CLINICAL RESEARCH METHODS Theory

The Scientific Method and Causal

1.

THE SCIENTIFIC METHOD AND CAUSAL THEORY
Characteristics of Scientific Inquiry

1.1

The word science originates from the Latin word scientia, which means ‘knowledge’. The purpose of scientific inquiry is to create knowledge that clarifies the world around us. Clinical research shares with other branches of science four major characteristics of scientific inquiry: positivism, theory, empiricism and objectivity.

Positivism
All sciences are based on the fundamental assumption that the world is not totally chaotic, but has logical and persistent patterns of regularity. Positivism is a particularly strong feature of biomedical types of clinical research. The assumption of positivism is sometimes challenged, however, especially with respect to clinical research concerning social and behavioural phenomena, such as doctor or patient behaviours, which are arguably the product of both social laws and human volitional action. Although, in general, social and behavioural phenomena cannot be predicted with complete accuracy, there are nevertheless sufficient patterns of regularity in social and behavioural phenomena to justify useful scientific investigation.

Theory
A clinical theory is a statement that seeks to explain or predict a particular clinical phenomenon. Scientific theories are used to derive research hypotheses, plan research, make observations and explain the patterns of regularity that are observed. Alternative theories may exist and scientific inquiry is directed towards testing and choosing from these. One clinical theory is judged to be superior to alternative theories if it: 1. involves the fewest number of statements and assumptions (more efficient); 2. explains the broadest range of phenomena (more comprehensive); and 3. predicts most accurately (more accurate). There is an intimate connection between theory and performing clinical research. Theories provide guidance for clinical research (a deductive process). Clinical research, in turn, verifies, modifies and reconstructs theory (an inductive process). In searching for clinical theories, scientists do not start with a clean slate, but are influenced by a range of general perspectives about what is important, legitimate and reasonable. These normative models are known as paradigms and often they represent the general perspective adopted by a particular clinical discipline such as oncology, gynaecology or cardiology. Sometimes a major new set of theories is introduced that challenges existing perspectives and becomes generally accepted as providing a superior model to explain the world. This is the paradigm shift. The discovery that peptic ulcers are caused by helicobacter pylori, previously though to be a harmless commensal in the stomach, is an example of a recent paradigm shift in clinical science.

Empiricism
Empiricism is the collection of evidence from the observation of experience in the world, used to corroborate, modify or construct theories. It is the most dominant characteristic of modern scientific inquiry in clinical medicine and this has three implications: 1. Non-empirical ways of acquiring knowledge, such as appeals to authority, tradition, common sense or intuition, cannot produce scientific evidence; 2. scientific researchers in clinical medicine focus on problems that can be observed; and 3. scientific inquiry cannot settle debates on ethical values, beliefs or what clinical policies ought to be adopted. Scientific inquiry has to do with what is, not what ought to be.

A Short-Course with Professor D’Arcy Holman © -1

Topic 1

 Design: Develop the overall plan or framework for investigation. Example: The increasing dependence of research into the effectiveness and safety of therapeutic substances on funding from the pharmaceutical industry has prompted a debate.  Sampling: Select the populations to be studied. These theories are known as grounded theories.  Hypotheses: Specify the testable propositions about relationships between variables. for even the most objective of clinical scientists to conduct valuefree research. it is argued that scientists with a significant conflict of interest. should declare this fact in their report so that readers may take this into account when considering the implications of the research results and conclusions.2 Steps in Conceptualising and Researching a Clinical Problem The 10 steps in conceptualising and researching a clinical problem are as follows: Groundwork: Specify the research topic and the existing body of theory based on literature review. Peer review is also an important measure to improve objectivity. Mechanisms used to enhance objectivity include the concept of control in clinical research. strengthen the objectivity of the observational aspects of clinical research. not by the clinical researchers. and therefore it is important that clinical researchers maintain objectivity in their observations. Rothman. However. about conflict of interest.  Measurement: Define measures to link concepts to empirically observable phenomena. It is argued that no amount of peer-review can guarantee the objectivity of scientists who have been commissioned to do research by those who have a vested interest in the conclusions being supportive of their products. 1. involving a number of North American journals. Note that new clinical theories are not always deduced from existing theories in the manner set out above. if those paradigm are in error.3 Major Types of Relationships Between Variables A Short-Course with Professor D’Arcy Holman © -2 Topic 1 . objectivity is enhanced. however.  Data Collection: Implement the chosen method of data collection on observable events or states. such as an industrial sponsor. It is generally impossible. When a group of clinical researchers can independently agree on how to interpret results of a study. properly used. the methods adopted and the ways that finding are interpreted.CLINICAL RESEARCH METHODS Theory The Scientific Method and Causal Objectivity Empirical evidence is assumed to exist independent of researchers. has argued that there is no reason to refuse to publish such research. This is because the paradigms of their disciplines affect the type and scope of problems they research.  Theory: Formulate propositions to explain the findings. as all scientists are subject to influences that may detract from their objectivity. and whether such research should be published in peer-reviewed journals. Objectivity may also be distorted. existing paradigms may still distort objectivity.  Application of Theory: Disseminate and apply new or updated theories in clinical practice. However. but by the study subjects as with the Hawthorne effect (a reactive effect of research on the phenomenon being studied). 1. including the study type. the Editor of the journal. uninfluenced by their personal feelings.  Data Analysis: Employ statistical or other procedures to draw conclusions from the data. conjectures or preferences. which is the use of methods of design or analysis to exclude or make less likely errors in interpretation due to biased observations. Sometimes a clinical researcher must commence an investigation without a hypothesis and simply describes what one observes.  Methods: Choose the types of research methods and data sources. Epidemiology. Research methods. explaining why it happened on the basis of the observations alone.

