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Research
Evidence
Clinical
Scientific Decision
Expertise Making
HEALTH
Evidence-based medicine = the process of systematically finding, appraising, and using
contemporaneous scientific research as the basis for clinical decisions.
This approach places less value on physiologic principles and clinical experience, instead
shifting the emphasis to
● systematic obser vation,
● understanding rules of evidence,
● systematic research and
● critical interpretation of literature.
Kyriacou DN. Evidence-based medical decision making: deductive versus inductive logical thinking. Acad Emerg Med. 2004 Jun;11(6):670-1.
OBM EBM EVIDENCE BASED MEDICINE
● Gordon Guyatt - 1992, JAMA - a new approach to teaching the practice of medicine
EBM coined in: Guyatt GH. Evidence-based medicine. ACP J Club. 1991;114:A–16.
● David Sackett - 1996 - “Evidence based medicine is the conscientious, explicit, and
judicious use of current best evidence in making decisions about the care of individual
patients. The practice of evidence based medicine means integrating individual clinical
expertise with the best available external clinical evidence from systematic research.”
(From BMJ 1996;312:71-72)
● Trisha Greenhalgh - 2010 - "the use of mathematical estimates of the risk of benefit
and harm, derived from high-quality research on population samples, to inform clinical
decision-making in the diagnosis, investigation or management of individual patients.“
(Greenhalgh, Trisha (2010). How to Read a Paper: The Basics of Evidence-Based
Medicine (4th ed.))
■ By integrating specialized medical education with clinical practice, evidence-based
medicine is promoted as a more efficient and effective method of clinical decision
making.
■ In the last decades evidence based medicine has been accepted as a method
logically superior to traditional medicine, and is a part of the specialized educational
systems.
PATIENT CENTERED MEDICINE
“A patient consults an orthopedist because of knee pain. The surgeon determines that no
operation is indicated and refers her to a rheumatologist, who finds no systemic inflammatory
disease and refers her to a physiatrist, who sends her to a physical therapist, who administers the
actual treatment. Each clinician has executed his or her craft with impeccable authority and skill,
but the patient has become a shuttlecock. Probably a hassled, frustrated, and maybe bankrupt
shuttlecock.”
Charles L. Bardes, M.D. Defining “Patient-Centered Medicine” N Engl J Med 2012; 366:782-783
EBM
Appraise
■ ASSESS the patient and the problem to determine the pertinent issues, which may include a
differential diagnosis, treatment decisions, or prognosis. A comprehensive understanding of
pathophysiology and the thorough history and physical remain a critical starting point for the process.
■ ASK a clear, answerable question to be pursued. The first critical step is to clarify one or two key issues
that come up in the course of caring for your patient and to develop a focused clinical question.
■ ACQUIRE the evidence from an appropriate source. Potential sources include original research studies,
systematic reviews, evidence-based journal abstracts, textbooks and computerized decision support
systems.
■ Finally, the process must conclude by returning to the individual patient, as the clinician has to decide
whether it is appropriate to APPLY the evidence to the particular patient and their unique values and
circumstances. Evidence alone is never sufficient to direct decision making. Rather, it must be put into
context with a patient’s values.
We need to consider how to generalize the results from clinical trials to our individual patient. We must
consider whether the patient populations and treatments or interventions are comparable to our
setting.
ASK
■ The first stage of EBM is to ask a clearly focused question, because it makes it much easier to
find a reliable answer. Asking focused questions is directly relevant to patients’ problems and
phrased to direct your search to relevant and precise answers.
1 2 3 4
Intervention Comparison
Patient or Problem (a cause, prognostic Intervention Outcomes
factor, treatment, etc.) (if necessary)
“… lead to lower
“… would adding
mortality or morbidity
“In patients with heart failure anticoagulation with “… when compared
from thromboembolism.
Example from dilated cardiomyopathy warfarin to standard with standard therapy
Is this enough to be
who are in sinus rhythm …” heart failure therapy alone …”
worth the increased risk
…”
of bleeding?”
ASK
Once you have formed the question using the PICO structure, you can think about what type
of question it is you are asking, and therefore what type of research would provide the best
answer.
ASK (PICO) In older patients (>= 65 years of age) with knee joint pain does
physiotherapy reduce level of pain compared to NSAI medication ?
■ Outcome
Which is the best method of reducing knee joint pain in
older patients ?
Ask: Ask an answerable clinical question based on the health needs of a specific patient
(may use the PICO framework: Patient, Intervention, Comparison, Outcome).
ACQUIRE Finding the Evidence
■ Finding the evidence is the second step in the five steps of evidence-based practice.
It is important when searching for evidence that search terms are referred back to your
original PICO question. The process of finding evidence therefore follow three key steps:
► Identify terms to fit your PICO question
► Look for secondary sources
► Search for primary sources
ACQUIRE Finding the Evidence
● Guidelines: UK National Library for Health, NICE, SIGN; US National Guidelines Clearinghouse;
Canadian Medical Association; New Zealand Guidelines Group.
● Critically Appraised Topics (CATs): CAT Crawler
● Evidence-Based Summaries: Bandolier, Clinical Evidence
● Structured Abstracts: EBM Online, ACP Journal Club
● Systematic Reviews: Cochrane Library
● To search several of the databases simultaneously you can use: www.tripdatabase.com
ACQUIRE Finding the Evidence
■ The integration of relevant evidence with clinical experience forms the cornerstone of evidence based-
practice.
■ To asses evidence of effectiveness of a therapeutic intervention there are two important concepts that need
to be addressed and understood. These are the internal and external validity of a given study.
■ External validity refers to the extent to which we can generalize the results of a trial to the population
of interest. Internal validity refers to the extent a study properly measures what it is meant to.
APPLY / MAKING A DECISION
■ strong recommendations
● strong methods
● large precise effect
● few downsides of therapy
■ weak recommendations
● weak methods
● imprecise estimates
● small effect
● substantial downsides
What is GRADE?
■ GRADE is a systematic and explicit approach to making judgements about quality of evidence
and strength of recommendations.
■ It was developed by the Grading of Recommendations, Assessment, Development and
Evaluations (GRADE) Working Group, and it is now widely seen as the most effective method
of linking evidence-quality evaluations to clinical recommendations.
Oxford Center for Evidence based Medicine common international grading system
Scottish Intercollegiate Guidelines (SIGN) Australian NMRC, SIGN, USPSTF, NICE, WHO,
US Preventative Services Task Force Oxford CEBM, CDC, CC
American Professional Organizations high concentration of methodologists
- AHA/ACC, ACCP, AAP, Endocrine Society etc frequent annual meetings
etc
Code Quality of Evidence Definition
Further research is very unlikely to change our confidence in the estimate of effect.
A High •Several high-quality studies with consistent results
•In special cases: one large, high-quality multi-centre trial
Further research is likely to have an important impact on our confidence in the estimate of
effect and may change the estimate.
B Moderate
•One high-quality study
•Several studies with some limitations
Further research is very likely to have an important impact on our confidence in the estimate of
C Low effect and is likely to change the estimate.
•One or more studies with severe limitations
■ Authority
■ Custom and tradition
■ Personal experience
■ Deductive reasoning
■ Scientific enquiry
Acquiring knowledge
■ RATIONALISM
■ EMPIRICISM
■ SKEPTICISM
■ TRANSCENDENTAL IDEALISM
■ REALISM
■ SCIENCE
■ science
a systematic enterprise that builds and organizes knowledge in the form of testable
explanations and predictions about the universe
"... modern science is a discovery as well as an invention. It was a discovery that nature
generally acts regularly enough to be described by laws and even by mathematics; and
required invention to devise the techniques, abstractions, apparatus, and organization for
exhibiting the regularities and securing their law-like descriptions.“
Heilbron, J. L. (editor-in-chief) (2003). The Oxford Companion to the History of Modern Science. New York: Oxford University Press
Roger Bacon (c. 1219/20 – c. 1292)
credited (mainly since the 19th century) as one of the earliest European advocates of the
modern scientific method inspired by Aristotle and by later scholars such as the Arab
scientist Alhazen
Statistics deals with all aspects of data including the planning of data
collection in terms of the design of surveys and experiments
Dodge, Y. (2006) The Oxford Dictionary of Statistical Terms, OUP.
Statistics is concerned with the use of data in the context of uncertainty and
decision making in the face of uncertainty
Moore, David (1992). "Teaching Statistics as a Respectable Subject". In F. Gordon and S. Gordon. Statistics for the Twenty-First Century.
Washington, DC: The Mathematical Association of America. pp. 14–25.
Statistical inference
Statistical inference is the process of deducing properties of an underlying distribution
by analysis of data.
Upton, G., Cook, I. (2008) Oxford Dictionary of Statistics, OUP.
Descriptive statistics (exploratory data analysis) is solely concerned with properties of the
observed data, and does not assume that the data came from a larger population.
Theory
Hypothesis
Deduction
Observation
Confirmation
Theory
Tentative
Induction
Hypothesis
Pattern
Observation
Research Methodology
Make sure that a reasonable answer to the proposed question is not already available.
The objective of all this exercise should be to identify the specific information gaps, and to
examine how the problem fits into the medical jigsaw puzzle.
Assess if the problem is really worth pursuing. If none or very little baseline information is
available, consider carrying out an exploratory study as a first step.
