This document discusses different types of clinical studies used in evidence-based medicine, including case reports/series, ecological studies, cross-sectional studies, case-control studies, cohort studies, randomized clinical trials, systematic reviews, and meta-analyses. It provides details on study designs, strengths and limitations, and how to interpret results including risk ratios, odds ratios, confidence intervals, and p-values. Key concepts covered include biases, confounding factors, prevalence versus incidence, and how study size influences precision.
An overview of ICH-GCP guidelines of clinical trials.
Good clinical practice (GCP): a standard for the design , conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected.
ICH-GCP is an International Conference on Harmonization Good Clinical Practice.
The guideline was developed with consideration of the current good clinical practices of the European union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the world health organization
An overview of ICH-GCP guidelines of clinical trials.
Good clinical practice (GCP): a standard for the design , conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial subjects are protected.
ICH-GCP is an International Conference on Harmonization Good Clinical Practice.
The guideline was developed with consideration of the current good clinical practices of the European union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the world health organization
Methods of randomisation in clinical trialsAmy Mehaboob
Randomization is the process by which allocation of subjects to treatment groups is done by chance, without the ability to predict who is in what group. A randomized clinical trial is a clinical trial in which participants are randomly assigned to separate groups that compare different treatments.
Randomized trials are gold standard of study designs because the potential for bias (selection into treatment groups) is avoided.
This document includes the purpose, types, advantages and disadvantages of each type of randomisation.
Table of contents
-Definition of CRF
-What is CRF
-Types & Methods of filling of CRF
-CRF Input team
-CRF Approval team
-Review team
-Facts about CRF
-Purpose of CRF
-CRF Development process & Guidelines
-Elements of CRF
-CRF Design
-CRF completion checklist
-CRF Design tools
-CRF use
-GCP connection
“CSR is a detailed regulatory document which gives the information about the methods and results (related to efficacy and safety) of a clinical trial. CSRs are created as a part of the process of submitting applications to the Regulatory Authorities for new medical treatments and for its approval. CSRs can be full, abbreviated, synopsis, supplementary, observational etc as per the results and requirements”.
Introduction to Aggregate Reporting in Drug Safety & Pharmacovigilance in Pharmaceuticals, Bio-Pharmaceuticals, Medical Devices, Cosmeceuticals and Foods.
Contact:
"Katalyst Healthcares & Life Sciences"
South Plainfield, NJ, USA
info@KatalystHLS.com
Methods of randomisation in clinical trialsAmy Mehaboob
Randomization is the process by which allocation of subjects to treatment groups is done by chance, without the ability to predict who is in what group. A randomized clinical trial is a clinical trial in which participants are randomly assigned to separate groups that compare different treatments.
Randomized trials are gold standard of study designs because the potential for bias (selection into treatment groups) is avoided.
This document includes the purpose, types, advantages and disadvantages of each type of randomisation.
Table of contents
-Definition of CRF
-What is CRF
-Types & Methods of filling of CRF
-CRF Input team
-CRF Approval team
-Review team
-Facts about CRF
-Purpose of CRF
-CRF Development process & Guidelines
-Elements of CRF
-CRF Design
-CRF completion checklist
-CRF Design tools
-CRF use
-GCP connection
“CSR is a detailed regulatory document which gives the information about the methods and results (related to efficacy and safety) of a clinical trial. CSRs are created as a part of the process of submitting applications to the Regulatory Authorities for new medical treatments and for its approval. CSRs can be full, abbreviated, synopsis, supplementary, observational etc as per the results and requirements”.
Introduction to Aggregate Reporting in Drug Safety & Pharmacovigilance in Pharmaceuticals, Bio-Pharmaceuticals, Medical Devices, Cosmeceuticals and Foods.
Contact:
"Katalyst Healthcares & Life Sciences"
South Plainfield, NJ, USA
info@KatalystHLS.com
Case-control study is a variety of analytical studies. This is a brief presentation regarding history, design, issues, advantages - disadvantages and examples of Case-control study.
Description of various ultrasound features of benign and suspicious thyroid nodules with multiple ultrasound systems for risk stratification of malignancy.