which is caused by the independent variable and affects the dependent variable. whereas the independent variable is the hypothesised explanation. someone must be prepared to interpret the empirical information that has been gathered for the purpose of making policies for the benefit of society. The variable that causes a spurious relationship is called a confounder. in a single instance. Verification School The verificationist accepts that induction is a fact of life and that repeated observations do often lead to useful scientific statements about the nature of the universe. A variable whose value is dependent upon one or more other variables is a dependent variable. who identified the essential conundrum of empirical science with his famous quotation (‫ . and in this way the verificationist's version of science intersects with public policy. A measurable concept that has more than one measurable value is a variable. follow the other. Their tentative solution to Hume's problem is to propose criteria or conditions to strengthen the validity of causal inference. which conceals the relationship between two variables because it directly affects one and inversely affects the other. any quality which binds the effect to the cause. We only find that one does actually.CLINICAL RESEARCH METHODS Theory The Scientific Method and Causal There are two types of measurable concepts used in clinical research. that is. A measurable concept with just a single never-changing value is known as a constant. the relationship is called spurious. to discover any power or necessary connection. has led to a divergence of opinion in scientific philosophy between two schools of thought. David Hume. reasoning that draws general conclusions from the observation of specific phenomena limited in time and place. There are three basic requisites to a causal relationship: statistical association. the verificationisits and falsificationists. and renders the one an infallible ‫معصوم‬ consequence of the other. A Short-Course with Professor D’Arcy Holman © -3 Topic 1 . rational sequence of influence and non-spuriousness. there is a causal relationship. but probably the best known is Sir Austin Bradford Hill's nine causal considerations published in 1965 at a time when the causal link between lung cancer and tobacco was still somewhat controversial.’ Hume's Problem with inductive reasoning. 1. in fact. A variable capable of effecting change in other variables is an independent variable. Verificationists tend to hold to the view that despite the lack of guarantee of infallibility. rather than by their interrelationship. There are more than 30 sets of such criteria published to date. The US Surgeon General also published causal criteria in the historic inaugural volume on Smoking and Health. We wish to explain the value of the dependent variable. An intervening variable is not a confounder. A relationship between two variables may also be caused by an intervening variable.)اقتباس‬known as Hume’s Problem from the Treatise ( ‫ )مقالة‬of Human Nature (1739): ‘We are never able.4 Schools of Thought on Causal Inference It was the 18th Century British philosopher. Establishing that these conditions exist is known as the process of causal inference. Another form of confounder is a suppressor variable. The scientist's intimate understanding of the processes of research make him or her the most suitable person to interpret the implications for decision-makers in society. If a change in the independent variable does indeed cause an effect in the dependent variable. Causal vs Spurious Relationships When the association between two variables has been caused by a third or extraneous variable.