What makes a good research question?
■ “Make sense”: In other words, you must clearly define your terms using known definitions outlined
in the literature.
For example, a poor research question would be: How do people’s lives improve after surgery? Not
only does this research question fail to specify the study population, it contains the vague term
“improve”. The researcher must specify what he/she means by this term—does it involve a physical
improvement or rather an improvement in mental state? The more specific your research question, the
better.
■ Address an important and relevant issue: A good research question will also always have relevance
to the time, place, and population of the study.
For example, a study of Vitamin A deficiency in Southern India would be a poor choice as this is not a
particularly significant problem in the area.
What makes a good research question?
■ Not already have been done: A good research study will be novel. When replicating a
pervious study, it is best to add or change one or two things to increase the novelty of the
research.
■ Be within a reasonable scope: In general, the more focused the research question the more
likely it will be a successful project.
For example, a study that seeks to identify the prevalence of eye disease in a specific village is
more likely to succeed than a comparable study that seeks to identify eye disease prevalence in
the world population.
ASK (PICO) In older patients (>= 65 years of age) with knee joint pain does
physiotherapy reduce level of pain compared to NSAI medication ?
■ Outcome
Which is the best method of reducing knee joint pain in
older patients ?
Ask: Ask an answerable clinical question based on the health needs of a specific patient
(may use the PICO framework: Patient, Intervention, Comparison, Outcome).
FINER criteria for a good research question
the primary trait of a hypothesis is that something can be tested and that those tests can be
replicated - deriving predictions from the hypotheses about the results of future experiments, and
then performing those experiments to see whether they support the predictions
HYPOTHESIS TESTING
RESEARCH STUDY CHARACTERISTICS
Statistical inference
■ Bayesian inference
- probability of an event based on prior knowledge of conditions that might be related to the event
- probability measures a “degree of belief” - before and after accounting for evidence
■ Frequentist inference
- draws conclusions from sample data by emphasizing the frequency or proportion of the data
- probability measures a “proportion of outcomes”
Type I Error/
■ Decide whether to reject the null hypothesis Type II Error
4. Decide! - interpretation of probability (frequentist, critical value, p -value)
■ most frequent technique in statistical inference is
null hypothesis testing/ test of significance
Falsifiable
Karl Popper
falsificationism thus strives for questioning, for falsification, of hypotheses instead of proving them
Alternate hypothesis:
All swans are white Probable!
SAMPLE!
■ in an European sample all swans were found white
the null hypothesis is REJECTED
the alternate hypothesis is ACCEPTED WITH A CERTAIN PROBABILITY - DEGREE OF BELIEF
■ the null hypothesis is either TRUE (always assumed true) or FALSE (rejected by the experiment)
NOT PROBABLE
the term "null hypothesis" usually refers to a general statement or default position that
there is no relationship between two measured phenomena, or no association among
groups
rejecting or disproving the null hypothesis—and thus concluding that there are grounds
for believing that there is a relationship between two phenomena (e.g. that a potential
treatment has a measurable effect)—is a central task in the modern practice of
science, and gives a precise criterion for rejecting a hypothesis.
Null / Alternate hypothesis - mutually exclusive !!
■ the null hypothesis is generally assumed to be true until evidence indicates otherwise
In statistics, it is often denoted H0 (read “H-naught”, "H-null", or "H-zero").
■ alternate hypothesis - prediction - that there is a relationship between two phenomena
(e.g. that a new treatment has a measurable effect)
•Ho: μ = μ0
Hypothesis to determine whether one population mean, μ1, is equal to a different population
mean μ2 :
•H0: μ1 = μ2
•H1: μ1< μ2 or
•H1: μ1> μ2 or
•H1: μ1≠ μ2
Truth
Type I error :
reject the null hypothesis when it is true - conclude there is an effect when in reality there is none
“false positive”
the probability of making a Type I error is denoted α = the significance level of test
α = 0,05 (by convention) (5%)
the significance level = the probability of rejecting the null hypothesis when it is true
Type II error :
do not reject the null hypothesis when it is false - conclude there is no effect when one really exists
“false negative”
the power of test = the probability of rejecting the null hypothesis when it is false
(ex.: the probability (chance) of detecting, as statistically significant, a treatment effect of a given size)
Decision! - Test statistics
■ compares your data with what is expected under the null hypothesis
measures the degree of agreement between a sample of data and the null hypothesis
■ reflects the amount of evidence in the data against the null hypothesis - the larger the
value, the greater the evidence
Decision! - probability interpretations
■ P - value approach
■ frequentist approach
an event's probability as the limit of its relative frequency in a ratio from an infinite series of trials
region of acceptance - a range of values defined so that the chance of making a Type I error is
equal to the significance level
if the test statistics falls within the region of acceptance, the null hypothesis is not rejected
region of rejection - set of values outside the region of acceptance
if the test statistic falls within the region of rejection, the null hypothesis is rejected
Decision! p value
■ p value = the probability of obtaining an effect at least as extreme as the one in your sample
data, assuming the truth of the null hypothesis
p-value is basically the probability of obtaining your sample data IF the null hypothesis was true
■ relate the value of the test statistics to the known probability distribution → p value
● the greater the power of test and test statistics the greater the evidence against H0
“p-value is the probability that the null hypothesis is false”
“p-value is the probability that the alternate hypothesis is true under the null hypothesis”
■ The typical convention in most fields of
science allows for a 5% chance of
erroneously rejecting the null
hypothesis (of making a Type I error)
■ Some researchers say that a hypothesis test can have one of two outcomes: you accept
the null hypothesis or you reject the null hypothesis. Many statisticians, however, take
issue with the notion of "accepting the null hypothesis." Instead, they say: you reject the
null hypothesis or you fail to reject the null hypothesis.
■ Why the distinction between "acceptance" and "failure to reject?" Acceptance implies
that the null hypothesis is true. Failure to reject implies that the data are not sufficiently
persuasive for us to prefer the alternative hypothesis over the null hypothesis.
■ If the p-value is less than the required significance level (convention value), then we say
the null hypothesis is rejected at the given level of significance.
Rejection of the null hypothesis is a conclusion. This is like a "guilty" verdict in a criminal
trial: the evidence is sufficient to reject innocence, thus proving guilt. We might accept the
alternative hypothesis (and the research hypothesis) BUT we can discuss about the quality
and magnitude of the evidence (think of evidence in a trial).
■ If the p-value is not less than the required significance level then we say we failed to
reject the null hypothesis. The test has no result.
The evidence is insufficient to support a conclusion. This is like a jury that fails to reach a
verdict.
Whether rejection of the null hypothesis truly justifies acceptance of the research
hypothesis depends on the structure of the hypotheses.
---- Rejecting the hypothesis that a large paw print originated from a bear does not
immediately prove the existence of Bigfoot.
Hypothesis testing emphasizes the rejection, which is based on a probability, rather than
the acceptance, which requires extra steps of logic.
■ The successful hypothesis test is associated with a probability and a Type-I error rate.
The conclusion might be wrong.
■ The conclusion of the test is only as solid as the sample upon which it is based. The
design of the experiment is critical.
■ multiple testing, in which a variety of tests for a variety of possible effects are
applied to a single data set and only those yielding a significant result are reported
■ Hypothesis testing - YES or NO - PROBABILITY
what about the magnitude of evidence?
■ p-value arises through the interaction of the effect size, the sample size (all things
being equal a larger sample size produces a smaller p-value) and sampling error
= insușirea unui lucru, a unui fenomen etc. de a varia, de a lua forme și aspecte diferite.
= proprietate a ființelor vii de a-și schimba, sub influența mediului și a eredității, însușirile
morfologice, fiziologice, biochimice etc.
= schimbare, transformare; stare a unui lucru care se prezintă sub diferite forme, în mod
variat; trecere de la o formă la alta; aspect variabil, schimbător
= schimbare a unei însușiri morfologice, fiziologice, biochimice etc. a organismului
■ range,
■ interquartile range,
■ variance,
■ standard deviation
Variation
■ fluctuation among clinical measurements reflects the combined effects of several phenomena
■ Measurement variation
■ True biologic variation
Definition -true biologic variation in clinical measurements is the sum of many unknown
factors, each of which contributes a small random effect
random effects, based on the laws of probability are as likely to be positive (causing the
measurement to exceed the true value) as they are to be negative (causing the
measurement to be less than the true value)
-random effect is governed by the laws of probability = laws of chance
True biologic variation
Definition
variation in clinical measurements occurs when the conditions under which the
measurements are made are known to affect the values obtained
this type of variation is more systematic rather than random, because its effect is
predictable and not based on the laws of chance
Systematic variation
-a patient's systolic blood pressure varies according to the time of day (temporal
variation) and the position of the person (postural variation) when the measurement is
taken
-the pattern associated with these fluctuations is somewhat regular and predictable
within a given person
■ Measurement variation
– -random component
– -systematic component
random measurement error
– is governed by the laws of chance and
– results in a measurement that is either above or below the true value with equal
probability
– a series of measurements affected only by random variation will center on the true
value of variable being measured
● for a given sample of urine, a series of measurements of pH made with the same meter
by the same analyst under theoretically identical conditions will not be exactly equal
Variation from patient to patient in the value of a clinical variable is attributable to:
- inherent biologic differences among patients – these biologic differences (variations)
can be:
▪ "true" – due to random changes
▪ "bias" – due to sampling error (a systematic change or variation)
- systematic variations (differences in conditions of measurement)
- measurement error
- a pathologic change
■ Error = The result of a measurement minus the “true”(conventional) value
● Random error (of a result) = A component of the error which, in the course of a
number of test results for the same characteristic,
varies in an unpredictable way.