Description of different ultrasound features of carpal tunnel syndrome before and after carpal tunnel release including Doppler imaging and elastography
Doppler ultrasound of visceral arteriesSamir Haffar
Doppler ultrasound of different diseases of visceral arteries including arterial stenosis and occlusion, arterial aneurysm, artrial pseudoaneurysm, arterio-venous fistula, artrial dissection, and abdominal vascular compression syndromes
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
1. Types of clinical studies
Samir Haffar M.D.
Assistant Professor of Gastroenterology
2. Glasziou P, Del Mar C & Salisbury J. Evidence based medicine Workbook.
BMJ Publishing Group – First edition – London – 2003.
Clinical epidemiology
Evidence-based medicine
Evidence-based practice
3. The 3 components of EBP
“EBM is the integration of best research evidence
with clinical expertise & patient values”
- David Sackett
Sackett et al. BMJ 1996; 312:72-3.
4. 1- Ask
PICO
2- Acquire
electonic database 4- Apply
5- Assess
Patient
dilemma
Evidence alone does not decide
Combine with other knowledge & values
3- Appraise
Principles of EBP: the 5 A
5. What is the best evidence?
• The best evidence is the evidence most likely to
provide an unbiased view of the truth
• Bias is difference between study results & truth
• Of course, we can never know the truth, but we can
try to come as close as possible by performing & using
well-designed & well executed studies
7. Types of clinical studies
• Case report/case series
• Ecological study
• Cross-sectional study
• Case control study
• Cohort study
• Randomized clinical trial
Primary research
• Systematic review
• Meta-analysis
Secondary research
8. McGovern D, Summerskill W, Valori R, Levi M. Key topics in EBM.
BIOS Scientific Publishers, 1st Edition, Oxford, 2001.
Evidence pyramid
Increase in
evidence level
Decrease in
bias risk
9. The amount of medical literature
0
500000
1000000
1500000
2000000
2500000
Biomedical MEDLINE Trials Diagnostic
MedicalArticlesperYear
5,000
per day
1,500
per day
95 per
day
55 per
day
Glasziou P, Del Mar C. Evidence based practice workbook.
Blackwell Publishing, 2nd edition, 2007.
So much evidence, so little time
10. • Interface to MEDLINE (NLM*) & easiest way to use it
• From 1950 to date
• 19 million articles as of November 2009
• Growing at rate of 700 000 articles/year
• ≈ 5 000 indexed journals
• > 70 million search done each month
• Search terms by topics, authors or journal
Free on the Internet since the mid-1990s
* US NLM: United States National Library of Medicine
12. 50,000 articles/yr
from 120 journals
~3,000 articles/yr
meet critical appraisal
& content criteria
(94% noise reduction)
McMaster PLUS project – First level
Critical appraisal filters
Valid
Ready for clinical attention
Health Information Research Unit – McMaster University – Canada
13. High quality/relevant data – Pearls
Glasziou P, Del Mar C. Evidence based practice workbook.
Blackwell Publishing, 2nd edition, 2007.
Finding high-quality evidence like searching for ‘rare pearls’
17. McGovern D, Summerskill W, Valori R, Levi M. Key topics in EBM.
BIOS Scientific Publishers, 1st Edition, Oxford, 2001.
Evidence pyramid
18.
19. McGovern D, Summerskill W, Valori R, Levi M. Key topics in EBM.
BIOS Scientific Publishers, 1st Edition, Oxford, 2001.
Evidence pyramid
20. Case report & case series
25% of published papers in clinical journals*
• Case report describes medical history of a single patient
• Case series is essentially the same of case report but
with more than one patient to illustrate an aspect of:
- Condition
- Treatment
- Adverse reaction to therapy (most commonly these days)
* Rough search of MEDLINE database from 1997 to 2000
21. Role of case reports/series
Roles Examples
Describe a new phenotype or
genotype of disease
First case report of sickle cell disease (1910)
Describe a new pathogen
(microbe, virus or
environmental exposure)
Discovery of AIDS was an observation of a
patient with immunodeficiency-related
diseases who otherwise had no reason to be
immunodeficient (1981)
Describe unknown adverse
effect of an existing drug
Reye syndrome and aspirin in children (1963)
Thalidomide & limbs defect in pregnancy(1962)
Describe a novel treatment for a
known condition
Colchicine for treatment of FMF (1972)
To remind or educate Case records in different journals for
postgraduate education ‘Care records of MJH’
Quality improvement ‘Lesson of the week’ published in BMJ
Do not make the same mistake as I did
Murad MH et al. BMJ EBM 2018;23:60-63.
