MED 106 Research Methods and Medical Statistics: Introduction to Biomedical Research (PDF)
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University of Nicosia Medical School
2024
Elena Critselis
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This document is an introduction to biomedical research, covering key historical figures, approaches, and concepts in epidemiology. It includes a detailed page-by-page explanation of the topics, likely used as lecture notes or study material.
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MED 106 Research Methods and Medical Statistics Introduction to Biomedical Research Elena Critselis, MPH PhD Associate Professor in Epidemiology and Public Health, Department of Primary Care and Population Health, University of Nicosia Medical S...
MED 106 Research Methods and Medical Statistics Introduction to Biomedical Research Elena Critselis, MPH PhD Associate Professor in Epidemiology and Public Health, Department of Primary Care and Population Health, University of Nicosia Medical School Overview of epidemiology and its applications Epidemiology: The study of the patterns, causes, and effects of health and disease. Identification of: Risk factors for disease. Efficacious prevention and clinical management of disease. Optimal targets for public health interventions. Epidemiology is the cornerstone of clinical medicine and public health since it informs evidence-based medicine and health policy decision-making. Development of robust research methodologies used in clinical research, public health investigations, and the health sciences. Adoption of optimal research study design, data collection, and statistical analysis, as well as interpretation and dissemination of results. Historical milestones in biomedical research Biomedical research in the prevention of disease Hippocrates: The father of medical research (400 BC) Ancient Greek physician who sought to elucidate the logic to illness by examining the relationships between environmental influences and the subsequent occurrence of disease. Believed that sickness was caused by an imbalance of the four Humors (i.e. air, fire, water and earth “atoms”). Hippocrates first coined terms: ‘Endemic’: Diseases that “reside within” a population ‘Epidemic’: Diseases that are “visited upon” a population Also first alluded to the study of ‘epidemiology’. Hippocrates: The first epidemiologist Hippocrates’ approach to epidemiology: Determined and described diseases which occurred in specific places at specific time periods. Introduced for the first time the concept of the ‘risk factor’ and suggested that each disease is caused by different risk factors. Terminology neglected until 1802 when the Spanish physician Joaquín de Villalba reintroduced the term “epidemiology” to describe the study of epidemics. Wrote 3 works regarding the epidemiology of diseases: Epidemic I On Airs, Waters and Places Epidemic III Early theories regarding the etiology of diseases From Plato through to Rousseau, it was believed that diseases occurred primarily due to the fault of human luxury. In 1543, Italian physician Girolamo Fracastoro proposed that miniscule (invisible to the naked eye) particles cause disease and were alive, could be spread by air, multiply on their own, and be destroyed by fire. In De contagione et contagiosis morbis he first promoted personal and environmental hygiene as methods for preventing disease. In 1675, Anton van Leeuwenhoek developed a sufficiently powerful microscope which provided the first visual evidence of living particles consistent with the germ theory of disease. John Snow: The father of modern epidemiology British physician John Snow (1813-1858) is famous for his investigations into the causes of the 1849 cholera epidemic in London. Approximately 15,000 attributable deaths. The problem: Despite the death toll, no one knew the reason causing cholera and/or how the outbreak could be contained. John Snow began his contribution to not only addressing the cholera outbreak, but also establishing modern epidemiology and public health, with a simple hypothesis and robust methodological approach. Snow’s cholera map showing cases of cholera in the London epidemics of 1854, clustered around the locations of water pumps Snow’s approach to elucidating the determinants of the cholera epidemic Snow’s epidemiological approach: He hypothesized that infections occurred after swallowing ‘something’ that multiplied in intestines. He initially observed significantly higher death rates in two areas supplied by Southwark Company. He rigorously investigated the frequency and distribution of cholera cases, revealing that cholera cases were more common in areas supplied by Southward Company from the banks of the river Thames (polluted by sewage areas), as compared to upstream (non-polluted areas). He subsequently identified the cause of the outbreak, namely the Broad Street pump as the cause of the Soho epidemic. Snow verified his theory by conducting an experiment in which he cleaned the water and sealed a water pump in a highly infected neighborhood. He used chlorine in an attempt to clean the water and had the pump handle removed. The above public health intervention resulted in cholera disappearing from the neighborhood and ending the cholera outbreak! To date, Snow’s approach is perceived as the founding event of modern epidemiology and public health interventions around the world. The British Doctors Study: The first large prospective study In October 1951, Sir Richard Doll and Sir Austin Bradford Hill sent a questionnaire on smoking habits to all registered British doctors. The British Doctors Study was the world’s first large prospective study which established convincing etiological associations between tobacco smoking and lung cancer (1954), as well as myocardial infarction and chronic obstructive pulmonary disease (1956). The Seven Countries Study: The first large multicenter prospective study regarding CVD determinants and outcomes Keys A et al. Epidemiological studies related to coronary heart disease: characteristics of men aged 40-59 years in seven countries. Acta Med Scand Suppl. 