Research Methodology Simplified: Every Clinician a Researcher Mahendra N Parikh, Joydev Mukherjee, Avijit Hazra, Nithya Gogtay
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Fundamentals of Medical ResearchChapter 1

“The art and science of asking questions is the source of all knowledge.”
—Thomas Berger
As human beings we are always curious. We ask questions all the time. Research is a formal way of going about asking questions, to increase our knowledge about the unknown. Research is searching for answers again and again (researching) in a systematic and scientific way.
Research can be broadly defined as a form of systematic inquiry that contributes to knowledge:
Research: critical and exhaustive investigation or experimentation having for its aim the discovery of new facts and their correct interpretation, the revision of accepted conclusions, theories or laws in the light of newly discovered facts, or the practical applications of such new or revised conclusions, theories, or laws.
—Webster's Third International Dictionary
The primary purpose of research is to conduct a scientific or scholarly investigation into a phenomenon or to answer a burning question.
Research is defined as a systematic approach to problem solving.
A core of common research skills and principles should be used in any good quality research. Central to these are the need to be:
  • Systematic
  • Purposeful
  • Organized
  • Critical
  • Analytical
  • Able to communicate findings effectively
  • Assertive; sometimes researchers have to report things others may not want to hear!
At the end of the day all research is a process of enquiry. Research findings offer a way of enhancing your existing knowledge, understanding or skill, or of uncovering something new.
There are many reasons why as a doctor you may want to understand and participate in research. It may just be simple curiosity. There may be a question 2about the physiology, natural history, or the treatment, diagnosis, and prevention of disease that interests you. Or importantly, it may be about how you can do the best for your patient. You may want to undertake research to improve your own training and knowledge, possibly as part of your continuing professional development. For example:
  • To learn how to design experiments and how scientific and clinical investigations differ in their aims and methods
  • To undertake a range of investigative techniques, including the application of statistics to the design and analysis of experiments
  • To learn how to write scientific papers and to present data at meetings
  • To learn how to assess scientific papers critically
  • To obtain a higher research degree, such as a MD or PhD.
“If you think research is expensive, try disease.” This famous quote is attributed to Mary Lasker, a philanthropist and advocate for medical research.
Words used to describe different kinds of biomedical research.
Biomedical research: The area of science devoted to the study of the processes of life, the prevention and treatment of disease, and the genetic and environmental factors related to disease and health.
Basic or “pure” research: Research conducted to increase the basic knowledge and understanding of the physical, chemical, and functional mechanisms of life processes and disease. It is fundamental and not directed to solving any particular biomedical problem in humans or animals. This type of research often involves observing, describing, measuring, and experimental manipulating and provides the building blocks upon which the other types of research (applied and clinical) are based. A basic researcher seeks to add to the store of knowledge about how living things work. A basic researcher's experiments add pieces to the immensely complex puzzles of life.
Examples of basic research:
  • How do certain types of cancer cells multiply and grow in a lab?
  • How cells talk to each other?
  • How are genes regulated?
  • How do nerves convey signals to the brain via biochemical mediators?
Unlike clinical research, basic science research does not require a medical qualification. This type of research is conducted mainly in the laboratory using in vitro and in vivo techniques. The main questions are developed to examine and understand a physiological/pathological process and find the parameters that may alter it. A major attraction of basic research is that fundamental advances in the understanding of disease mechanisms can be achieved. However, basic research does not necessarily produce results that are immediately relevant for clinical care, but the knowledge gained often is essential for progress in the various steps involved in new discoveries. Understanding the changes in cells and molecules associated with illnesses provides the 3knowledge that helps eventually find new ways to diagnose, treat, and prevent a variety of ailments. Clinical research, on the other hand, usually involves testing medications and other treatments for specific illnesses and conditions.