22. Thalidomide & limb defect
• Classic example published in 1961 as a letter to the
editor by an obstetrician in Sydney
• 3 newborn infants had same rare limb defect over 6 wk
Suspected link between thalidomide & limb defect
• > 10,000 affected children born worldwide before this
association confirmed & drug removed from the market
McBride WG. Lancet 1961 ; 278 : 1358.
23. Case Records of the Massachusetts General Hospital
NEJM
N Engl J Med 2016;375:2082-92.
25. Advantages & disadvantages of case series
• Advantages
Useful for hypothesis generation
Informative for rare disease with few established risk factors
Characterizes averages for disorders
• Disadvantages
Prone to bias
Cannot study cause and effect relationships
Cannot assess disease frequency
26. • Between different groups during same period of time
• In the same population at different point of time
Ecological (correlation) studies
Look for associations between exposure and
outcomes in population rather than in individuals
Association between exposure and outcome:
Pearson correlation coefficient “r”
27. Ecological (correlation) study
Armstrong B.K, Doll R. Envoronmental factors and cancer incidence and moratality in different
countries, with special reference to dietary practices. Int.J.Cancer. 1975;15:617.
28. Limitations
Inability to link exposure with disease in particular
individuals
Lack to study effects of potential confounding factors
Data represent average exposure levels rather than
actual individual values
Ecological studies
29. Confounding factors
• If a study demonstrates that men who drink more alcohol
have increased risk to develop lung cancer
• This is not a causal relationship:
Drinking alcohol is confounder to risk factor & outcome
Men who drink more also smoke more
• Confounding factor corrected by
Data stratification - OR for each strata
30. Confounding factor
Systematic error due to influence of a third variable
Risk factor
Smoking
Outcome
Lung cancer
Confounder
Drinking alcohol
Glasser SP. Essentials of clinical research. Springer , 1st Edition, 2008.
Drinking more alcohol is confounder to both
the risk factor (smoking) & the outcome (lung cancer)
Association of smoking & lung cancer
31. McGovern D, Summerskill W, Valori R, Levi M. Key topics in EBM.
BIOS Scientific Publishers, 1st Edition, Oxford, 2001.
Evidence pyramid
33. Means of determining exposure
• Questionnaires (e.g., age, sex, smoking history)
• Laboratory tests (e.g., cholesterol, hemoglobin)
• Physical measurements (e.g., blood pressure, height)
• Special procedures (e.g., electrocardiogram, x-rays)
• Medical records
34. Role of cross-sectional survey
• Determines presence or absence of a disease at one
point of time (prevalence) in a sample population
• Determines association between exposure & disease
e.g.: ischemic heart disease in smokers
• Exposure and disease determined simultaneously
It is not possible often to establish a causal relationship
Hypothesis generating rather than hypothesis testing
35. Incidence & prevalence
• Incidence:
Number of new cases of a disease per year
• Prevalence:
Overall proportion of population suffering from a disease
Prevalence = Pre-test probability
37. • Qualitative data (e.g. disease present or absent):
Express results into “2 by 2 contingency table”
Risk Ratio (RR) and Odds Ratio (OR) with 95% CI
• Quantitative data (e.g. body weight):
First look at data in a scatter diagram
Correlation “r” with p value
Simple linear regression “R2” with p value
Multiple logistic regression
Analytical cross-sectional study
Measurement of association between variables
CSS: cross-sectional study
38. “2 by 2” table in qualitative data
Exposure
(smoking)
Disease (lung cancer) Total
Disease No disease
Exposed a b a + b
Unexposed c d c + d
Total a + c b + d a + b + c + d
39. Risk & Relative Risk (RR)
Number of patients fulfill criteria for a given end point
divided by total number of patients
Risk in patients (diarrhea during antibiotic tt): 4/10 = 0.4
Risk in controls (diarrhea in control group): 1/10 = 0.1
• Risk
Risk of patients / risk of controls
RR: 0.4 / 0.1 = 4
• Relative Risk
40. Odds & Odds Ratio (OR)
Number of patients fulfill criteria for given endpoint
divided by number of patients who do not
Odds of patients (diarrhea during antibiotic tt): 4/6 = 0.66
Odds of controls (diarrhea in control group): 1/9 = 0.11
• Odds
Odds of patients / odds of controls
OR = 0.66 / 0.11 = 6
• Odds Ratio
42. Interpretation of RR & OR
RR or OR should be accompanied by their CIs
RR or OR > 1
Increased likelihood of outcome in exposed group
RR or OR < 1
Decreased likelihood of outcome in exposed group
RR or OR = 1
No outcome difference between exposed & control groups
CI: confidence interval
43. Odds ratio or relative risk?
OR will be close to RR if endpoint occurs infrequently (<15%)
If outcome is more common, OR will differ increasingly from RR
Altman DG et all. Systematic reviews in health care: Meta-analysis in context.