– It is not possible to correct for random error
-unlike random variation, bias results in measurements that are systematically higher or
lower than the true underlying value of a diagnostic variable
– Sampling error arises when statements about reality (for an individual or group)
are made on the basis of incomplete information obtained from a sample
Example
-a biopsy of the right side of the liver will give biased results, or results that are
not representative of the truth (i.e., the presence of the tumor), if a tumor is
located on the left side of the liver
■ Bias due to a flaw in the measurement process
– A faulty measuring instrument may yield values that are consistently higher
or lower than the true value of the variable being measured
Example
-a physician with a hearing impairment may obtain diastolic blood pressure
measurements that are consistently above the true diastolic pressure
■ Relationship between bias and chance
– the sphygmomanometer values are systematically shifted (i.e., biased) to the right of
the true value, possibly owing to improper cuff size or hearing deficit of the person
making the observation
● Validity ● Reliability
validitate fiabilitate
● Consistency
consecventa/coerenta
● Accuracy the closeness of a measurement to the true value
When throwing darts at a dart board “accuracy” refers to whether the darts are hitting
the bull’s eye (an accurate dart thrower will throw darts that hit the bull’s eye)
Accuracy consists of Trueness (proximity of measurement results to the “true” value)
and Precision (repeatability or reproducibility of the measurement)
■ Accuracy - The closeness of agreement between a test result and the accepted reference value
Accuracy is essentially absence of error
■ Trueness - Closeness of agreement between the average value obtained from a large series
of test results and an accepted reference value
Trueness is equivalent to absence of bias
■ Precision - The closeness of agreement between independent test results obtained under
stipulated conditions
Repeatability conditions - the same method on identical test items in the same laboratory by the same
operator using the same equipment within short intervals of time
Reproducibility conditions - the same method on identical test items in different laboratories with different
operators using different equipment
● Validity – the extent to which a test measures what it is supposed to measure
e.g Screening tests should be able to identify the presence or absence of a specific
disease (validity)
● Reliability - the degree to which an assessment tool produces stable and consistent results.
■ Inter-rater reliability - the degree of agreement between two or more raters in their appraisals.
■ Test-retest reliability - the degree to which test scores are consistent from one test administration
to the next. Measurements are gathered from a single rater who uses the same methods or
instruments and the same testing conditions. This includes intra-rater reliability.
■ Inter-method reliability - the degree to which test scores are consistent when there is a variation
in the methods or instruments used. This allows inter-rater reliability to be ruled out.
■ Internal consistency reliability - the consistency of results across items within a test.
■ Internal consistency refers to the general agreement between multiple items that
make-up a composite score of a survey measurement of a given construct. This
agreement is generally measured by the correlation between items.
Sensitivity and specificity
■ sensitivity
(true positive rate, the recall, or probability of detection) measures the proportion of positives that
are correctly identified as such (e.g., the percentage of sick people who are correctly identified as
having the condition).
avoid false negatives - Type II errors
■ specificity
(true negative rate) measures the proportion of negatives that are correctly identified as such (e.g.,
the percentage of healthy people who are correctly identified as not having the condition).
avoid false positives - Type I errors
■ sensitivity or true positive rate (TPR) ■ precision or positive predictive value (PPV)
TPR = TP/P = TP / (TP+FN) PPV = TP / (TP + FP)
■ specificity (SPC) or true negative rate ■ negative predictive value (NPV)
SPC = TN/N = TN / (TN+FP) NPV = TN / (TN + FN)
■ accuracy (ACC)
ACC = (TP + TN) / (TP + FP + TN + FN) = 1 / (FP + FN)
Predicted condition
If a test subject has an abnormal screening The percentage of sick people who are
test (i.e., it's positive), what is the probability correctly identified as having the
that the subject really has the disease? condition
If a test subject has a negative screening The percentage of healthy people who
test, what is the probability that the subject are correctly identified as not having the
really does not have the disease? condition
One more time!
■ Type I error - reject H0 when it is true - false positive (diagnosis or medical test)
■ Type II error - do not reject H0 when it is false - false negative (diagnosis or medical test)
false negative
false positive rate rate
1 - FPR = 1 - FNR =
specificity sensitivity
a series of analyses of a data set to assess whether altering any of the assumptions made
leads to different final interpretations or conclusions
is the study of how the uncertainty in the output of a mathematical model or system (numerical or
otherwise) can be apportioned to different sources of uncertainty in its inputs
• How confident can I be about the results?
• Will the results change if I change the definition of the outcome (e.g., using different cut-off
points)?
• Will the results change if I change the method of analysis?
• Will the results change if we take missing data into account? Will the method of handling
missing data lead to different conclusions?
• How much influence will minor protocol deviations have on the conclusions?
• What if the data were assumed to have a non-Normal distribution or there were outliers?
• Will the results change if one looks at subgroups of patients?
• Will the results change if the full intervention is received (i.e. degree of compliance)?
TYPES OF STUDY
SAMPLING
Types of research
Type of information
Application Purpose
sought
Descriptive
Pure/Basic
Quantitative
Explanatory
Exploratory
Applied Qualitative
discovery of new knowledge, theoretical in nature
takes many years for the results of fundamental research to find a practical utility
Amount of uncertainty
characterizing decision Clearly defined Highly ambiguous Partially defined
situation
■ descriptive studies
■ cross sectional studies
■ case control
■ cohort studies
■ randomized trials
Types of study design
Clinical questions may be categorized as either background or foreground. Why is this important?
Determining the type of question will help you to select the best resource to consult for your answer.
Background questions ask for general knowledge about an illness, disease, condition, process or thing.
For example
•How overweight is a woman to be considered slightly obese?
•What are the clinical manifestations of menopause?
•What causes migraines?
Background questions are best answered by medical textbooks and narrative reviews.
Foreground questions ask for specific knowledge to inform clinical decisions.
■ Foreground questions are best answered by consulting medical databases such as MEDLINE (via
PubMed or Ovid), Embase, Cochrane Database of Systematic Reviews and ACP Journal Club.
Foreground questions may be further categorized into one of 4 major types:
► treatment/therapy,
► diagnosis,
► prognosis,
► etiology/harm.
For example
• Is Chondroitin sulfate effective when compared with placebo in slowing the rate of functional
impairment in a 72 year old male patient with osteoarthritis?
• In pediatric patients with Allergic Rhinitis, are Intranasal steroids more effective than
antihistamines in the management of Allergic Rhinitis symptoms?
■ Therapy: Questions of treatment/intervention in order to achieve some outcome. May
include drugs, surgical intervention, change in diet, counseling, prevention, etc.
Prevention Questions about the effectiveness of an intervention or exposure in RCT or Prospective Study
preventing morbidity and mortality. Similar to treatment questions.
When assessing preventive measures, it is particularly important to
evaluate potential harms as well as benefits.
Diagnosis Questions about the ability of a test or procedure to differentiate RCT or Cohort Study
between those with and without a condition or disease.
Prognosis (Forecast) Questions about the probable cause of a patient's disease or the Cohort Study and/or Case-
likelihood that he or she will develop an illness. Control Series
Etiology (Causation) Questions about the harmful effect of an intervention or exposure on Cohort Study
a patient.
■ Case series
→ pre-test/post-test studies measure the change - a variation of the cross-sectional design - two
sets of cross-sectional data collection on the same population to determine if a change has
occurred
→ the sample frame used to select a sample and the response rate determine how well results
can be generalized to the population as a whole
■ Cross sectional
Advantages:
▪ short term ▪ design less complex
▪ more easily controlled ▪ useful for planning health services and medical programs
▪ relationship between attributes of disease and characteristics of various groups (e.g. elderly)
● prevalence-incidence bias (also called Neyman bias). Especially in the case of longer-lasting
diseases, any risk factor that results in death will be under-represented among those with the
disease
● do not determine temporal relationship between exposure and outcome (lacks time element)
● only a snapshot: the situation may provide differing results if another timeframe had been chosen
Explanatory studies (analytical)
1. may play an instrumental role in terms of identifying reasons behind a wide range of processes, as well
as, assessing the impacts of changes on existing norms, processes etc.
2. offer the advantages of replication if necessity arises
3. are associated with greater levels of internal validity due to systematic selection of subjects
■ Disadvantages
2. difficult to reach appropriate conclusions due to the impact of a wide range of factors and variables
while casualty can be inferred, it cannot be proved with a high level of certainty.
3. while correlation between two variables can be effectively established, identifying which variable is a
cause and which one is the impact can be a difficult task to accomplish.