Applied research: Research that is directed towards specific objectives such as the development of a new drug, therapy, or surgical procedure. It involves the application of existing knowledge, much of which is obtained through basic research, to a specific biomedical problem. Applied research can be conducted with animals, non-animal alternatives such as computer models or tissue cultures, or with humans. Basic research is necessary to generate new knowledge and technologies to deal with major unresolved problems; applied research is necessary to identify priority problems and to design and evaluate policies and programs that will deliver the greatest health benefit, making optimal use of available resources.
Examples of applied research:
  • What drug can be developed to help cure cancer of the skin?
  • Can we “teach” a mouse's body to regenerate a severed leg?
Preclinical research is research in basic science, which precedes the clinical trials, and is almost purely based on theory and experiments. The term preclinical research is commonly used when the goal is specifically to elaborate knowledge which may be utilized later, for the development of new therapeutic strategies by clinical trials.
Clinical research: This is using the knowledge gained in basic and applied research to conduct research (generally with humans) in treating disease or dysfunction in a new way. It usually takes place in a hospital or clinical setting and is focused on treating specific human and animal diseases and other ailments. Clinical research builds upon the knowledge learned through applied and basic research. Clinical research is conducted on human beings and takes shape in treatments and drugs that directly improve human healthcare.
Examples of clinical research
  • Will the new drug work in children?
  • What are the adverse reactions of the new drug?
United States National Institutes of Health (NIH) defines clinical research as:
  • Patient-oriented research. Research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator directly interacts with human subjects. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual. Patient-oriented research includes: (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, or (d) development of new technologies.
  • Epidemiologic and behavioral studies.
  • Outcomes research and health.
The traditional categorization of medical research identifies just two categories: basic research (also labelled fundamental or pure research) and clinical research. An attempt to bridge these research activities has been 4undertaken where the term translational medicine has been applied to a research approach that seeks to move “from bench to bedside” or from laboratory experiments through clinical trials to actual point-of-care patient applications. To improve human health, scientific discoveries must be translated into practical applications. Such discoveries typically begin at “the bench” with basic research in which scientists study disease at a molecular or cellular level then progress to the clinical level, or the patient's “bedside.”
Translational research a new paradigm to biomedical research focuses on iterative feedback loops between the basic and clinical research domains to accelerate knowledge translation from the bedside to the bench, and back again.
Translational research transforms scientific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce disease incidence, morbidity, and mortality (Fig. 1.1).
In a broader context clinical research is considered synonymous with clinical epidemiology where epidemiological study designs are used to analyze the systematically collected clinical observations to answer clinical queries related to history, diagnosis, treatment, and prevention. Table 1.1 summarises the key questions in clinical research that may be addressed through epidemiologic studies:
Clinical research has already been described as “bedside” research. A doctor is responsible not only for clinical care, but also for recording and reporting new discoveries to the entire medical profession. Questions are asked at the bedside and then the appropriate measurement techniques or scientific disciplines are selected to answer them. Once a research hypothesis has been formed, the study is ideally a matter of teamwork. It can include a mix of healthcare professionals working in laboratories or in the field. While less likely to lead to the cause of disease, clinical research is always important in challenging and developing the scientific basis of medical practice. Clinical research is vital for the critical evaluation of existing treatments and for the responsible introduction of new ones.
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Fig. 1.1: Basics of reseach
Table 1.1   Key questions that may be addressed through epidemiologic studies
What causes disease?
What factors predispose to disease and to what extent?
What are the outcomes from the disease?
How good is a given diagnostic tool and how does it compare to other tools?
How is outcome altered by treatment?
Can disease occurrence or recurrence be prevented?
What is the economic impact of disease, its diagnosis and its treatment?
The research process consists of a series of steps necessary to carry out research effectively.
One particular model is the research spiral (Fig. 1.2). The model shows that one might enter the process at a number of points. It also shows that the experience of later stages might lead to a revision of earlier knowledge and methods, mirroring the general process of learning.
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Fig. 1.2: The research spiral
“Do not condemn the opinion of another because it differs from your own. You both may be wrong.”
