Exam II Flashcards
What are design selections based on?
- perspective of question (hypothesis)
- ability/desire to force group allocation (randomization)
- ethics of methodology
- efficiency and practicality (time and resource devotion)
- cost
- validity of acquired information
What are the different hypotheses researchers formulate before the study takes place?
null hypothesis (Ho)- a research perspective which states there will be no (true) difference between the groups being compared
-conservative and commonly utilized
-perspectives
alternative hypothesis (H1): perspective which states there will be a (true) difference between the groups being compared
What are the two blanket designs for human designs?
observational: study design considered “natural”
- researchers observe subject elements occurring naturally or selected by individual (naturally or freely)
- typically not able to prove causation
- NO RESEARCHER FORCED GROUP ALLOCATION
- useful for forced interventions (not ethical)
Interventional: study designs considered experimental
- investigator selects interventions (exposure)
- there is researcher forced group allocation -> randomization
What the studies that can be found under the two blanket designs?
Observational:
- cases (reports/seres)
- ecological
- cross sectional (analytical)
- case control (analytical)
- cohort (analytical)
Interventional:
- pre-clinical
- phase I
- phase II
- phase III
- phase IV
What are the two types of error and what do they mean?
Type I error: false positive
Type II error: false negative
What three perspectives are taken for a hypothesis?
- superiority
- noninferiority
- equivalency
What is the difference between a population and sample?
population: all individuals making up a common group, from which a sample can be obtained, if desired
- not study population which is group of individuals selected for the study
sample: a subset or portion of the full complete population -> representatives
- random processes to draw sample
- when complete population is not feasible
How is a study population selected?
-research hypothesis/question
-inclusion and exclusion selection criteria and case and control group or exposed vs nonexposed
+desired vs logical vs plausible
+impact generalizability -> external validity
-ethics (principles of bioethics must be met)
+some don’t agree with the use of placebo when treatment is available
-equipoise (genuine confidence that an intervention may be worthwhile in order to use on humans)
What are the 4 key principles of bioethics?
- autonomy: self rule/self determination. Participants must…
- have full and complete understanding of the risks and benefits
- decide for oneself without outside influences
- beneficence: benefit or do good for the patient (NOT SOCIETY)
- justice: equal and fair treatment regardless of patient characteristics
- nonmaleficence: DO NO HARM! Researchers must not…
- withhold information
- provide false information
- exhibit professional incompetence
What is the Belmont Report? What are the three guiding principles?
-document that determines ethicality of a study.
- respect for persons: research voluntary, subjects autonomous
- beneficence: research risks are justified by potential benefits
- justice: risks and benefits are equally distributed
What is consent vs assent?
consent: agreement to participate, based on being fully and completely informed (given by mentally capable individuals of legal consenting age)
assent: agreement to participate, based on being fully and completely informed, given by mentally capable individuals NOT able to give legal consent (children and mentally handicapped)
- requires assent of subject and consent of guardian
Who determines the ethicality of a study?
Institutional Review Board (IRB) or the Ethics Committee
- protect human subjects from undue risk BEFORE study
- IRB regulated by Federal statues developed by Department of Health and Human Services -> follow Common Federal Rules
What are the different levels of IRB review?
Full Board: used for ALL interventional trials with more than minimal/no risk to patients -> medication related studies
Expedited: minimum risk and/or no patient identification
Exempt: no patient identifiers, low/no risk, data set analysis, environmental studies, use of existing data/specimen
Who determines safety AFTER a study has begun?
-Data Safety and Monitoring Board (DSMB)
-semi-independent committee not involved with the conduct of the study but charged with reviewing study data as study progresses, to assess for undue risk or benefit
+pre-determined review period
+can end study early for overly positive or negative effects
What occurs during the pre-clinical phase of an interventional study?
- occurs prior to human research
- bench and animal research
Whats occurs during Phase I of an interventional study?
SAFETY
-small N (20-80), usually healthy volunteers to assess safety/toxicity, dosing and pharmacokinetics in population of interest, short duration
*doesn’t always include healthy subjects
What occurs during Phase II of an interventional study?
safety and EFFICACY
-larger N (100-300), commonly utilize patients with condition of interest and nothing else, used to expand on purpose of phase I study(safety) but also begin assessing efficacy in diseased population, short-medium duration
*narrower inclusion criteria
What occurs during phase III of an interventional study?
EFFICACY
-larger N(1000-3000), used patients with condition of interest to continue determination of safety, primary purpose is to assess efficacy, longer duration
+superiority v noninferiority v equality format
+FDA mandates phase 3 before drug approval, must beat placebo and exhibit equipoise
+companies only have to show efficacy in 3 out of 5 studies
What occurs during phase IV of an interventional study?
SAFETY
-assesses long term effects (risks and benefits) in a large population of diseased patients, drug CAN die after phase 4 due to long term effects, always named drug/device
What are the advantages and disadvantages of interventional trials?
advantages:
- cause precedes effect -> shows causation
- only design used by FDA approval process
disadvantages:
-cost
-complexity/time (development/approval/conductance)
-ethical considerations**this is good***
-generalizability (external validity)
+study pop may not be equivalent to general pop
What is the difference between an explanatory and pragmatic study?
explanatory: trying to prove causation or explain why something is happening, set methods and they can’t change to suit patient
pragmatic: clinical setting (adjust dosage, etc to treat patients), allow people with comorbidies and multiple meds
+bad -> no control or regiment (adds extra confounding)
Differentiate between simple and factorial studies.
simple: randomizes(divides) subjects into 2 groups, tests a single hypothesis, randomizes only once
factorial: randomizes multiple times! Tests multiple hypotheses, but must increase sample size
What are some positives and negatives of the factorial study?