Time Order: The exposure must precede the outcome. However. strongly supports or detracts from a causal hypothesis. Incoherence between biological knowledge and study observations detract from a causal hypothesis. findings that are implausible in terms of pre-existing theory detract from the evidence. For example. or lack of evidence. However. Ruling out alternative explanations other than cause. confounding and other bias (selection or information bias) is an important part of causal inference. Conversely. the conjecture that it had something to do with the poor dead cock is falsified and a new conjecture about the reason for the sunrise is entertained. Contrary to popular belief among scientists. but a weak association does not necessarily detract from the evidence of causality. Specificity of Cause: Limitations in the number of other known causes of the outcome are supportive. developed as recently as 1934 by the physicist and philosopher Karl Popper. Popper's hypothetico-deductive reasoning leads the scientist to wring the rooster's neck and when the sun rises nevertheless. Regarding the problem of the crowing rooster. A strong association is highly supportive of causality. that relies on falsification of alternative hypotheses. Their solution to Hume's Problem. variation in the active component of the exposure should be associated with variation in risk within the same gross exposure level. the falsificationist argues that although the rooster crows each morning as the sun rises. Consistency on Replication: Consistency of the evidence. such as chance variation. Causal inference in Practice Most clinical researchers rely on a combination of falsification and verification to make judgments about whether observed associations are causal or spurious. However. it is impossible to induce that the crow of the rooster causes the sun to appear. Induction is seen as entirely a psychological process that has no basis in logic.     A Short-Course with Professor D’Arcy Holman © -4 Topic 1 . Incompatible pre-existing facts strongly detract from evidence of causality. For example. Factual Coherence: Compatibility of a new result with pre-existing facts is affirming. It takes only one dissonant observation to disprove a conjectural theory considered to have general application. Corroborating evidence of this type is strongly supportive of causality. Theoretical Coherence: Findings plausible in terms of pre-existing theory are affirming. place. For example. circumstances and population. is to turn inductive reasoning on its head and to use empirical observations to refute conjectural theories about the nature of the world. ecological correlation may have been previously described between the drug exposure across different populations and the corresponding rates of disease or injury. under this model nothing is ever proven and the purist adherent to this philosophy will argue that causal inference has nothing to do with empirical science. but does not necessarily support causation. failure of corroboration detracts from the evidence. as well as research design.CLINICAL RESEARCH METHODS Theory The Scientific Method and Causal Falsification School The falsificationist has a contrary view. An example of predictive performance is the observation of a reduced risk of outcome in a population which has ceased a previous exposure. Biological Coherence: Pre-existing knowledge which identifies a pathway or mechanism by which the exposure may cause the outcome is affirming. This criterion is compatible with. but lies strictly in the domain of policy. in the face of study diversity in time. Reversal of the time order is the most decisive basis available for rejection of causation. failure of a test of statistical significance does not detract from the evidence unless accompanied by adequate statistical power. its absence is not necessarily falsifying. Statistical Coherence: A response proportional to exposure level is strongly persuasive of a causal relation. However. specificity of effect is not a causal criterion. Strength of Association: The greater the strength of association the more likely it is to be causal. Predictive Performance: This criterion requires that a secondary hypothesis is drawn from the existence of the causal relationship that predicts an otherwise unexplained fact or consequence. the absence of specificity does detract from a causal hypothesis. Verification of an association as causal is also more readily accepted if the evidence has the following attributes:  Statistical Significance and Power: If the criterion of statistical significance is satisfied then the      evidence is supportive.

or ought not. Causal Inference. Oxford: Clarendon Press. revised and reprinted. 1985.5 The Divide between Clinical Science and Clinical Policy ‘In every system of morality. Am J Epidemiol 1976. unless one makes value judgments about what constitutes the public interest in the context of people gathered in a sports stadium. and the degree to which the stadium owners or the individuals have a duty and a right to take appropriate measures against the risk of cardiac arrest (autonomy). and value. ed. significance. the opportunity cost of alternative uses of the public funds to benefit worthy social objectives (justice). known as Hume’s Guillotine. which describes and explains. and at the same time that a reason should be given. London: John Noon. A Short-Course with Professor D’Arcy Holman © -5 Topic 1 . and the hiatus in logic that exists between the indicative language of scientific discourse. For as this ought. Hume D. Treatise of Human Nature. the desire not to do harm if the equipment is used improperly (non-maleficence). ….CLINICAL RESEARCH METHODS Theory The Scientific Method and Causal 1. and the prescriptive language of ethics. or an ought not. Merely because ‘early electroversion in people who suffer a sudden cardiac arrest due to ventricular fibrillation is a cause of improved survival’ does not mean that ‘automated cardiac defibrillators ought to be installed in the public interest in sports stadiums. which proffers standards for acceptable behaviour and public policy. ed. I meet with no proposition that is not connected with an ought. how this new relation can be a deduction from others. for what seems altogether inconceivable. and is not. A large-scale social science experiment in health finance: findings. 20: 1051-61. which are entirely different from it. 1963. This would need to include considerations about the value of the survival benefit (beneficence). 104: 587-92. which I have hitherto met with. I have always remark’d. J Health Politics. Rothman KJ. Chestnut Hill: Epidemiology Resources. Policy and Law 1995. …. New York: Harper Torchbooks.’ The latter (ethical) statement cannot be logically derived from the former (scientific) statement.’ This remark. Hill AB. draws the fundamental distinction between science and ethics. The point is that ethical decisions cannot be deduced from mere scientific facts. SelbyBigge LA. Rothman KJ. ‘tis necessary that it shou’d be observed and explain’d. 58: 295-300. that instead of the usual copulations of propositions. 1988. Conjectures and Refutations: The Growth of Scientific Knowledge. also taken from the writings of 18th Century British philosopher. 1739. that the author proceeds for some time in the ordinary way of reasoning. Causes. References Brandon WP. when of a sudden I am surpriz’d to find. expresses some new relation or affirmation. David Hume. Popper KR. The environment and disease: association or causation? Proc Roy Soc Med 1965. is.