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Synopsis of a lecture given on 27th October 2006 to MPH (Epidemiology) students at the Department of Social and Preventive Medicine, Universiti Malaya by Professor Omar Hasan Kasule, Sr. MB ChB (MUK), MPH (Harvard), DrPH (Harvard)
DEFINITIONS, SCOPE, and ROLES
Clinical epidemiology is defined as study of outcome of disease and the factors that affect the variation in outcome. It applies epidemiological methodology to patient care. The ‘exposures’ are therapy and the etiological factor. The ‘outcomes’ are disease progression, disease complications, and mortality. The scope of clinical epidemiology covers definition of abnormality, diagnosis (symptoms, signs, and diagnostic procedures), frequency, risk, prognosis, treatment, and prevention. It also involves study of the natural history of disease, study of the sensitivity, specificity, and predictive value of diagnostic and screening tests; study of therapy using randomized clinical trials. It also studies treatment efficacy, and effectiveness. It is used in the investigation of disease etiology, identification of risks, identifying syndromes, classifying diseases, differential diagnosis, planning and follow-up of treatment. The conceptual basis and methodology of clinical epidemiology are the same as those of general population-based epidemiology.
HISTORICAL EVOLUTION OF CLINICAL MEDICINE
In Pre-historic times magic and superstition were mixed with medical care and were closely related to the prevailing belief systems. Mesopotamian medicine was magico-religious with priests serving also as physicians. Divination was used beside treatment with vegetables, animals, and minerals. Early Egyptian medicine was mystical and priestly. Pills, potions, suppositories, purgatives, enemas, emetics, inhalants, and ointments were used. Egyptians knew circumcision, plaster for closing wounds, cautery for hemostasis, and incision & drainage for abscesses. Chinese medicine can be traced back to Fu Hse in about 3322BC. Traditional Indian Medicine knew the diseases of tuberculosis, cancer, diabetes mellitus, leprosy, and smallpox. Diagnoses were made by listening to the breath sounds, observing the color of eyes, the tongue, and the skin; feeling the pulse; tasting the sweetness of urine. Stress was put on diet, hygiene, and mental preparation. Herbs were used. Rauwolfia serpentina and opium were used as drugs. Indians knew excision, suturing, drainage, cauterization, laparatomy, removal of bladder stones, repair of fistulae, cesarean section, and cataract removal. The ancient Indian medicine is what has grown into Ayurdevic medicine of India today.
Greek medicine benefited by learning from Asia Minor, Mesopotamia, and Egypt. It was closely related to religions and the temples. The main figures of Greco-Roman medicine were Hippocrates, Galen, and Aristotle. Normal physiology, disease, and treatment were based on the concepts of the 4 humors (blood, phlegm, yellow bile, and black bile), the 4 elements (earth, air, fire, and water), and the 4 qualities (hot vs. cold and wet vs. dry). Rest and diet were used in treatment. With the death of Galen in 199 BC Greco-Roman medicine entered its dark ages. Aulius Cornelius Celsius formulated the 4 cardinal signs of inflammation: pain, redness, heat, and swelling. Romans made practical but no theoretical contributions to the development of medicine.
Muslim medicine started with translations. Nestorians had translated Greek medical works into Syriac. Muslims translated these Greek works into Arabic. They in addition made their own observations and discoveries. Abubakar al Razi described measles and wrote al Hawi. Ibn Sina wrote al Qanun fi al Tibb. Zahrawi wrote on surgery.
European medicine in the Middle Ages was in general decay. The Christian Church contributed to lack of scientific growth. Superstition became wide spread. Muslim medicine was transferred to Europe through Andalusia (modern Spain) and Sicily in Italy creating the medieval medical reawakening (800-1500 CE). As a result of contacts with Muslims, the Salermo medical school emerged in Southern Italy in the 9th century CE. Muslim medical writings were translated into Latin by Constantine Africanus (1010-1087 CE) at Salermo. Muslim works were expanded and annotated by Europeans and were taught at Universities in Bologne and elsewhere. The Renaissance (1500-1700 CE) was a period of the rise of anatomical knowledge. Besides translations of Muslim writings, Europeans undertook human dissections. Following the renaissance rapid developments were mad in physiology, microbiology, Pathology, and Pharmacology by use of empirical research. In clinical sciences, internal medicine lagged behind surgery. In 1636 CE clinical teaching of medicine started at Leyden. Schools of medicine developed in the 18th century in London, Vienna, Paris, Edinburgh, and Dublin. The industrial revolution witnessed building of new hospitals. Modern medicine (20th century CE onwards) has three distinguishing characteristics. It is evidence-based medicine. It uses advanced technological interventions. It uses human experimentation extensively.