- improves efficiency for answering clinical qs
- increases study pop size
- increases complexity
- increase risk of drop out (due to complexity)
- may restrict generalizability of results
What is the difference between a parallel and cross-over study?
parallel: group simultaneously and exclusively managed
-NO SWITCHING of intervention groups after randomization
+simple and factorial are parallel
cross-over (Self control): groups serve as their own control by crossing over from one intervention to another during the study
- allows for smaller N
- control for the same person taking the same drugs (identical people)
- requires wash out period
What is a wash out period?
- required in a cross over study
- controls for lingering effects of previous drug before switching groups
- gets drug out of system of patient before taking another
What are the different research studies? Put them in order from increasing strength.
- meta-analyses (most evidence)
- systemic reviews
- pragmatic trials, randomized, double blind controlled trials
- cohort
- case controlled
- cross sectional
- ecological
- case series
- case reports
- animal research
- in vitro research
What is a run-in/lead in phase?
-study subjects are blindly given one or more placebos for initial therapy (defined time period) to determine a “new” base-line of disease (standardization)
+can assess protocol compliance (determine how much of the meds were taken and keep or ditch patient based on how well they follow the protocols)
+can be a “wash out” for existing meds -> reduces one common exclusion criteria
+determines amount of placebo effect
+assesses placebo and Hawthorne effects
What are some disadvantages to a cross over study?
- only suitable for long term conditions which are not curable or which treatment provides short-term relief
- duration of study for each subject is longer
- carry over effects during cross over (wash out required -> prolongs study)
- treatment by period interaction -> disease that get better or worse during different times of the year (ex. depression or allergies)
- smaller N requirement only applicable if within subjects variation less than between subjects variation
- complexity in data analysis
What are the different outcomes that can be talked about?
primary- MOST IMPORTANT, key outcome
+main research question used for developing the study
secondary/tertiary- lesser importance, but still valuable and possible for future hypothesis generation
composite- combines multiple endpoints into a single outcome
What is the difference between a patient oriented endpoint and a surrogate marker?
patient oriented endpoint: most clinically relevant outcome, more important in a study, can be increased or decreased
ex. death, stroke or MI, hospitalization, preventing need for dialysis
surrogate marker: elements used in place of evaluating patient oriented/direct endpoints, risk factors for disease
ex. blood pressure (risk of stroke), cholesterol (risk of MI), change in SCr worsening renal function)
What is the difference between non-random and random selection and group allocation?
Non-random: subjects don’t have an equal probability of being selected or assigned to each intervention group, not good protocol
ex. morning vs evening clinic attendance
+patients attending clinic on odd days vs even days
+first 100 patients admitted to hospital
Random: most commonly utilized, subject do have an equal probability of being assigned to each intervention group
What is the purpose of randomization?
to make groups as equal as possible based on known and unknown factors (confounders)
+attempts to reduce systematic bias between groups which impacts results
+Table 1 customarily used to show group characteristics
+equality is NOT guaranteed
How is the effectiveness of the randomization process documented?
- p values shown in table format
- p values not shown but text-statement given in key of table
- p value not shown but given in article
What are the three different types of randomization?
simple- equal probability for allocation into any study group
blocked- ensures balance within each intervention group -> researchers want to assure that all groups are equal in size
stratified- ensures balance within known confounding variables, makes characteristics of patients equal reducing confounding
+gender, age, disease, severity/duration, comordodities
What are three types of blinding?
single-blinding- subjects are not informed which intervention they are receiving (researchers do)
double-blinding- neither researchers or subjects know which group they have been allocated into
open-label- everyone knows which intervention each subject subject is receiving
How can one determine the effectiveness of blinding?
A post hoc study: ask patients and researchers, depending on blindness, which group they think they were apart of. If a high percentage guesses correctly, then the blinding wasn’t very effective
What is a placebo?
- also know as a dummy
- inert treatments made to look identical in all aspects to the active treatments (dosage form, dosing frequency, monitoring, therapy requirements, etc)
What is a double dummy?
more than one placebo used…such as an inhaler and injection
What is the placebo effect?
- improvement in condition by power of suggestion and due to the care being provided
- improvement can be as large as 30-50%
What is the Hawthorne effect?
-desire of the study subject to please investigators by reporting positive results regardless of treatment allocation, want a positive outcome for study
What is a post hoc group analysis and why are these generally frowned upon in a study?
- not accepted as appropriate when not prospectively planned -> “data dredging or fishing”
- if there is no difference between the two studied groups then the researcher starts comparing groups in different ways until they find a difference
What should be considered when determining an appropriate sample size?
-take into consideration the number of drop outs
How can a researcher control for drop outs in a study?
-intent to treat (most conservative): keeping the dropped out patients’s data and utilizing in the study
+last observation carried forward: data from the last known data collection and carry that forward throughout the study
+no benefit: convert all subsequent yet missed assessments for a subject to a null effect
-per-protocol/efficacy analysis: compliance is predefined, only accept subjects with 80-90% compliance of study protocol
as treated: ignores group assignments, allows subjects to switch groups and be evaluated in group they moved to, end up in, or spent the most time in
Why is intent to treat beneficial to a study aka why is it good to keep the data?
- preserves randomization process
- preserves baseline characteristics and group balance at baseline which controls for known and unknown confounders
- maintains statistical power (original sample size)