1966;460:1-392 Edward Jenner and smallpox: The first vaccine In 1796 the British physician Edward Jenner sought to address a smallpox outbreak. Jenner’s approach: He observed that milkmaids who had gotten cowpox were protected from smallpox. He hypothesized that exposure to cowpox could protect against smallpox. He tested his hypothesis by taking material from a cowpox sore on a milkmaid’s hand and inoculated it into the arm of James Phipps, the 9-year-old son of Jenner’s gardener. Months later, he exposed Phipps several times to the variola virus, but Phipps never developed smallpox. In 1801 Jenner published On the Origin of the Vaccine Inoculation. Vaccination became widely accepted and gradually replaced the practice of variolation (the deliberate inoculation of an uninfected person with the smallpox virus). History of vaccine development Saleh et al, Cureus 2021 Addressing emerging health challenges: COVID-19 Historical milestones in biomedical research Biomedical research in the management of disease Ambroise Paré and battlefield wounds: First unintentional clinical trial In 1537, the French military surgeon Ambroise Paré conducted an unintentional trial, now commonly noted as the first clinical trial in history. Paré’s approach: The standard treatment of battlefield wounds (namely boiling oil), ran out. Paré developed a novel therapy for battlefield wounds which was a mixture of turpentine, egg yolk, and oil of roses for the sealing of soldiers’ wounds. He found they were in little pain, their wounds were minimally swollen and irritated, and were overall in better condition than the soldiers who had received the hot oil. Paré’s innovation was the first approach for proving that a novel method could be much more effective than the standard treatment. Thus, the idea of advancement of care through experimentation was introduced! James Lind and scurvy: First intentional clinical trial The British military surgeon James Lind (1716-1794) observed that sailors suffered from a devastating disease (now known as scurvy) during their long trips at sea. Lind’s approach: Lind observed that sailors consumed a poor diet which lacked fresh fruits. He hypothesized that giving limes to sailors would eradicate the disease. He conducted the first ever ‘clinical trial’ on The Salisbury in 1747. Following random selection of 12 sailors, he allowed 6 to receive their usual diet, while 6 additionally received 2 oranges and 1 lime daily for 6 days. Amongst the latter group, 2 sailors had complete symptom withdrawal. Thus, Lind proved that scurvy was caused by a lack of citrus fruit consumption! Patulin Trial: The first multicentre double blinded clinical trial The 1944 Patulin Trial conducted by the UK Medical Research Council (MRC) was the first multicenter double blinded clinical trial. The UK MRC / Patulin Trial approach: Patulin, an extract of Penicillium patulinum, was investigated as a potential treatment for the common cold. A preliminary formal controlled clinical trial was conducted by the Royal Navy showing that patulin was very unlikely to be a cure. However, the MRC sought to further investigate its efficacy by conducting a larger trial in widely distributed areas of Great Britain. Extensive efforts were made to ensure double blinding of the medical personnel and patients. The trial findings showed that there were no significant differences in treatment success between the control and patulin treatment groups. Double blinding served as a model for later clinical trials. The MRC Streptomycin Trial: Randomization in clinical trials In 1946, Sir Austin Bradford Hill and Sir Philip Hart were assigned by the MRC to conduct tests of a promising antibiotic, streptomycin, in TB. The approach: Given extreme shortage of streptomycin, participants were randomly assigned to control groups and treatment (streptomycin) groups. They decided whether a patient should be treated with streptomycin plus bed rest, or bed rest alone, by using a table of random numbers. The investigators didn’t know which patient got each treatment since the details were in sealed envelopes. Patients were not told they were in a trial. The patients’ X-rays were analyzed by experts who did not know patients’ treatment assignments. Allocation concealment The results of the trial initiated the use of randomization as a gold standard in later clinical trials. Clinical trials for optimizing patient health outcomes ALL Clinical Trial, UC Davis Comprehensive Cancer Center, USA From the past to the present... Local Admissions (EU) The Scientific Method The scientific method is the process by which the scientific community endeavors to construct a reliable, consistent and non-biased (i.e. accurate) representation of various world phenomena. The scientific method is comprised of 5 steps: 1. Observation (or literature review) 2. Devise a testable research question 3. Formulate a specific research hypothesis 4. Test the hypothesis with an experiment (or other analysis) 5. Derive a conclusion (i.e. accept or reject your hypothesis) The Scientific Method www. BSPHI.com Different types of biomedical research In vitro studies (lab-based research) Studies on animal models (usually rodents) Small-scale experimental studies in humans Large-scale observational epidemiological studies in humans (cross-sectional, case-control, and/or cohort studies) Large-scale interventional studies in humans (clinical trials) Meta-analyses and umbrella reviews Types of epidemiological studies and hierarchy of research design Interventional Studies Analytic Observational Studies Descriptive Observational Studies Main purposes of biomedical research Disease prevention and management: Identification of risk factors and protective factors of different diseases. Design of appropriate public health interventions for: Primary prevention of disease: Prevention of disease onset by avoiding etiological agents of disease and/or adopting vaccination. Secondary prevention: Timely screening and detection of disease. Tertiary prevention: Deterrence of adverse outcomes of disease. Quarternary prevention: Protection of patients from medical interventions that are likely to cause more harm than good. Optimal clinical management based on Evidence-based medicine (EBM): The process of systematically reviewing, appraising and using current best evidence from clinical research findings to aid the delivery of optimum clinical care to patients. Biomedical research for disease prevention Global disease burden, 2019 Public health interventions for improving patient and community health American Heart Association Guide for Improving CVD Health at the Community Level, 2013 Biomedical research for evidence-based medicine Biomedical research for evidence-based medicine Future outlook for global public health Further material (optional) Rosenberg W, Donald A. Evidence based medicine: an approach to clinical problem- solving. BMJ 1995; 310:1122 Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn't. BMJ 1996; 312:71 The BMJ - What is epidemiology? http://www.bmj.com/about- bmj/resourcesreaders/publications/epidemiology-uninitiated/1- whatepidemiology John Snow and the London Cholera Epidemic (Video) https://www.youtube.com/watch?time_continue=3&v=753XHXPLr n 4 For additional information: [email protected]