As the research spiral shows above, before actually conducting the research study, the essential prerequisite steps are to formulate a research question and do a literature review. To find answers to problems that have not already been resolved, we need to know a lot about the problem and precisely where the boundary between current knowledge and ignorance lies. Without knowing a lot about the problem, it is difficult to imagine that plausible diagnostic tests and interventions will be developed.
Without knowing the current state of knowledge, it is difficult to know whether one is headed in the right “next-step” direction.
The reasons we do literature search are:
  • Discover what exists on a topic
  • Increase your knowledge of that topic
  • Use earlier work as a foundation or a springboard
  • Find gaps, errors, or inconsistencies in previous work
  • Generate ideas for your own work
  • Avoid duplication of previous work
  • Justify and lend authority to your work
Developing a question is an iterative process, not a “light bulb” phenomenon. The iterative components include, to name a few the basic dimensions of the clinical problem, the plausibility and feasibility of the design, the colleagues you will work with, the other resources you can muster to address the question, and the contingencies that emerge as you conduct the study. The basic dimensions of a problem that lead to the formulation of important research questions include understanding the biology and physiology of the problem, its epidemiology, and frustrations/deficiencies in its clinical management that lead to unsatisfactory results for patients. Once these basic issues have been addressed, and an initial direction for a question seems promising, some additional key questions must be addressed. These include:
  • What is the appropriate stage for evaluation?
  • Can internal validity be achieved?
  • To what extent is external validity (generalizability) achievable?
  • What will your circumstances permit?
  • What can you afford?
  • What is the best balance between “idea” and “feasibility”?
Performing literature search in a time efficient manner represents an important component of research that is relevant to all researchers. In essence, a literature review is the effective evaluation of current knowledge on a research topic. The ‘literature’ implies the works you consulted in order to understand and investigate your research problem. An effective review of medical literature should answer or clarify the following:
  • What we already know in terms of theory and clinical practice?
  • What is lacking?7
  • Why study the problem - Rationale / Relevance of study?
  • What methods to use?
Before embarking on literature search, one should be clear as to what type of sources should be accessed.
Primary literature is generated by researchers or observers themselves and hence report research first-hand. This research can be through numerous forms, including questionnaires and telephone interviews amongst others. They are usually published in scholarly journals and include laboratory experiments, clinical trials, cohort, case-control or other epidemiological studies, diagnostic evaluations, case reports or case series, methodological studies and evaluation research. Apart from journal articles, other primary sources of research-based knowledge include university theses/dissertations and governmental or private research reports.
Some journals also report conference proceeding and/or abstracts. These provide short summaries of in-progress or completed primary studies that are presented at conferences, but are not yet peer-reviewed for publication as complete articles. Conference proceeding and/or abstracts thus provide an ‘early picture’ of current research that is likely to appear later in one or more of the primary article forms listed above. Because selection processes are highly variable, the quality of conference proceeding and/or abstracts vary widely.
Secondary literature summarize and draw conclusions from secondary research (also known as desk research) that involves the summary, collation and/or synthesis of existing research, rather than reporting data collected directly from research subjects or experiments. This is very important as primary literature may be too in-depth or too elaborate for most information seekers. Secondary or integrative studies are regularly found in professional journals. Outside the journal literature, books and book chapters are the most common secondary source materials, but these may often carry an element of personal opinion or judgment. The specific types of secondary studies that form a large part of medical literature include the following.
Review Articles (Overviews)
There are two types of review articles: non-systematic (or journalistic) reviews and systematic reviews. Non-systematic or journalistic reviews provide a summary of evidence derived from primary studies that have been selected and synthesized according to the author's personal and professional perspective. Non-systematic reviews can cover a wide range of subject matter at various levels of completeness and comprehensiveness. The decision to include or exclude articles depends to a large extent on the author's view, which in this type of reviews often does not take in account the methodological quality of the studies. Moreover, if there is no systematic search strategy of the literature, it is 8likely that the review does not include some important studies that could significantly alter its conclusions.