■ Case control
→ subjects are defined as cases and controls, and exposure histories are compared
→ begin with the outcomes and do not follow subjects over time
PAST PRESENT
Example: lung cancer cases and non-cancerous controls recall past exposure to cigarette smoke
Case control
■ Advantages
Relatively inexpensive
Less time-consuming than cohort studies
Can evaluate effects of multiple exposures
Efficient for rare outcomes or outcomes with long induction or latency periods
■ Disadvantages
Limited to one outcome variable
Subject to recall bias (based on subjects’ memory and reports)
Difficult to establish clear chronology of exposure and outcome
Inefficient for rare exposures
Cohort Study
■ when good evidence suggests an association of a disease with a certain exposure or exposures
■ examines multiple health effects of an exposure;
■ subjects are defined according to their exposure levels ;
■ subjects are followed over time for outcome occurrence;
■ subjects who presently have a certain condition or receive a particular treatment are followed
over time and compared with another group of subjects who are not affected by the condition;
■ the exposure of interest is determined for each member of the cohort and the group is followed
to document incidence of disease in the exposed and non-exposed members;
■ changes and variation in the disease or health status of a study population as the study group
moves through time
■ Cohort Study: a non-experimental study design that follows a group
of people (a cohort), and then looks at how events differ among
people within the group. A study that examines a cohort, which
differs in respect to exposure to some suspected risk factor (e.g.
smoking), is useful for trying to ascertain whether exposure is likely
to cause specified events (e.g. lung cancer). Prospective cohort
studies (which track participants forward in time) are more reliable
than retrospective cohort studies.
Cohort Study
■ Retrospective - makes use of historical data to determine exposure level at some baseline in
the past and then determine subsequent disease status in the present.
■ Advantages
Can evaluate multiple effects of a single exposure
More efficient for rare exposures and outcomes with long induction and latency periods
Can directly measure incidence
Clear chronological relationship between exposure and outcome
■ Disadvantages
Expensive
Time-consuming
Inefficient for rare outcomes with long induction or latency periods
Experimental
■ research designs which use manipulation and controlled testing to understand
causal processes
■ one or more variables are manipulated to determine their effect on a dependent variable
■ The effect that the researcher is interested in, the dependent variable(s), is
measured.
■ Identifying and controlling non-experimental factors which the researcher does not
want to influence the effects, is crucial to drawing a valid conclusion. This is often
done by controlling variables, if possible, or randomizing variables to minimize
effects that can be traced back to third variables.
■ aim:
investigate the possible cause and effect relationship by manipulating one variable to
influence the other variable in the experimental/study/intervention group and by
controlling the other relevant variables and measuring the effects of the manipulation
by statistical means
■ a true experiment - the researcher manipulates one variable, and control/randomizes
the rest of the variables
■ it has a control group, the subjects have been randomly assigned between the groups,
and the researcher only tests one effect at a time; know what variable(s) you want to test
and measure
yes no
yes no
quasi-experiment non-experiment
■ An ad hoc analysis is a hypothesis invented after testing is done, to try to explain why
the contrary evidence. A poor ad hoc analysis may be seen as the researcher's inability
to accept that his/her hypothesis is wrong, while a great ad hoc analysis may lead to
more testing and possibly a significant discovery.
■ First conduct a pilot-study or two before you do the real experiment. This ensures that
the experiment measures what it should, and that everything is set up right.
■ The key to designing any experiment is to look at what research variables could affect the
outcome.
■ There are many types of variable but the most important, for the vast majority of research
methods, are the independent and dependent variables.
■ The independent variable is the core of the experiment and is isolated and manipulated
by the researcher.
■ The dependent variable is the measurable outcome of this manipulation, the results of
the experimental design.
If you designed an experiment to determine how quickly a cup of coffee cools, the manipulated
independent variable is time and the dependent measured variable is temperature.
Experimental
■ similar groups of individuals, from the same source population, are allocated at random to
receive and not to receive an intervention, then observed for occurrence of outcome(s)
random allocation
■ the “gold standard” of research design;
■ provide the most convincing evidence of the relationship between exposure and
outcome/effect - causal
■ expensive
■ ethics
■ dropout rates, lost to follow-up - intention to treat analysis (ITT)/efficacy subset analysis
Systematic Review
■ A type of literature review that collects and critically analyzes multiple research studies
or papers.
■ A systematic review is a critical assessment and evaluation of all research studies that
address a particular clinical issue.
■ The researchers use an organized method of locating, assembling, and evaluating a
body of literature on a particular topic using a set of specific criteria.
■ A systematic review typically includes a description of the findings of the collection of
research studies.
■ The systematic review may also include a quantitative pooling of data, called a meta-
analysis.
Systematic Review
■ Defining the review question(s) and developing criteria for including studies
■ Searching for studies
■ Selecting studies and collecting data
■ Assessing risk of bias in included studies
■ Analysing data and undertaking meta-analyses
■ Addressing reporting biases
■ Presenting results and "summary of findings" tables
■ Interpreting results and drawing conclusions
Systematic Review
The main stages of a systematic review are:
■ A revision of these guidelines, renamed PRISMA (Preferred Reporting Items for Systematic
reviews and Meta-Analyses), which have been updated to address several conceptual and
practical advances in the science of systematic reviews has been published.
Section/topic # Checklist item
PRISMA 2009 Checklist
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both.
ABSTRACT
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and
interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review
registration number.
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known.
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and
study design (PICOS).
METHODS
Protocol and 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information
registration including registration number.
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication
status) used as criteria for eligibility, giving rationale.
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the
search and date last searched.
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-
analysis).
Data collection 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and
process confirming data from investigators.
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
Risk of bias in 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or
individual studies outcome level), and how this information is to be used in any data synthesis.
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means).
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2) for each
meta-analysis.
Section/topic # Checklist item PRISMA 2009 Checklist
Risk of bias across 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within
studies studies).
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-
specified.
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage,
ideally with a flow diagram.
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the
citations.
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).
Results of individual 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b)
studies effect estimates and confidence intervals, ideally with a forest plot.
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.
Risk of bias across 22 Present results of any assessment of risk of bias across studies (see Item 15).
studies
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).
DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g.,
healthcare providers, users, and policy makers).
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research,
reporting bias).
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.
FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic
review.
From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097
PRISMA 2009 Flow Diagram
Example Table: Summary of included studies evaluating the efficacy of antiemetic agents in acute gastroenteritis.
Example Figure: Overall failure (defined as failure of assigned regimen or relapse) with T-R versus T-S.
Example Table: Quality measures of the randomized controlled trials that failed to fulfill any one of six markers of
validity.
Qualitative Research - not everything can be quantified
■ investigation in which the researcher attempts to understand some larger reality by
examining it in a holistic way or by examining components of that reality within their
contextual setting
“Qualitative Research…involves finding out what people think, and how they feel - or at
any rate, what they say they think and how they say they feel. This kind of information is
subjective. It involves feelings and impressions rather than numbers”
- Bellenger, Bernhardt and Goldstucker, Qualitative Research in Marketing, American Marketing Association
■ purpose is understanding
■ oriented toward discovery
■ uses subjective data
■ extracts meaning from data
■ interprets results in context
■ focus is holistic
■ Advantages
→ in depth examination of phenomena
→ not limited to rigidly definable variables
→ examines complex questions (impossible with numbers)
→ explore new areas of research (unanticipated responses)
→ build new theories
■ Disadvantages
→ subjectivity leads to procedural problems
→ replicability is difficult
→ researcher bias is built in and unavoidable
→ labor intensive, expensive
→ not understood well by “classical” researchers
■ Participant observation is appropriate for collecting data on naturally occurring
behaviors in their usual contexts.
■ In-depth interviews are optimal for collecting data on individuals’ personal histories,
perspectives, and experiences, particularly when sensitive topics are being
explored.
■ Focus groups are effective in eliciting data on the cultural norms of a group and in
generating broad overviews of issues of concern to the cultural groups or subgroups
represented.
→ Designing a research hypothesis is supported by a good research question and will
influence the type of research design for the study.
Acting on the principles of appropriate hypothesis development, the study can then
confidently proceed to the development of the research objective
→ The study objective is an active statement about how the study is going to answer
the specific research question.
Study: Warden SJ, Metcalf BR, Kiss ZS, et al. Low-intensity pulsed ultrasound for chronic
patellar tendinopathy: a randomized, double-blind, placebo-controlled trial. Rheumatology
2008;47:467–71.
Research question: How does low-intensity pulsed ultrasound (LIPUS) compare with a
placebo device in managing the symptoms of skeletally mature patients with patellar
tendinopathy?
Research hypothesis: Pain levels are reduced in patients who receive daily active-LIPUS
(treatment) for 12 weeks compared with individuals who receive inactive-LIPUS (placebo).
1. Identify the population of interest - a population is the group of people that you want to
make assumptions about - as you cannot study every individual from a population go to
next step
2. Specify a sampling frame - a sampling frame is the group of people from which you will
draw your sample - groups you have access to
3. Specify a sampling method - randomly (can use strata) or non-randomly
4. Determine the sample size
5. Implement the plan
■ Inferential statistics tries to infer information about a population by using information
gathered by sampling.
■ to gather data about the population in order to make an inference that can
be generalized to the population
Population
■ study population - the segment from the target population you have access to
■ target population - a set of elements/units larger than the sampled population to which
the researcher would like to generalize the study findings
population sample
The definition of the subject of study and the target population should be clearly spelt out.
Besides inclusion criteria, the exclusion criteria should also be clearly stated.
