MWU - RDM: Test 3

*Clinical trials: Phases I-IV* With regard to anticancer drugs, what are the special considerations regarding clinical trials? - Usually *phase* ____ trials for *anti-cancer* drugs are not completed on *healthy individuals *for ethical reasons, and are instead conducted on patients with *advanced stage or refractory cancers* - This prevents exposure of *healthy volunteers to toxic drugs* - The hope is that those suffering from the cancer will receive some *therapeutic effect* from the trial - The few anti-cancer drug trials that have been done on healthy individuals were done with safety as a top priority

1;

*Clinical trials: Phases I-IV* Differentiate between the various phases of clinical research. Understand the objectives, outcomes/endpoints, inclusion/exclusion criteria, average time to complete, number of participants, success rate, and use of a placebo. 3) *Phase II*: "1st time in patient" g. *Process*: I. *Phase IIa*: - EARLY PHASE - ____-____ pts - This is a "____ ____" to evaluate *efficacy* (and safety) in select population of patients with the disease or condition to be treated, diagnosed, or prevented - Objectives focus on *dose-response, type of patient, frequency of dosing,* or other characteristics of *efficacy and safety* - Single blind comparison with *standard drug* (only patient knows)

20-200; pilot trial

*Clinical trials: Phases I-IV* Differentiate between the various phases of clinical research. Understand the objectives, outcomes/endpoints, inclusion/exclusion criteria, average time to complete, number of participants, success rate, and use of a placebo. 2) *Phase I*: "1st time in man" (*contd.*) g. *Process*: I. Small number of volunteers (___-___ people) taking a *diluted amount* (1/10 - 1/5) of the *animal dose*, and slowly building up the amount to find a safe, *tolerated* dose --> If it's deemed safe in that small group, you move to a larger group II. Must be performed by *clinical pharmacologists* at a *single center*, *no blinding* h. *Considerations*: - *NOAEL* (No Observed Adverse Effect Level) = ____ level that does *not produce significant adverse effects* compared to the control group - *STD10* = dose severely toxic to 10% of animals - *HNSTD* = highest non-severely toxic dose - If determined safe, increase the amount of volunteers to ___-___ people i. *Study designs:* - Includes dose escalation studies (MTD, DLT (severe->fatal), PK) - Dose escalation arithmetics (arithmetic escalation, geometric escalation, modified Fibonacci escalation) - Pharmacokinetic (PK) studies - SAD (single ascending dose) studies - MAD (multiple ascending dose) studies - ADME (absorption, distribution, metabolism, excretion) studies - DDI (drug-drug interactions) studies - Food effect studies - Bioavailability (BA) studies --> *Phase Ia* = SAD trials --> *Phase Ib* = MAD trials

20-25; highest; 50-75;

*Systematic reviews and meta-analysis* How many people review the systematic review prior to its publication? - Minimum of ____ primary reviewers; can add a ____ if disagreement needs to be settled - Reviewers review each study to describe its parameters and record information on a data extraction sheet

2; 3rd

*Systematic reviews and meta-analysis* What is a meta-analysis? - A meta analysis is a method of statistically combining the results from ___ or more *separate studies* to estimate the *average* or ____ effect What are the two stages in a meta-analysis? 1) 1st stage: *calculation* of ____ ____ for *each study* - Evaluate homogeneity (the degree to which the collected studies are similar) - Heterogeneity may be due to *random effect* (d/t chance differences btwn studies - i.e. study samples drawn from different studies) - Statistic used to test for *heterogeneity* = ____ ____

2; common; confidence intervals; chi square

*Clinical trials: Phases I-IV* What phase in Clinical Trials corresponds to the Randomized Clinical Trial studies referred to in the Evidence based Pyramid? - Phase ____

3;

*Systematic reviews and meta-analysis* Is the literature review for a systematic review exhaustive? If so, what does that mean? - *Yes*, it's exhaustive, you need to look through at least ____ different databases and find *every associated paper* - the idea is that you exhaust *all available databases* for articles to review ("Big Data" ties into this where we use AI to perfect data collection)

3;