Systematic reviews, on the other hand, provide summaries of related primary studies that have been searched for, evaluated, and selected and reported according to a rigorous and predefined methodology. A systematic review is an exhaustive review of the literature addressing a clearly defined question, which uses a systematic and explicit methodology to identify, select and critically evaluate all the relevant studies, and collect and analyse the data emerging from the studies included in it. A systematic review is an overview that contains a thorough, unbiased search of the relevant literature, explicit criteria for assessing studies, and structured presentation of the results. A systematic review that uses quantitative methods to summarize results is a meta-analysis. Statistical methods (meta-analysis) may or may not be used to analyse and summarize the results of the studies included in the review.
A meta-analysis is an integrative study that statistically combines the numeric results of several separate studies addressing the same question into a single estimate of their combined effect (commonly referred to as ‘pooling data’). Typically, the results are presented as a graph depicting the individual and pooled odds ratios (with confidence intervals) for all studies included in the analysis.
Guidelines (e.g. clinical practice guideline, standard treatment protocols) are systematically developed statements designed to help practitioners make appropriate decisions about health care in specific clinical circumstances. Good guidelines draw their conclusions from careful review of primary studies; some guidelines also involve quantitative assessment of alternative risks and benefits (see decision analysis).
Decision Analyses
Decision analyses use the results of primary studies to develop quantitative measures or estimates of the risks and benefits of alternative diagnostic or therapeutic options. These estimates are then used to develop a probability tree that can help health professionals and/or patients make informed choices about clinical management. Decision analysis also can be used to help develop clinical guidelines or consensus statements.
Economic Analyses
Economic analyses use the results of primary studies to say whether a particular course of action is a good use of resources. There are three common types of 9economic analyses appearing in the journal literature. Cost-effectiveness analysis assesses the ratio of costs to some naturally occuring health-related outcome (e.g. cost per additional year of survival). Cost-benefit analysis assesses costs relative to an outcome defined in actual monetary units (e.g. cost per dollar value of gained worker productivity). Cost-utility analysis assesses the ratio of costs to outcomes defined in units of ‘utility’ (e.g. cost per additional quality adjusted year of life).
Any literature, that cannot be clearly categorized as primary or secondary literature, can be grouped in this category. For instance drug prescribing literature, consensus statements, clinical protocols, personal observations, editorials, and letters can be placed in this category. They are not necessarily research based, often carry an element of personal bias or judgment, but nevertheless may convey important observations.
These can be conveniently grouped as follows:
Evidence-based (filtered) Medical Databases
Evidence-based databases contain only information that has been ‘filtered’ or screened for its quality by the application of standards that typically ensure a high level of accuracy and clinical relevance. They should be visited first when trying to answer a clinical (foreground) question. The following are the most common of the health and medical-oriented evidence-based databases:
  • ACP Journal Club
  • Clinical Evidence
  • The Cochrane Database of Systematic Reviews
  • Cochrane Central Register of Controlled Trials
  • Database of Abstracts of Reviews of Effects (DARE)
  • InfoRetriever
Unfiltered Medical Databases
Unfiltered databases provide searchable access to ‘raw’ bibliographic data, i.e. citations, abstracts and (in some cases) full-text of all forms of articles found in the health and medical-oriented periodical literature. Given the wide range of quality and different levels of evidence found throughout the journal literature, the burden is on the user to identify relevant information and evaluate its quality. For these reasons, unfiltered databases should be second choice when trying to answer a specific clinical question. Examples of such databases include.
  • Excerpta Medica Database (EMBase)10
  • IndMED
  • Current Contents
  • HealthStar
  • International Pharmaceutical Abstracts (IPAB)
  • PsycINFO
  • BIOSIS Previews
Research is focused, systematic inquiry aimed at generating new knowledge. In this era of evidence based medicine, evidence is derived from high quality research. Understanding clinical research is a prerequisite for the clinician if patients are to receive best care.