Study Study
Sample Sample
Study
Population
REPRESENTATIVENESS
● sampling procedure
● sample size
● participation (response)
When might you sample the entire population ? statistic = parameter
■ sample size - the number of units sampled for inclusion in the study
every unit in the population has a chance (greater than zero) of being selected in the sample, and
this probability can be accurately determined
- 'equal probability of selection' (EPS)
some elements of the population have zero chance of selection, or the probability of selection can't
be accurately determined
non-probability sampling
■ a sample in which the individuals selected for analysis share all properties except
that under investigation
■ The goal of matching is, for every treated unit, to find one (or more) “non-treated”
unit(s) with similar observable characteristics against whom the effect of the
intervention can be assessed.
• cross-over trials in which individuals are randomized to two treatments and then the
same individuals are crossed-over to the alternative treatment,
• any circumstance in which each data point in one sample is uniquely matched to a data
point in the second sample.
■ In a paired sample design, we model the data as if there is a single bucket of balls,
and each draw from the bucket results in a pair of numbers (that we can distinguish
as first and second).
■ However, the standard error for a paired design does not equal the standard error
computed from the same data assuming two independent samples
Sample Size
■ when reduced to most simple terms, all medical research is simply the
study of relationships among variables
■ a variable is any:
■ quality
■ characteristic
■ constituent
of a person or thing
that can be measured
■ by definition a variable is subject to change - variability
Variables
■ When you selected the variables for your study, you did so with the
assumption that they either:
■ would help to define your problem (dependent variables -
represents the output or effect, or is tested to see if it is the effect)
and its different components
or that
■ they were contributory factors to your problem (independent
variables – the inputs or causes, or are tested to see if they are the
cause)
Variables
■ Other way of expressing that is:
– dependent variable is the response
– independent variable is the predictor
■ Ex: – relationship between:
– cardiovascular risk (response) and body mass (predictor)
– species number (response) and island area (first predictor) and
island age (second predictor)
■ The key to designing any experiment is to look at what research variables could affect the
outcome.
■ There are many types of variable but the most important, for the vast majority of research
methods, are the independent and dependent variables.
■ The independent variable is the core of the experiment and is isolated and manipulated
by the researcher.
■ The dependent variable is the measurable outcome of this manipulation, the results of
the experimental design.
the manipulated independent variable is time and the dependent measured variable is temperature.
Classification of variables
■ independent variables
■ controlled variables - confounding variables/third variable
■ dependent variables
Classification of variables
■ Univariate data. When we conduct a study that looks at only one variable, we say that
we are working with univariate data.
Suppose, for example, that we conducted a survey to estimate the average weight of high school
students. Since we are only working with one variable (weight), we would be working with univariate
data.
■ Bivariate data. When we conduct a study that examines the relationship between two
variables, we are working with bivariate data.
Suppose we conducted a study to see if there were a relationship between the height and weight of
high school students. Since we are working with two variables (height and weight), we would be
working with bivariate data.
Bias, confounding and effect modification
■ Bias: A systematic error in the design, recruitment, data collection or analysis that results in
a mistaken estimation of the true effect of the exposure and the outcome.
■ Effect modification : a variable that differentially (positively and negatively) modifies the
observed effect of a risk factor on disease status. Different groups have different risk
estimates when effect modification is present.
■ If the method used to select subjects or collect data results in an incorrect
association,
THINK >> Bias!
■ If an effect is real but the magnitude of the effect is different for different
groups of individuals (e.g., males vs females or blacks vs whites).
THINK >> Effect modification!
Classification of variables
■ Between-subjects Variable Values of the variable are examined as they are observed to
change from one individual to another. When a variable is administered Between-
Subjects, subjects each receive ONE level of the Independent Variable
■ Within-subject Variable Values of the variable are examined as they are observed to
change from time to time within an individual. When a variable is administered
Within-Subject, subjects receive ALL levels of the Independent Variable (also called
Repeated Measures).
Data analysis
■ descriptive statistics,
■ exploratory data analysis (EDA) - discovers new features in the data - patterns
■ confirmatory data analysis (CDA) - rejects or fails to reject existing hypotheses
p -value
CDA
EDA+IDA
Variables
■ Some of the variables may have produced numerical data, while other
variables produced categorical data
Data Levels of measurement
■ Qualitative/categorical data
● nominal
● dichotomous
● ordinal
■ Quantitative/numerical data
● ordinal
● interval
● ratio
Qualitative variables
- a measurement of serum sodium concentration (e.g., 140 mEq/l) expresses the exact amount
of sodium in the serum
- serum cholesterol level, systolic blood pressure, and blood ureea nitrogen (BUN) level are other
quantitative clinical variables
Scales used to measure variables
■ 1.Nominal Scale
■ categories that cannot be ordered one above the other
■ limited number of categories
■ 2.Ordinal Scale
■ limited number of categories that are ranked in terms of a graded order
■ 3.Interval Scale
■ unlimited number of categories that are equally spaced
■ NO true zero point
■ 4.Ratio Scale
■ true zero point
Levels of Measurement
■ Nominal: Nominal data have no order and thus only gives names or labels to various
categories.
■ Ordinal: Ordinal data have order, but the interval between measurements is not
meaningful.
■ Interval: Interval data have meaningful intervals between measurements, but there is
no true starting point (zero).
■ Ratio: Ratio data have the highest level of measurement. Ratios between
measurements as well as intervals are meaningful because there is a starting point
(zero).
Types of data
dichotomous
■ ordinal - the order
■ interval - space in between - no absolute 0
■ ratio
Time
Ordinal time of day - indicates direction or order of occurrence; spacing between is uneven
Interval time of day - equal intervals; analog (12-hr.) clock, difference between 1 and 2 pm is same as
difference between 11 and 12 am
Ratio - 24-hr. time has an absolute 0 (midnight); 14 o'clock is twice as long from midnight as 7 o'clock
Descriptive statistics
■ descriptive statistics, unlike inferential statistics, are not developed on the basis of
probability theory
■ descriptive statistics aim to summarize a sample, rather than use the data to learn
about the population that the sample of data is thought to represent
■ useful for two purposes: 1) to provide basic information about variables in a dataset
and
2) to highlight potential relationships between variables.
■ quantitative
■ pictorial
- frequency tables
- graphs
● distribution
● distribution shape
● location - central tendency - quantiles
data patterns
● dispersion (scatter, spread)
● association
■ Distribution
The distribution of a statistical data set is a listing or function showing all the possible
values (or intervals) of the data and how often they occur (frequency).
- when a distribution of categorical data is organized, you see the number or percentage of
individuals in each group (category)
- the simplest distribution would list every value of a variable and the number of persons
who had each value
- for the distribution of numerical data we use groups or class intervals
■ relative frequency - represent the percentage of the number of observations falling in a
specific category/group
■ cumulative frequency - is the fraction (or percentage) of observations that are less than the
upper limit of each interval/category/group; is obtained by adding the relative frequencies for
the intervals in questions
one bag of M&M; there are 55 M&M's: 17 brown, 18 red, 7 yellow, 7 green, 2 blue, and 4 orange
Relative frequency
Color Frequency (%)
Brown 17 30.9
Red 18 32.72
Yellow 7 12.72
Green 7 12.72
Blue 2 3.63
Orange 4 7.27
Total 55 100
Figure 1. Distribution of 55 M&M's.
what about the distribution of all M&Ms?
Table 1 - Frequency Distribution Table for Sex Table 2 - Frequency Distribution Table for Marital Status
Fig. 2 - Frequency bar chart for marital status
45.9
54.1
male female
Smoking Frequency Relative
Status Frequency, %
40
30
20
10
0
non-smoker former current
Numerical data – frequency distribution
Health centers of District X are submitting numbers of malaria cases and you wish to
summarize them
Compare the daily and weekly summaries of the same data as presented in next Table
Table: Daily and weekly summaries of malaria cases in health centers in District X
– Both daily and weekly data show an increasing amount of malaria, but the
improving situation shown in days 19, 20 and 21 is not reflected in the weekly
summary.
– It would therefore be better to use the daily data if you want to indicate when
exactly the numbers of reported malaria cases started going down.
Class intervals
-the intervals are chosen such that a given data value can be placed in only one
interval
the number of class intervals used to group data is arbitrary, although 5–12 intervals
usually suffice
– too few, obscure detail and lead to loss of information
– too many, defeat the purpose of grouping
-the endpoints of the intervals can be specified in terms of true class limits, which are
specified to one decimal place more than the recorded data and reflect the precision
of the measuring process
■ Histogram
- distributions for continuous variables are called continuous distributions. They also
carry the fancier name probability density.
- numerical data are often presented in histograms, which are very similar to the bar
charts which are used for categorical data.
- In a histogram as well as in a bar chart, the height of the bars represent the
number of items (frequency) which fall into a class interval or a category
- An important difference is that in a histogram the ‘bars’ are connected (as long as
there is no gap between the data), whereas in a bar chart the bars are not
connected, as the different categories are distinct entitles.
■ bar chart ■ histogram
- on the x axis we have categories - on the x axis we have values (numbers) which
(no low end and high end) are ordered (low end and high end)
The height of the column indicates the size of the group defined by the column
a histogram reveals the shape of a frequency distribution
■ Distribution shape
• Symmetry. When it is graphed, a symmetric distribution can be divided at the center so that each half is
a mirror image of the other.