*Ethical issues in clinical research* What is the IRB? What is the composition of an IRB? - *IRB* = Institutional Review Board --> needed to conduct a clinical research project ----> Ex: IRB form for midwestern in slide - includes: abstract, type of data, subject use and recruitment, summary of proposal, informed consent, cost, risk/benefit - IRB contains ___ members (minimum), who must be... --> Not all *male or female* --> Not from *same profession* --> One *non-scientific* member --> One *non-affiliated* member - *OPRR* is responsible for reviewing and approving IRB documents

5

*Clinical trials: Phases I-IV* Differentiate between the various phases of clinical research. Understand the objectives, outcomes/endpoints, inclusion/exclusion criteria, average time to complete, number of participants, success rate, and use of a placebo. 3) *Phase II*: "1st time in patient" g. *Process*: II. *Phase IIb* - LATE PHASE - ____-____ pts - *Very well-controlled*, *"pivotal"* trials to evaluate *efficacy* (and safety) in select population of patients with the disease or condition to be treated, diagnosed, or prevented - These clinical trials represent the most rigorous representation of a treatments efficacy - *Double blind* compared with ____

50-500; placebo

*Clinical trials: Phases I-IV* Differentiate between the various phases of clinical research. Understand the objectives, outcomes/endpoints, inclusion/exclusion criteria, average time to complete, number of participants, success rate, and use of a placebo. 3) *Phase II*: "1st time in patient" a. *Endpoint*: efficacy (Do you get a response? Does it do what it's supposed to do?) b. *Success rate*: ____% c. *Time to complete*: ___-___ *months* d. *Objectives*: - To determine *activity* or "response" of a new treatment in a specific patient population - To examine acute and cumulative _____ - To define *optimal* schedule and dosing - To further establish *pharmacokinetics* - To determine biological *effectiveness* e. *Inclusion/exclusion criteria* might be the following factors: - Age - Date of diagnosis - Other therapies received - Other illnesses of the patient - Stage of the illness - How active the participant is - Ability to take oral meds f. *Clinical trial outcomes* - Asses efficacy against a defined therapeutic endpoint - *Detailed pharmacokinetic* and pharmacodynamic data - Establishes a *dose* and a *dosage form* for future trials

58; 16-24; toxicity;

*Clinical trials: Phases I-IV* Differentiate between the various phases of clinical research. Understand the objectives, outcomes/endpoints, inclusion/exclusion criteria, average time to complete, number of participants, success rate, and use of a placebo. 4) *Phase III*: a. *Endpoint*: survival (How long does the pt live when they're taking this drug?) b. *Success rate*: ____% c. *Time to complete*: up to ___ *YEARS* d. *Objectives*: - Confirm *safety and efficacy* e. *Target population*: ____-____ pts --> This minimizes errors that could've been present in the phase I and II studies f. *Methods*: - Use of a multicenter (instead of single center) testing facility to ensure *geographic* and *ethnic* variations - Use many different patient subgroups (Ex: pediatric, geriatric, renal impaired) - Randomized allocation of treatment / standard care / placebo - *Double blinded crossover* design - Vigilant recording of *all adverse drug reactions* - Rigorous *statistical analysis* of all clinical data e. Measure *"surrogate" endpoints* ----> Ex: in cancer, the endpoint is overall survival, but this is hard to measure in a phase II study, and this takes too long as well, so you need a "surrogate" endpoint that relates to overall survival, such as tumor size - One hopes their *surrogate endpoint* mimics your *real*, i.e. ____ *endpoint* (e.g. SURVIVAL; but can be subjective (sx score, QOL), or objective like survival (also dz exacerbation, clinical event (MI, CVA), etc.) f. Phase III studies have a *high failure rate* because researchers unable to *demonstrate efficacy* for many treatments because their *endpoints are different than phase II trials* g. Study design includes parallel and crossover designs f. *NDA* paperwork submitted here