BMJ Publishing Group, London, 2nd edition, 2001.
44. Significance of CI
• When we test a new Crohn’s disease drug on randomly
selected sample of patients, the treatment effect we will
get will be an estimate of the ‘‘true’’ treatment effect for
the whole population of patients with CD in the country
• 95% CI of estimate will be range within which we are
95% confident the true population treatment effect will lie
C.I.: confidence interval
CD: Crohn’s disease
45. Confidence intervals
Value 95 % CI are commonly used
90 or 99% CI are sometimes used
Width of CI Indicates precision of the estimate
Wider the interval, less the precision
CI includes 1 No statistically significant difference
CI doesn’t include 1 Statistically significant difference
46. CI: statistical significance & precision
(a) Statistically significant , low precision
(b) Statistically significant, high precision
(c) Not statistically significant, low precision
(d) Not statistically significant, high precision
CI: confidence interval
Glasziou P et al. Evidence based practice workbook. Blackwell, 2nd edition, 2007.
47. Influence of sample size on CI precision
Width of CI (precision of the estimate)
decreases with increasing sample size
CI: confidence interval
Peat JK, et al. Health science research. Allen & Unwin, Australia, 1st ed, 2001.
48. “2 by 2” table in qualitative data
Exposure
(smoking)
Disease (lung cancer) Total
Disease No disease
Exposed a b a + b
Unexposed c d c + d
Total a + c b + d a + b + c + d
49. “2 by 2 table” in qualitative data
Exposure
(smoking)
Disease (hypertension) Total
Disease No disease
Exposed (smoking) 120 280 400
Unexposed (no smoking) 30 570 600
Total 150 850 1000
Prevalence of HTA in smokers: a/a + b = 120/400 = 0.3
Prevalence of HTA in non-smokers: c/c + d = 30/600 = 0.05
Risk Ratio (RR): 0.3/0.05 = 6
Odds of HTA in smokers a/b = 120/280 = 0.43
Odds of HTA in non-smokers c/d = 30/570 = 0.053
Odds Ratio (OR) (a/b) / (c/d) = 8.11
50. Scatter diagram
Relationship between urinary cortisol creatinine (UCC) ratio
and asthma control (N = 62)
Each dot represents one patient
AbuRuz S et al. Br J Clin Pharmacol 2006;1: 110-115.
51. Correlation “r”
AbuRuz S et al. Br J Clin Pharmacol 2006;1: 110-115.
(N = 62)
“r” expressed by Pearson correlation coefficient
52. Interpretation of correlation coefficient “r”
lies between – 1 & + 1
• Positive r One variable increases as the other increases
• Negative r One variable decreases as the other increases
• r = 0 No linear association between 2 variables
• 0 < r < 0.25 Weak association between 2 variables
• 0.25 ≤ r < 0.75 Intermediate association between 2 variables
• 0.75 ≤ r < 1 Strong association between 2 variables
• r = 1 Perfect association between 2 variables – rare
Correlation does not necessarily imply causation
53. When not to calculate “r” ?
Non-linear relationship
Presence of outliers
Data comprise subgroups of individuals
54. Probability value (p value)
• p value is probability that observed difference between
2 groups might occur by chance
• Many use p value of 0.05 as cut off for significance
p < 0.05 Observed difference between groups is so
unlikely to have occurred by chance
Considered as statistically significant
p > 0.05 Observed difference between groups might
have occurred by chance
Considered as not statistically significant
55. • p > 0.05 Statistically insignificant
• p < 0.05 Statistically significant
Probability value (p value)
Statistically
significant
Clinically
significant
Doesn't
mean
56. Statistical versus clinical significance
• Pentoxifylline vs placebo in PAD* (1992)
40 patients randomized to pentoxifylline or placebo
Maximum pain-free walking distance longer in
pentoxifylline group than in placebo group (p < 0.001)
Conclusion: pentoxiphylline clinically effective
• Close examination of data:
Difference in maximum walking distance: 3.5 feet
Doctors & patients consider it not clinically significant
* PAD: peripheral arterial disease
McGovern D et al. Key topics in EBM. BIOS Scientific Publishers, Oxford, 2001.