• Number of peaks. Distributions can have few or many peaks. Distributions with one clear peak are
called unimodal, and distributions with two clear peaks are called bimodal. When a symmetric
distribution has a single peak at the center, it is referred to as bell-shaped (normal distribution/Gaussian
distribution).
• Skewness. When they are displayed graphically, some distributions have many more observations on
one side of the graph than the other. Distributions with fewer observations on the right (toward higher
values) are said to be skewed right and have a left tail; and distributions with fewer observations on
the left (toward lower values) are said to be skewed left and have a right tail.
• Uniform. When the observations in a set of data are equally spread across the range of the
distribution, the distribution is called a uniform distribution. A uniform distribution has no clear peaks.
remember! frequency distribution is a probability distribution! sample → population; probability of population falling
into sample! area under the curve!
a histogram reveals the shape of a frequency distribution
Unusual Features
Sometimes, statisticians refer to unusual features in a set of data. The two most
common unusual features are gaps and outliers.
mean (media) - the arithmetic mean is the most common measure of central
tendency. It is simply the sum of the numbers divided by the number of numbers.
median (mediana) - the midpoint of a distribution: the same number of scores is
above the median as below it
the median of 2, 4, and 7 is 4
the median of the numbers 2, 4, 7, 12 is (4+7)/2 = 5.5
mode (modul) - the most frequently occurring value - for continuous data - grouped
frequency distribution = histogram
■ Dispersion/spread
The range (amplitudine) is a basic statistic that tells you the range of values.
For example, if your minimum value is $10 and the maximum value is $100 then the range is
$90 ($100 – $10). A similar statistic is the interquartile range, which tells you the range in the
middle fifty percent of a set of data; in other words, it’s where the bulk of data tends to lie.
The standard deviation (SD) is a measure of how spread out data is around center of the
distribution (the mean)
Quartiles divide your data set into quarters according to where those numbers falls on the
number line. Like the variance, the quartile isn’t very useful on its own. Instead, it’s used to find
more useful values like the interquartile range.
divide your data into four segments according to where the numbers fall on the number line. The four
quarters that divide a data set into quartiles are:
■ a method for graphically depicting groups of numerical data through their quartiles
■ central tendency and shape of the distribution
■ lines extending vertically from the boxes (whiskers) indicate variability outside the upper and
lower quartiles
■ the bottom and top of the box are always the first and third quartiles, and the band inside the
box is always the second quartile (the median)
■ any data not included between the whiskers should be plotted as an outlier with a dot, small
circle, or star
■ the ends of the whiskers can represent several possible alternative values:
- the minimum and maximum of all of the data
- the lowest datum still within 1.5 IQR of the lower quartile, and the highest datum still within 1.5
IQR of the upper quartile (often called the Tukey boxplot)
- one standard deviation above and below the mean of the data
■ “In a skewed distribution, the mean is farther out in the long tail than is the
median.” (Moore and McCabe 2003, p. 43)
■ “For skewed distributions, the mean lies toward the direction of skew (the longer
tail) relative to the median.” (Agresti and Finlay 1997, p. 50)
relative risk
odds ratio
chi square
student t test
■ A t-test requires two variables; one must be categorical and have exactly two levels, and the
other must be quantitative and be estimable by a mean. For example, the two groups could
be Republicans and Democrats, and the quantitative variable could be age.
■ A chi-square test requires categorical variables, usually only two, but each may have any
number of levels. For example, the variables could be ethnic group — White, Black, Asian,
American Indian/Alaskan native, Native Hawaiian/Pacific Islander, other, multiracial; and
presidential choice in 2008 — (Obama, McCain, other, did not vote.
■ The t-test allows you to say either "we can reject the null hypothesis of equal
means at the 0.05 level" or "we have insufficient evidence to reject the null of
equal means at the 0.05 level."
■ A chi-square test allows you to say either "we can reject the null hypothesis of no
relationship at the 0.05 level" or "we have insufficient evidence to reject the null at
the 0.05 level."
Binary or categorical outcomes (proportions)
Are the observations correlated? Alternative to the chi-square
Outcome test if sparse cells:
Variable independent correlated
Kim et al. Effect of probiotic mix (Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus) in the primary prevention of eczema: a double-blind,
randomized, placebo-controlled trial. Pediatric Allergy and Immunology. Published online October 2009.
Statistical question: Does the proportion of infants with eczema differ in the
treatment and control groups?
■ What is the outcome variable? Eczema in the first year of life (yes/no)
■ What type of variable is it? Binary
■ Are the observations correlated? No
■ Are groups being compared and, if so, how many? Yes, two groups
■ Are any of the counts smaller than 5? No, smallest is 12 (probiotics group
with eczema)
a. Repeated-measures ANOVA.
b. One-way ANOVA.
c. Difference in proportions test.
d. Paired ttest.
e. Chi-square test.
Review Question 1
I divide my study population into smokers, ex-smokers, and never-smokers; I
want to compare years of schooling (a normally distributed variable) between
the three groups. What test should I use?
a. Repeated-measures ANOVA.
b. One-way ANOVA.
c. Difference in proportions test.
d. Paired ttest.
e. Chi-square test.
Review Question 2
I divide my study population into smokers, ex-smokers, and never-smokers; I
want to compare the proportions of each group that went to graduate school.
What test should I use?
a. Repeated-measures ANOVA.
b. One-way ANOVA.
c. Difference in proportions test.
d. Paired ttest.
e. Chi-square test.
Review Question 2
I divide my study population into smokers, ex-smokers, and never-smokers; I
want to compare the proportions of each group that went to graduate school.
What test should I use?
a. Repeated-measures ANOVA.
b. One-way ANOVA.
c. Difference in proportions test.
d. Paired ttest.
e. Chi-square test.
Risk ratios and odds ratios
From an RCT of probiotic supplementation during pregnancy to prevent eczema in the infant:
Kim et al. Effect of probiotic mix (Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus) in the primary prevention of eczema: a double-blind,
randomized, placebo-controlled trial. Pediatric Allergy and Immunology. Published online October 2009.
Corresponding 2x2 table
Treatment Group
Treatment Placebo
Eczema
+ 12 22
- 21 13
Risk ratios and odds ratios
Statistical question: Does the proportion of infants with eczema differ in the
treatment and control groups?
■ What is the outcome variable? Eczema in the first year of life (yes/no)
■ What type of variable is it? Binary
■ Are the observations correlated? No
■ Are groups being compared and, if so, how many? Yes, binary
■ Are any of the counts smaller than 5? No, smallest is 12 (probiotics group
with eczema)
36.4%
■ Risk ratio: 0.58 There is a 26.5%
62.9% decrease in absolute
risk, a 42% decrease in
■ Corresponding odds ratio: relative risk, and a 66%
decrease in relative
odds.
36.4% /(1 36.4%)
0.34
62.9% /(1 62.9%)
Why do we ever use an odds ratio??
Rare Outcome
Odds ratio Odds ratio
Common Outcome
Odds ratio Odds ratio
General Rule of
Thumb:
“OR is a good
approximation as
long as the
probability of the
outcome in the
unexposed is less
than 10%”
In a study that is designed and conducted as a case-control study, you cannot
calculate incidence. Therefore, you cannot calculate risk ratio or risk difference.
You can only calculate an odds ratio. However, in certain situations a case-
control study is the only feasible study design.
Interpreting ORs when the outcome is
common…
If data are from a cross-sectional or cohort study, then you can convert ORs
(from logistic regression) back to RRs with a simple formula:
OR
RR
(1 Po ) ( Po OR)
Where:
OR = odds ratio from logistic regression (e.g., 3.92)
P0 = P(D/~E) = probability/prevalence of the outcome in the unexposed/reference group (e.g. ~45%)
Formula from: Zhang J. What's the Relative Risk? A Method of Correcting the Odds Ratio in Cohort
Studies of Common Outcomes JAMA. 1998;280:1690-1691.
MEDICAL RESEARCH
ETHICS
World Medical Association (WMA)
https://www.wma.net/who-we-are/
■ As an organization promoting the highest possible standards of medical ethics, the
WMA provides ethical guidance to physicians through its Declarations, Resolutions
and Statements. These also help to guide National Medical Associations,
governments and international organizations throughout the world. The
Declarations, Resolutions and Statements cover a wide range of subjects,
including an International Code of Medical Ethics, the rights of patients, research
on human subjects, care of the sick and wounded in times of armed conflict,
torture of prisoners, the use and abuse of drugs, family planning and pollution.
■ The WMA is in official relations with the World Health Organization (WHO).
WMA
Preamble
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a
statement of ethical principles for medical research involving human subjects, including research on
identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be
applied with consideration of all other relevant paragraphs.
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians.
The WMA encourages others who are involved in medical research involving human subjects to adopt
these principles.
General Principles
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient
will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall
act in the patient’s best interest when providing medical care.”
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients,
including those who are involved in medical research. The physician’s knowledge and conscience are
dedicated to the fulfilment of this duty.
5. Medical progress is based on research that ultimately must include studies involving human subjects.
6. The primary purpose of medical research involving human subjects is to understand the causes,
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions
(methods, procedures and treatments). Even the best proven interventions must be evaluated continually
through research for their safety, effectiveness, efficiency, accessibility and quality.
