for history-taking and physical examination can be helpful and should be used when possible. The improvement will not occur, however, without a renaissance of attention to the three observational disciplines that are the primary and unique skills of the clinician: history-taking, physical examination and maintenance of a record of human illness. These skills: appear to be atrophying at many academic centers where clinical science has been caught in the arc of a vicious circle. Some investigators assume that research can be done only in the laboratory, not at the bedside. The bedside therefore remains scientifically barren because its science is not taught or practised. The subsequent absence of scientific clinical work then confirms and continues the original assumption. Clearly, medicine needs good research at the bedside as well as in the laboratory. If one area becomes exclusive or suppressive of the other, neither can achieve maximum growth or fruition, since they are interdependent and complementary. Perceptive scientific experiments can be done in the ward or examining room as well as in the cage or test tube, but human subjects must be managed by abilities, skills and techniques completely different from those of the laboratory. The clinician who is not a scientist cannot perform an accurate examination. The scientist who does not care for patients may be unable to cope well with human beings as his experimental subjects, and may fail to develop the rapport and understanding that produce a complete and accurate history and that help sustain the patient’s continued experimental participation. A good relationship between physician and
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patient is thus important, not merely as an honorable and traditional part of good medical practice, but as a necessary tool for acquiring scientific data. These concepts may seem trivial and obvious to investigators who are unaware that a major distinction between laboratory and clinical science is the ease with which experimental material can be reproduced. To attain reproducibility for intricate clinical data is extraordinarily difficult and requires careful attention to improving the techniques for recording and classifying symptoms, signs, and clinical patterns. Some investigators may feel that these observational activities of ‘clinical taxonomy’ do not offer the experimental excitement of the laboratory. Without an effective, accurate, descriptive taxonomy, however, biologic investigation has no order or logic for its data or its concepts. Human illness is too complex for its research to be confined to laboratory techniques and laboratory data. The observation and classification of diseased patients must begin. scientifically as well as medically, by realizing their individual distinctions as sick patients and not merely as diseased tissues. Investigation at the bedside will never attain the exact precision achieved in the laboratory. Nevertheless, scientific advances depend not upon where but upon how the work is done. Science comes from the intelligence, imagination, perseverance and insight of the investigator. whether the basic elements of his data are obtained from molecules or man. Unless the basic elements of clinical medicine-symptoms, signs and patterns-are studied and used scientifically, the continued clinical application of isolated advances from the laboratory may bring only scientific dignity without scientific clarity. Without science at the bedside, modem medical research may yield an intricately designed, expensively produced, doubly-blind controlled. statistically significant chaos.
ALVAN R. FEINSTEIN
Assistant Professor of Medicine, Yde University School of Medicine and Chief, Clinical Pharmacology. West Haven Veterans Administration Hospital