57. Confidence interval or p value?
• Authors of articles could report both p values & CIs
• CI convey more useful information than p values
• If only one is to be reported, then it should be the CI
• p value is less important & can be deduced from CI
59. R-square in linear regression
• R-squared is always between 0 and 100%
• 0% indicates that the model explains none of the
variability of the response data around its mean
• 100% indicates that the model explains all the
variability of the response data around its mean.
Regression does not necessarily imply causation
60. Multiple logistic regression
Statistically significant difference between black & white mothers
Large CI: imprecise result
Larger study needed to generate more precise estimate of effect
832 pregnant women, 22 (2.7%) develop preeclampsia
61. Hill’s criteria for causal relationship
Hill AB. Proceedings of the Royal Society of Medicine. 1965;58:295-300.
Hill’s criteria Criteria definition
1. Strength
effect size
A small association does not mean there is not a causal effect,
though the larger the association, the more likely it is causal
2. Consistency
reproductibilty
Consistent findings observed by different persons in different
places with different samples strengthens likelihood of an effect
3. Specificity Causation is likely if there is very specific population at specific
site and disease with no other likely explanation
4. Temporality The effect has to occur after the cause
5. Biological
gradient
dose-response
Greater exposure should generally lead to greater incidence of
the effect
6. Plausibility Plausible mechanism between cause and effect is helpful
7. Coherence Coherence between epidemiological & laboratory findings
increases likelihood of effect
8. Experiment Occasionally it is possible to appeal to experimental evidence
9. Analogy Effect of similar factors may be considered
62. Naranjo probability score of adverse drug reaction
Items Yes No Don’t
know
1. Are there previous conclusive reports on this reaction?
2. Did adverse event appear after the drug was administered?
3. Did adverse reaction improve when the drug was discontinued
or a specific antagonist was administered?
4. Did the adverse reaction reappear with drug readministiond?
5. Are there alternative causes that could caused the reaction?
6. Did the reaction reappear when a placebo was given?
7. Was the drug detected in the blood (or other fluids) in
concentrations known to be toxic?
8. Was the reaction more severe when the dose was increased or
less severe when the dose was decreased?
9. Did the patient have similar reaction to the same or similar
drug in any previous exposure?
10. Was the adverse event confirmed by any objective evidence?
+1
+2
+1
+2
–1
–1
+1
+1
+1
+1
0
–1
0
–1
+2
+1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Adverse drug reaction probability: definite 9, probable 5-8, possible 1-4, doubtful < 0
Naranjo CA et al. Clin Pharmacol Ther 1981;30:239-245.
63. Advantages & disadvantages of
cross-sectional study
Advantages Disadvantages
Provide estimate of prevalence Dos not provide incidence
Easy, quick and cheap Prone for biases
Useful for chronic conditions
with low case fatality
Rare diseases, short duration,
high case fatality not detected
Provide wealth of data for
further research
Minimal information of natural
history of disease
64. Diagnostic study
Suspected target
condition
Guyatt G et all. Users’ guides to medical literature: manual for EBP.
McGraw-Hill, New York, USA, 2nd edition, 2008.
Accuracy of diagnostic test compared to gold standard
Gold standard test
Positive
Negative
Diagnostic test
Positive
Negative
65. Accuracy of a diagnostic test
• Dichotomous test (only 2 results)
Sensibility (Sn) & Specificity (Sp)
Positive Predictive Value (PPV)
Negative Predictive Value (NPV)
Likelihood Ratios + & – (LRs)
Diagnostic Odds Ratio (OR)
• Multilevel test (> 2 results)
Receiver Operating Characteristic (ROC)
Newman TB & Kohn MA. Evidence-based diagnosis.