7. Medical research is subject to ethical standards that promote and ensure respect for all human
subjects and protect their health and rights.
8. While the primary purpose of medical research is to generate new knowledge, this goal can never take
precedence over the rights and interests of individual research subjects.
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity,
integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects.
The responsibility for the protection of research subjects must always rest with the physician or other health
care professionals and never with the research subjects, even though they have given consent.
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving
human subjects in their own countries as well as applicable international norms and standards. No national or
international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for
research subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that minimises possible harm to the environment.
12. Medical research involving human subjects must be conducted only by individuals with the appropriate
ethics and scientific education, training and qualifications. Research on patients or healthy volunteers requires
the supervision of a competent and appropriately qualified physician or other health care professional.
13. Groups that are underrepresented in medical research should be provided appropriate access to
participation in research.
14. Physicians who combine medical research with medical care should involve their patients in research
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the
physician has good reason to believe that participation in the research study will not adversely affect the health
of the patients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in
research must be ensured
Risks, Burdens and Benefits
16. In medical practice and in medical research, most interventions involve risks and burdens.
Medical research involving human subjects may only be conducted if the importance of the objective
outweighs the risks and burdens to the research subjects.
17. All medical research involving human subjects must be preceded by careful assessment of
predictable risks and burdens to the individuals and groups involved in the research in comparison with
foreseeable benefits to them and to other individuals or groups affected by the condition under investigation.
Measures to minimise the risks must be implemented. The risks must be continuously monitored, assessed
and documented by the researcher.
18. Physicians may not be involved in a research study involving human subjects unless they are
confident that the risks have been adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or when there is conclusive proof of definitive
outcomes, physicians must assess whether to continue, modify or immediately stop the study.
Vulnerable Groups and Individuals
19. Some groups and individuals are particularly vulnerable and may have an increased
likelihood of being wronged or of incurring additional harm.
All vulnerable groups and individuals should receive specifically considered protection.
20. Medical research with a vulnerable group is only justified if the research is responsive to the
health needs or priorities of this group and the research cannot be carried out in a non-vulnerable
group. In addition, this group should stand to benefit from the knowledge, practices or interventions
that result from the research.
Scientific Requirements and Research Protocols
21. Medical research involving human subjects must conform to generally accepted scientific principles,
be based on a thorough knowledge of the scientific literature, other relevant sources of information, and
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research
must be respected.
22. The design and performance of each research study involving human subjects must be clearly
described and justified in a research protocol.
The protocol should contain a statement of the ethical considerations involved and should indicate how the
principles in this Declaration have been addressed. The protocol should include information regarding
funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and
information regarding provisions for treating and/or compensating subjects who are harmed as a
consequence of participation in the research study.
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions.
Research Ethics Committees
23. The research protocol must be submitted for consideration, comment, guidance and approval to the
concerned research ethics committee before the study begins. This committee must be transparent in its
functioning, must be independent of the researcher, the sponsor and any other undue influence and must be
duly qualified. It must take into consideration the laws and regulations of the country or countries in which
the research is to be performed as well as applicable international norms and standards but these must not
be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration.
The committee must have the right to monitor ongoing studies. The researcher must provide monitoring
information to the committee, especially information about any serious adverse events. No amendment to
the protocol may be made without consideration and approval by the committee. After the end of the study,
the researchers must submit a final report to the committee containing a summary of the study’s findings
and conclusions.
Privacy and Confidentiality
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of
their personal information.
Informed Consent
25. Participation by individuals capable of giving informed consent as subjects in medical research must
be voluntary. Although it may be appropriate to consult family members or community leaders, no individual
capable of giving informed consent may be enrolled in a research study unless he or she freely agrees.
26. In medical research involving human subjects capable of giving informed consent, each potential
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of
the study and the discomfort it may entail, post-study provisions and any other relevant aspects of
the study. The potential subject must be informed of the right to refuse to participate in the study or to
withdraw consent to participate at any time without reprisal. Special attention should be given to the specific
information needs of individual potential subjects as well as to the methods used to deliver the information.
After ensuring that the potential subject has understood the information, the physician or another
appropriately qualified individual must then seek the potential subject’s freely-given informed consent,
preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be formally
documented and witnessed.
All medical research subjects should be given the option of being informed about the general outcome and
results of the study.
27. When seeking informed consent for participation in a research study the physician must be
particularly cautious if the potential subject is in a dependent relationship with the physician or may consent
under duress. In such situations the informed consent must be sought by an appropriately qualified
individual who is completely independent of this relationship.
28. For a potential research subject who is incapable of giving informed consent, the physician must
seek informed consent from the legally authorised representative. These individuals must not be included in
a research study that has no likelihood of benefit for them unless it is intended to promote the health of the
group represented by the potential subject, the research cannot instead be performed with persons capable
of providing informed consent, and the research entails only minimal risk and minimal burden.
29. When a potential research subject who is deemed incapable of giving informed consent is able to
give assent to decisions about participation in research, the physician must seek that assent in addition to
the consent of the legally authorised representative. The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally incapable of giving consent, for example,
unconscious patients, may be done only if the physical or mental condition that prevents giving informed
consent is a necessary characteristic of the research group. In such circumstances the physician must seek
informed consent from the legally authorised representative. If no such representative is available and if the
research cannot be delayed, the study may proceed without informed consent provided that the specific
reasons for involving subjects with a condition that renders them unable to give informed consent have been
stated in the research protocol and the study has been approved by a research ethics committee. Consent to
remain in the research must be obtained as soon as possible from the subject or a legally authorised
representative.
31. The physician must fully inform the patient which aspects of their care are related to the research. The
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must never
adversely affect the patient-physician relationship.
32. For medical research using identifiable human material or data, such as research on material or data
contained in biobanks or similar repositories, physicians must seek informed consent for its collection,
storage and/or reuse. There may be exceptional situations where consent would be impossible or
impracticable to obtain for such research. In such situations the research may be done only after
consideration and approval of a research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of
the best proven intervention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or
Where for compelling and scientifically sound methodological reasons the use of any intervention less
effective than the best proven one, the use of placebo, or no intervention is necessary to determine the
efficacy or safety of an intervention
and the patients who receive any intervention less effective than the best proven one, placebo, or no
intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving
the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. In advance of a clinical trial, sponsors, researchers and host country governments should make
provisions for post-trial access for all participants who still need an intervention identified as beneficial in the
trial. This information must also be disclosed to participants during the informed consent process.
Research Registration and Publication and Dissemination of Results
35. Every research study involving human subjects must be registered in a publicly accessible database
before recruitment of the first subject.
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the
publication and dissemination of the results of research. Researchers have a duty to make publicly available
the results of their research on human subjects and are accountable for the completeness and accuracy of
their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative and inconclusive
as well as positive results must be published or otherwise made publicly available. Sources of funding,
institutional affiliations and conflicts of interest must be declared in the publication.
Reports of research not in accordance with the principles of this Declaration should not be accepted for
publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven interventions do not exist or other known
interventions have been ineffective, the physician, after seeking expert advice, with informed consent
from the patient or a legally authorised representative, may use an unproven intervention if in the
physician’s judgement it offers hope of saving life, re-establishing health or alleviating suffering. This
intervention should subsequently be made the object of research, designed to evaluate its safety and
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available.
Good Clinical Practice (GCP)
International Council of Harmonisation (ICH)
■ Good clinical practice (GCP) is an international ethical and scientific quality standard for
designing, recording and reporting trials that involve the participation of human subjects.
Compliance with this standard provides public assurance that the rights, safety and wellbeing
of trial subjects are protected and that clinical-trial data are credible.
International Council of Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH) 1990, 2015
- brings together the regulatory authorities and pharmaceutical industry to discuss scientific and
technical aspects of drug registration
- to respond to the increasingly global face of drug development
- mission is to achieve greater harmonisation worldwide to ensure that safe, effective, and high
quality medicines are developed and registered in the most resource-efficient manner.
USA
Europe
Japan
■ European Commission
■ European Federation of Pharmaceutical Industries and Associations (EFPIA)
■ Ministry of Health, Labour and Welfare (Japan) (MHLW)
■ Japan Pharmaceutical Manufacturers Association (JPMA)
■ Food and Drug Administration (FDA)
■ Pharmaceutical Research and Manufacturers of America (PhRMA)
■ Medicine developers are responsible for ensuring that they and any parties working for them
comply with standards set out in European Union (EU) legislation and guidelines for good
clinical practice (GCP), good laboratory practice (GLP) and good manufacturing
practice (GMP) for investigational medicinal products.
■ The European Medicines Agency (EMA) is responsible for harmonising these standards at EU
level. It also coordinates inspections to verify that medicine developers comply with them.
■
E1 Clinical Safety for Drugs used in Long-Term Treatment
■ E2A - E2F Pharmacovigilance
■ E3 Clinical Study Reports
■ E4 Dose-Response Studies
■
■ E5 Ethnic Factors E11 - E11A Clinical Trials in Pediatric Population
■ E6 Good Clinical Practice ■ E12 Clinical Evaluation by Therapeutic Category
■ E7 Clinical Trials in Geriatric Population ■ E14 Clinical Evaluation of QT
■ E8 General Considerations for Clinical Trials ■ E15 Definitions in Pharmacogenetics / Pharmacogenomics
■ E9 Statistical Principles for Clinical Trials ■ E16 Qualification of Genomic Biomarkers
■ E10 Choice of Control Group in Clinical Trials ■ E17 Multi-Regional Clinical Trials
■ E18 Genomic Sampling
■ E19 Safety Data Collection
■ Cross-cutting Topics
1 December 2016
EMA/CHMP/ICH/135/1995 Committee for
Human Medicinal Products
■ 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.