NATURAL HISTORY OF ILLNESS
Natural history is the course of disease in patients who are not receiving any therapy or intervention. Knowledge of the natural history is necessary for planning rational treatment strategies. The stages of disease on the basis of clinical manifestation are: essentially normal (low risk), Establishment of disease-causing agent, appearance of signs, appearance of symptoms, disability, and death.
CLINICAL EPIDEMIOLOGY IN DIAGNOSIS
Disease is anatomical, biochemical, physiologic or psychological derangement. Clinical diagnosis is an effort to recognize the class or group to which a person's illness belongs. Epidemiology as the study of the distribution and determinants of disease provides background information needed in clinical diagnosis. Statistical abnormality, used to define disease, is defined as deviation beyond 2 standard deviations. The most often used strategy in clinical diagnosis is the hypothetico-deductive in which a hypothesis is formed from early clues and then history, clinical examination, and diagnostic tests are undertaken to confirm or reject the hypotheses. Epidemiological knowledge provides prior probabilities for clinical decision making. The clinician combines his empirical findings with the prior probabilities top reach a diagnosis. This may be informal or formal using Bayesian techniques. In formal clinical decision making, the problem is defined. Alternative actions and possible outcomes are determined. Probabilities are determined on the decision tree and the value of the outcome is computed.
Diagnostic tests are used for assessing severity, predicting prognosis, estimating likely response to treatment, and to determine the actual response to treatment. The precision of each test, its sensitivity and specificity must be taken into consideration in interpreting its findings. Diagnostic procedures can be evaluated by computing their predictive value. Epidemiological parameters are used to choose a diagnostic procedure. Diagnostic tests are also useful in predicting illness outcome. Random controlled trials, follow up and case control study designs can be used to assess the role of diagnostic tests in predicting outcome. A hospital stores a lot of clinical data about patients. This data may be shared with other hospitals using local area net-works (LAN). Data-bases have been developed with AI capabilities and they can provide much support to the physician who is trying to diagnose a disease. This is done by comparison of the patient's data with several profiles stored in the data-base.
CLINICAL EPIDEMIOLOGY IN TREATMENT and PROGNOSIS
The objective of treatment must be identified: cure vs. palliation. The specific treatment modalities to be used must then be selected. Treatment targets must then be decided: dose, frequency, start, and end. Treatment decisions are based on clinical experience or medical literature. Formal decision analysis techniques using prior probabilities from clinical epidemiological studies can be used. Decision trees are used with decision nodes employing probabilities are from empirical data. Epidemiological measures of treatment are efficacy, effectiveness, safety, incidence of side effects, incidence of treatment failure, compliance, and functional status. The clinical data base can be used to predict patient compliance. Functional status is measured using: restricted activity days, workless days, bed-disability days. Clinical practice guidelines have been developed for many conditions. They are based on results of clinical trials and epidemiologic studies. The guidelines can be evaluated using specific criteria. Both randomized and non-randomized clinical trials are used in studying treatment efficacy. Therapeutic safety can be measured using case control, follow up, and case reports. Two main issues arise: characterization of patients who receive a particular treatment and ascertainment of unintended effects. Prognosis can be based on clinical experience or expert opinion and review of literature. Prognosis can also be assessed by comparing the patient's profile to the information in the clinical data-base
CLINICAL TRIALS ON HUMANS
Therapeutic clinical trials are controlled experiments to compare the effectiveness of different treatments by random allocation of study participants to treatment and control groups, observing the outcome of interest, and at the same time studying time-varying potential confounding variables. Trials can also be designed to be intervention or preventive trials. They may be accrual or non-accrual. Unadjusted censoring causes bias. Random allocation prevents selection bias. Double blinding prevents observer bias. The primary objective of drug clinical trials is efficacy and the secondary objective is assessing ADR. Complete randomization is simple but requires a large sample size. Stratified randomization balances prognostic factors. The trial can use historical, concurrent, self, untreated, placebo, negative, or positive controls. Clinical trials are preceded by screening in vivo in animals and in vitro in human tissues. Phase 1 trials study maximum tolerated doses, drug administration schedules, drug toxicity, and evidence of anti-tumor activity. Phase 2 studies assess therapeutic activity of a drug in advanced disease. Phase 3 trials compare a drug to a placebo or a new drug to an existing drug. Comparability is assured by randomization and equal handling of the 2 groups. Phase 4 studies involve post-marketing surveillance by collecting data on short term and long term effects. Clinical trials on humans have several ethico-legal considerations. Search for better treatment justifies clinical trials. The ethical issues of trials are withholding a potentially beneficial treatment from the controls, unknown risks of new agents, lack of informed consent or consent under stress, trials if an effective treatment exists, trial when one treatment is known to be better, testing with no evidence of usefulness, unscientific research, violation of the normal doctor-patient relation, randomization when there is prior knowledge that one treatment is the better one, and failure to stop the study when harmful/beneficial effects appear.