Cambridge University Press, Cambridge, UK, 1st edition, 2009.
with 95%CIs
66. Key components of your clinical question
Concept of PICO
P Patient Elderly patient with IDA
I Intervention Bone marrow aspirates
C Comparaison Ferritin
O Outcome Accuracy (Sn – Sp – PPV – NPV – LR)
* IDA: Iron Deficiency Anemia
67. Diagnosis of IDA in elderly patients
2 x 2 contingency table
Gold standard test
Bone marrow aspirates Row totals
Disease present Disease absent
Diagnostic test
Ferritin
Positive
Negative
Column totals
Disease: Iron deficiency anemia (IDA)
Gold standard test: Bone marrow aspirates
Diagnostic test: Serum ferritin
69. ROC curve
Disease: Iron deficiency anemia
Gold standard test: Bone marrow aspirate
Diagnostic test: Serum ferritin
AUC ROC: area under the curve of receiver operating characteristic
70. McGovern D, Summerskill W, Valori R, Levi M. Key topics in EBM.
BIOS Scientific Publishers, 1st Edition, Oxford, 2001.
Evidence pyramid
71. • Investigates association between disease/suspected causes
• People with disease identified & their medical history
examined retrospectively to identify the risk factors
• Matched control group free from disease identified
& data collected from them in identical fashion
• 2 groups well matched to avoid confounding factors
Case-control Study
73. “2 by 2” table in qualitative data
Exposure Disease Total
Disease No disease
Exposed a b a + b
Unexposed c d c + d
Total a + c b + d a + b + c + d
Odds of disease in exposed group: a/b
Odds of disease in unexposed group: c/d
Odds ratio (OR): (a/b) / (c/d)
74. Advantages & disadvantages of
case-control study
Advantages Disadvantages
Cheap Cannot establish prevalence
Quick & easy to conduct Retrospective/more prone to bias
Good for disease with long
latency periods
Can only assess one disease
Can assess multiple exposures Probably not generalizable
Good for rare diseases
75. McGovern D, Summerskill W, Valori R, Levi M. Key topics in EBM.
BIOS Scientific Publishers, 1st Edition, Oxford, 2001.
Evidence pyramid
76. What is cohort?
Ancient Roman military unit, a band of warriors
Persons banded together
Group of persons with a common statistical characteristic
77. Cohort study
• Investigates link between a hypothetical cause and
a defined outcome
• Subjects exposed to suspected risk factor (cohort) &
similar subjects not exposed (control) are identified &
followed prospectively over a period of time (years or
decades) to identify incidence of outcome in both group
• Can be retrospective (if clear point of 1st exposure)
• 2 groups well matched to avoid confounding factors
79. • Express results into “ 2 by 2 table”
Qualitative data: p value (chi-square test) & 95%CI
Quantitative data: grouping – correlation calculations
• Confounding factors
Data stratification & OR for each strata
Correlation & regression
• Association does not prove a causal relationship
Number of questions need to be answered
Cohort Study
80. British doctors study
One of the most famous cohort study
• 34 440 British male & female doctors recruited in 1951
4 groups: nonsmokers, light, moderate & heavy smokers
• Publication of 10-year interim results in 1964
Substantial excess in lung cancer mortality & all cause
mortality in smokers, with dose-response relationship
• Publication of 20-, 40- and 50-year results: same results
• Follow up: 94% of those recruited in 1951 & not died
Doll R et al. BMJ 1964;i:1399–1467.
Doll R et al. BMJ 1976;Ii:1525–1536.
Doll R et al. BMJ 1994;309:901–911.
Doll R et al. BMJ 2004;328:1519–1528.