Implementation
■ :EC, Europe - Adopted by CHMP, 15 December 2016, issued as EMA/CHMP/ICH/135/1995
■ :MHLW/PMDA, Japan - To be notified
■ :FDA, US - To be notified
■ :Health Canada, Canada - To be notified
■ :Swissmedic, Switzerland - Refer to the press release on Swissmedic, Switzerland's website
The principles of ICH GCP
■ 2.1. Clinical trials should be conducted in accordance with the ethical principles that have
their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable
regulatory requirement(s).
■ 2.2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against
the anticipated benefit for the individual trial subject and society. A trial should be initiated
and continued only if the anticipated benefits justify the risks.
■ 2.3. The rights, safety, and well-being of the trial subjects are the most important
considerations and should prevail over interests of science and society.
■ 2.4. The available nonclinical and clinical information on an investigational product should be
adequate to support the proposed clinical trial.
■ 2.5. Clinical trials should be scientifically sound, and described in a clear, detailed protocol.
■ 2.6. A trial should be conducted in compliance with the protocol that has received prior
institutional review board (IRB)/independent ethics committee (IEC) approval/favourable
opinion.
■ 2.7. The medical care given to, and medical decisions made on behalf of, subjects should always
be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.
■ 2.8. Each individual involved in conducting a trial should be qualified by education, training, and
experience to perform his or her respective task(s).
■ 2.9. Freely given informed consent should be obtained from every subject prior to clinical trial
participation.
■ 2.10. All clinical trial information should be recorded, handled, and stored in a way that allows its
accurate reporting, interpretation and verification.
■ 2.11. The confidentiality of records that could identify subjects should be protected, respecting
the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
■ 2.12. Investigational products should be manufactured, handled, and stored in accordance with
applicable good manufacturing practice (GMP). They should be used in accordance with the
approved protocol.
■ 2.13. Systems with procedures that assure the quality of every aspect of the trial should be
implemented.
Good Laboratory Practice (GLP)
The Organisation for Economic Co-operation and Development (OECD)
■ Good Laboratory Practice (GLP) is a quality system concerned with the organisational process
and the conditions under which non-clinical health and environmental safety studies are
planned, performed, monitored, recorded, archived and reported.
■ Principles of Good Laboratory Practice should be applied to the non-clinical safety testing of test
items contained in pharmaceutical products, pesticide products, cosmetic products, veterinary
drugs as well as food additives, feed additives, and industrial chemicals. These test items are
frequently synthetic chemicals, but may be of natural or biological origin and, in some
circumstances, may be living organisms. The purpose of testing these test items is to obtain
data on their properties and/or their safety with respect to human health and/or the
environment.
■ The principles of Good Laboratory Practice (GLP) promote the quality and
validity of data generated in the testing of chemicals and prevent fraudulent
practices.
■ The principles have been developed in accordance with the Organisation for
Economic Cooperation and Development (OECD) and the EU has adopted
these principles and the revised OECD Guides for Compliance Monitoring
Procedures for GLP as annexes to its two GLP Directives.
The Organisation for Economic Co-operation and Development (OECD)
- a forum of countries committed to democracy and the market economy, providing a setting to
compare policy experiences, seek answers to common problems, identify good practices, and co-
ordinate domestic and international policies
- its mandate covers economic, environmental, and social issues. The organisation works through
consensus to develop policy recommendations and other "soft law" instruments to encourage
policy reform in member countries.
Good manufacturing practice (GMP)
■ Good manufacturing practice (GMP) describes the minimum standard that a medicines
manufacturer must meet in their production processes. The European Medicines Agency (EMA)
coordinates inspections to verify compliance with these standards and plays a key role in
harmonising GMP activities at European Union (EU) level.
■ Any manufacturer of medicines intended for the EU market, no matter where in the world it is
located, must comply with GMP.
■ GMP requires that pharmaceutical products, dietary supplements, and medical devices:
- are of consistent high quality;
- are appropriate for their intended use;
- meet the requirements of the marketing authorisation or clinical trial authorisation.
Good epidemiological practice (GEP)
Research should be an activity devoted to the exploration of the laws of nature driven only by a
desire to know the truth. In the real world, other factors often interfere with this ideal aspiration
and can result in conflicts of interest. Research has to be funded, conducted and published, and
researchers like to promote their reputations. Research is, therefore, often carried out amid many
competing elements.
■ Research findings in public health should serve the public good but may not be welcomed by all.
Findings of serious side-effects of a given drug, for example, may be welcomed by those taking the
drug and their physicians, but may seriously reduce sales and the expected profits of the
manufacturer. Alternatively, a promising hypothesis may not be supported by new data.
■ We must also be sure to obtain a reasonable balance between ethical constraints and the
opportunities for legitimate research of importance to public health.
■ background to epidemiological research
■ the role of ethics committees
■ general ethical principles for research
■ informed consent
■ rules for good research behaviour under the headings of working with personal
data, data documentation, publication, and exercise of judgment
■ scientific misconduct
ETHICAL PRINCIPLES OF RESEARCH
The Council for International Organizations of Medical Sciences (CIOMS) is an international, non-
governmental, non-profit organization established jointly by WHO and UNESCO in 1949. CIOMS
represents a substantial proportion of the biomedical scientific community through its member
organizations, which include many of the biomedical disciplines, national academies of sciences
and medical research councils. CIOMS mission is to advance public health through guidance on
health research including ethics, medical product development and safety.
■ information,
■ understanding,
■ consent
information
■ Individuals should be able to understand what they are told and to make a reasoned choice
based on that information. Experience shows that this ideal is difficult to achieve. Too much
information may be given in excessive detail, mainly to protect the researcher and the
institution. An understanding of the main ideas and risks of the study may be more important
than being informed about all the specific scientific details.
■ When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be
enrolled in the trial with the consent of the subject’s legally acceptable representative
(e.g., minors, or patients with severe dementia), the subject should be informed about the
trial to the extent compatible with the subject’s understanding and, if capable, the subject
should sign and personally date the written informed consent.
consent
■ Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to
participate or to continue to participate in a trial.
■ None of the oral and written information concerning the trial, including the written informed
consent form, should contain any language that causes the subject or the subject's legally
acceptable representative to waive or to appear to waive any legal rights, or that releases or
appears to release the investigator, the institution, the sponsor, or their agents from liability for
negligence.
■ Prior to a subject’s participation in the trial, the written informed consent form should be
signed and personally dated by the subject or by the subject's legally acceptable
representative, and by the person who conducted the informed consent discussion.
• Plagiarism is using other people’s work and ideas without giving proper credit to the original
source, thus violating the rights of the original author(s) to their intellectual outputs.
unacceptable practices
The bar chart below shows a comparison of AIMM scores for the 27 countries surveyed, according to scores based on survey results for nine categories
as shown. The categories were scored in the range 0-4, the nine scores were summed (equal weighting) to give a maximum score of 36
Consiliul Național de Etică a Cercetării Științifice, Dezvoltării Tehnologic și Inovării
(CNECSDTI)
Legea nr. 398/2006 publicata in Monitorul Oficial, Partea I nr. 892 din 02/11/2006. -
Ordonanta nr. 28/2011 publicata in Monitorul Oficial, Partea I nr. 628 din
02/09/2011
■ plagiatul - expunerea intr-o opera scrisa sau o comunicare orala, inclusiv in format
electronic, a unor texte, expresii, idei, demonstratii, date, ipoteze, teorii, rezultate ori
metode stiintifice extrase din opere scrise, inclusiv in format electronic, ale altor autori, fara
a mentiona acest lucru si fara a face trimitere la sursele originale;
■ autoplagiatul - expunerea intr-o opera scrisa sau o comunicare orala, inclusiv in format
electronic, a unor texte, e) autoplagiatul - expunerea intr-o opera scrisa sau o comunicare
orala, inclusiv in format electronic, a unor texte, expresii, demonstratii, date, ipoteze, teorii,
rezultate ori metode stiintifice extrase din opere scrise, inclusiv in format electronic, ale
aceluiasi sau acelorasi autori, fara a mentiona acest lucru si fara a face trimitere la sursele
originale
evitarea plagiatului
■ NU folositi copy/paste
■ mai mult de 3 cuvinte fara semnele citarii si bibliografie - plagiat; USA mai mult de 8 cuvinte -
federal offence
■ parafrazarea, rezumatul, reformularea frecventa SI fara citarea sursei in text - plagiat
■ citarile/bibliografia din text trebuie sa se regaseasca in lista bibliografica de la finalul lucrarii si sa
corespunda informatiei respective
■ orice material grafic refolosit NUMAI cu permisiunea autorilor
■ utilizarea propriilor cuvinte, idei, informatii publicate anterior fara citare - autoplagiat
■ cunostintele generale (“omul este un mamifer”) nu necesita citare
■ rezumat, rezultate, concluzii - fara citari