81. “2 by 2” table in qualitative data
Exposure Disease Total
Lung cancer No lung cancer
Smoking a b a+b
No smoking c d c+d
Total a + c b + d a + b + c + d
82. Incidence rate in cohort study
Exposure Disease Total
Lung cancer No lung cancer
Smoking 70 a 6 930 b 7 000 a+b
No smoking 3 c 2997 d 3 000 c+d
Total 73 a+c 9927 b+d 10 000 a+b+c+d
IR of lung cancer exp a/a+b = 70/7 000 = 10 per thousand
IR of lung cancer non-exp c/c+d = 3/3 000 = 1 per thousand
Relative risk (RR): IR exp / IR unexp = 10 / 1 = 10
Attributable Risk: (IR exp– IR unexp ) / IR exp . 100 = 90%
IR: incidence rate
83. Framingham Heart Study
Framingham city, MA (1948)
• Original cohort 5,000 of 30,000 residents in Framingham
30 to 59 years of age
without established coronary disease
• Exposures Smoking, obesity, HTA, high cholesterol,
physical activity, and others
• Outcomes Development of CHD, stroke, gout, & others
Examining study population every 2 years
• Duration Now on its third generation of participants
• Publications Over 1,000 published papers
CHD: coronary heart disease
84. Milestones from Framingham Heart Study
• 1948 Start of Framingham Heart Study „(FHS)
• 1960 Cigarette smoking increased risk of heart disease
• 1961 Cholesterol & high BP increased risk of heart disease „„
• 1967 Physical inactivity/obesity increased risk of heart disease
• 1970 High blood pressure increased risk of stroke
• 1974 DM associated with cardiovascular disease
• 1988 Elevated HDL cholesterol reduced risk of heart disease
• 1998 Framingham risk score (10-year CV risk w/o CV disease)
CV: cardiovascular
www.framingham.com/heart/timeline.htm
85. Survival curve
Informative way to depict results of a prognosis study
Number of events over time
or conversely
Chance of being free of these events over time
86. Overall survival after age 35 among cigarette
smokers and non- smokers
Doll R et al. BMJ 1994;309:901–911.
British Doctors Study
87. Survival curve
Patients with low grade follicular lymphomas
Earlier follow-up periods include results from more patients:
loss to follow-up – patients not enrolled in study at the same time
Survival curves more precise in earlier periods (narrower CIs)
Wood LA et al. Cancer 1999;85(6):1361-1368.
88. Survival curve after acute MI
RCTs also address issues of prognosis
Each arm of a RCT represents a cohort study
Experimental group: prognosis in patients receiving therapy
Control group: prognosis in patients who did not receive therapy
Mortality higher shortly after MI: initial steep downward slope
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.
Lancet 1988;2(8607):349-360.
89. Advantages & disadvantages of cohort study
Advantages Disadvantages
Used if no possible randomization Long time to complete
Prospective (less prone to bias) Expensive
Incidence can be calculated Not good for rare disease
Provide direct estimate of risk Loss to follow up bias
Can establish cause and effect Study may alter people’s behavior
90. The cohort study is the gold-standard of
analytical epidemiology
91. Case-control & cohort studies
• Case-control & cohort studies are used to demonstrate
association between suspected causes & disease
• Despite important differences between these 2 studies,
many of the rules regarding design & interpretation
of the results of the studies are applicable to both
McGovern DPB et al. Key topics in evidence-based medicine.
Bios Scientific Publishers, Oxford, UK, 1st Edition, 2001
94. Are the results of the study valid?
Did the authors choose the appropriate study design?
What were the criteria used for the disease/condition?
Was the population adequately defined?
Was the sample volume adequate?
Are there biases that the investigator did not address?
Critical appraisal of observational studies
What were the results?
How large was the point estimate?
How precise was the point estimate? (95% CI)
Can I apply the results to my population?
Were the patients similar to those in my practice?
Was the follow-up sufficiently long?
95. Biases in observational studies
Biases Explanation
Selection bias Select participants into exposed and not exposed
based on characteristics that may affect outcome
Information bias Collect different quality and extent of information
from exposed and not exposed groups
Recall bias Recall is better among cases than controls
because of the presence of the disease
Misclassification bias e.g.: same cut off level of weight for male
and female to determine malnourishment
96. Controlling confounding
• Study design
Randomization
Restriction: limiting type of individuals participating in study
Matching: making like-to-like comparisons (eg: age, sex, ..)
• Data analysis
Stratification: subset analyses of homogenous subgroups
Mathematical modeling: Multiple regression model
Cox proportional hazard
97. McGovern D, Summerskill W, Valori R, Levi M. Key topics in EBM.
BIOS Scientific Publishers, 1st Edition, Oxford, 2001.
Evidence pyramid
98. Perhaps the first large-scale clinical trial using
a properly designed randomized schema
99. Sir Austin Bradford Hill (1897 – 1991)
British epidemiologist & statistician
The father of modern RCTs
101. Basic structure of a RCT
Akobeng AK. Arch Dis Child 2005 ; 90 : 840 – 844.
Parallel trial is the most frequently used design
102. McGovern D, Summerskill W, Valori R, Levi M. Key topics in EBM.
BIOS Scientific Publishers, 1st Edition, Oxford, 2001.
Evidence pyramid
103. Systematic review & meta-analysis
Systematic reviews
(SR)
Meta-analyses
(MA)
MA may, or may not, include a SR
Egger M et all. Systematic reviews in health care: Meta-analysis in context.
BMJ Publishing Group, London, 2nd edition, 2001.
104. Number of SR/Ma published in PubMed
Harris JD et al. Am J Sports Med 2014; 42:2761-2768
105. Antibiotic prophylaxis & pancreatic necrosis
Bai Y et al. Am J Gastroenterol 2008 ; 103 : 104 – 110.
Forest plot
Reporting the results of meta-analysis
106. Bai Y et al. Am J Gastroenterol 2008 ; 103 : 104 – 110.
Antibiotic prophylaxis & pancreatic necrosis
Diamond shows the overall result of a meta-analysis
107. There can be overlap of evidence at any level
A well designed RCT can be more useful than
mediocre meta-analysis
109. Direct and indirect evidence
Riley et al. BMJ 2017;358:j3932
interventions A and B have been compared to placebo (head to head)
No trials have compared A to B directly
Effect of A versus B: Subtract A versus placebo from B versus placebo
110. Number of published network meta-analysis
Bafeta A et al. BMJ 2013;347:f3675.
111. Network meta-analysis of RCTs
Intra-gastric balloons for treatment of obesity
Network of included studies with direct comparisons
Node size reflects number of studies evaluating each treatment
Line thickness reflects number of included patients
Bazerbachi F et al. Obes Surg. 2018 Apr 16.
112. Results at 6 months after balloon placement
% total body weight loss (%TBWL)
Orbera
0.01 (-7.24,7.45) Heliosphere
2.72 (0.97,4.48) 2.72 (-4.93,10.34) ReShape
3.42 (1.89,4.96) 3.41 (-4.18,11.00) 0.70 (-0.95,2.35) Obalon
6.72 (5.55,7.89) 6.71 (-0.82,14.23) 4.00 (2.69,5.31) 3.30 (2.30,4.30) Control
Bazerbachi F et al. Obes Surg. 2018 Apr 16.
Comparisons should be read from left to right
Results are expressed in OR & 95% CI
Bold numbers are statistically significant
113. SUCRA in network meta-analysis
SUCRA: surface under the cumulative ranking curves
Outcome: percentage of total body weight loss (% TBWL)
Bazerbachi F et al. Obes Surg. 2018 Apr 16.
114. Question type & study design
Study DesignQuestion
Intervention RCT
Incidence & prognosis Cohort study
Prevalence Cross-sectional study
Etiology & risk factors Cohort or case-control
Diagnosis Cross-sectional study
In each case, SR of all available studies better than individual study
115. Improving quality of reports
Type of study Tool
Case report/series CARE guidelines
Riley et al. J Clin Epidemiol 2017;89:218-235.
Diagnostic study STARD statment
Bossuyt PM et al. BMJ 2003;326:41–44.
Observational study STROBE statement
https://www.strobe-statement.org
RCTs CONSORT statement
Moher et al. BMJ 2010;340:c869.
SR/MA PRISMA statement
https://www.prisma-statement.org
CARE: case report – CONSORT: consolidated standards of reporting trials – PRISMA: preferred
reporting items of SR & MA – STARD: standards for reporting of diagnostic accuracy –
STROBE: strengthening the reporting of observational studies in epidemiology
116. Limitations of evidence
• Evidence simply doesn’t exist
• Some of what is available
Not easily accessible
Not clinically relevant
Not of good quality
Not applicable to your patient
It takes time to develop high quality evidence
& more time to get it to publication
117. New evidence pyramid
Murad MH et al. Evid Based Med 2016;21 (4):125-127.
Traditional pyramid
Revised pyramid
2 modifications
1. wavy lines between studies
2. remove SR/MA from top
use them as lens to see other
types of studies
Revising the pyramid
118. Conclusion
• Hierarchy of evidence serves to guide clinicians in an
ordered manner to the best available evidence
• Evidence from case reports becomes more significant in
case of absence of higher evidence
• There can be overlap of evidence at any level
• A well designed RCT more useful than a mediocre MA
119. Learning through play
• Try all “buttons”
• Make lots of “mistakes”
• Have fun
• Self-learning