59; 5; 250-1000; direct

*Clinical trials: Phases I-IV* Differentiate between the various phases of clinical research. Understand the objectives, outcomes/endpoints, inclusion/exclusion criteria, average time to complete, number of participants, success rate, and use of a placebo. 2) *Phase I*: "1st time in man" a. *End point*: toxicity (is it safe?) b. *Success rate*: ___% c. *Time to complete*: ___-___ *months* d. *Objectives*: --> To assess a safe and tolerable dose --> To determine if the pharmacokinetics differ between ____ and ____ --> To assess the if kinetics show proper *absorption* and *bioavailability* --> To detect effects ____ to the *expected* effect --> To detect any predictable toxicity e. *Inclusion criteria*: - Informed consent from healthy volunteers, who are _____ in *age, sex, nutritional status* --> Exception: patients only for toxic drugs (ex: anti-HIV, anti-cancer drugs) f. *Exclusion criteria*: - Women of child bearing age, children

66; 3-12; animal; man; unrelated; toxicity; uniform

*Clinical trials: Phases I-IV* Differentiate between the various phases of clinical research. Understand the objectives, outcomes/endpoints, inclusion/exclusion criteria, average time to complete, number of participants, success rate, and use of a placebo. 5) *Phase IV*: "post-marketing surveillance* a. *Endpoint*: QOL, cost, etc. (Once it's out in the population, how well is it working? Are there any adverse effects that you didn't see in clinical trials?) b. *Success rate*: ____% c. *Time to complete*: no fixed duration (continue on for however long the drug is available) d. *Pt population:* no fixed population e. *Objectives*: - Compare the drug with other drugs already on the market - Monitor the drug's *effectiveness and long-term effect* on patient's quality of life (QOL) - Determine the *cost-effectiveness* relative to other traditional and new therapies f. *Pharmacists* must report ANY and ALL ____ ----> Note: depending on findings, the *drug can be taken off the market or added with new restrictions* - Monitor the target population

ADRs (adverse drug rxns)

*Ethical issues in clinical research* What are the guiding principles of clinical research? How are they defined? 1) *Personal* ____ = individual able to decide for himself what is appropriate - "Intentional actions carried out with understanding and without controlling influence" - Vulnerable subjects (young children, older adults, people who live in nursing homes / jail) need a guardian or parents to decide if it is in their best interest to participate 2) _____ = obligation to attend to well-being of patient, i.e. intend to do no harm - Goal: maximize potential benefits while minimizing possible harm --> If the risk > benefit, do not perform a clinical study 3) _____ = fairness in the selection of the research subjects, benefits, and burdens - If pt says they meet inclusion and exclusion criteria, they have equal opportunity to be a part of the study and be assigned to either group (do via random selection) ----> Ex: which of these is more ideal to be selected for a clinical trial testing a new anti-cancer drug w/ significant side effects? a. 30 yr old woman who can have tumor removed b. 80 yr old man w/ terminal cancer - There are risks with this clinical trial, so choose the old man bc he has more benefits to gain (since he's going to die anyways), whereas the 30 y/o does not need to withstand these side-effects because we know we can surgically remove the tumor

Autonomy; beneficence; justice

*Epidemiology - Study of health and disease* What are vital statistics measurements and how are they calculated? What do they tell you? - *Birth rate* = # live births (year)/total population at mid-year - *Mortality rate* = # deaths (year)/population at mid-year --> Usually #deaths/100,000 population --> Subtypes: a. *_____-specific* mortality rate = # deaths from specific disease (year)/average mid-year population ----> Ex: deaths of covid in a year of the dz/average of population b. *____-fatality* rate = #deaths from disease/ #individuals who actually have the disease --> Within a specific time frame ----> Limitation: covid- while we know the # of deaths, the number of individuals that have tested positive, there's ppl who get tested multiple times, overinflating the amount of seemingly positive tests c. *Age*-_____ mortality rate = mortality rate for specific age group d. *Age*-_____ morality rate (AAMR) = to compare more fairly between ages --> (Age specific death rate for age group) x (proportional distributions of age group in the population)

Cause; case; specific; adjusted

*Epidemiology - Study of health and disease* What are the characteristics of epidemiological studies? - Epidemiology - study of health and disease (but originally study of epidemics, morbidity/mortality) - Today, study of... --> Chronic dz (like obesity epidemic) --> _____ --> Health status/QOL --> Includes... AIDS, CV disease, Arthritis, Cancer, etc. - Works to make people healthy! What type of information is gathered in epidemiological studies? - Determining ____ of dz, *health states*, and their *trends* - Determining factors that affect development of a particular dz/health state and why they're important ----> Ex: comorbidities/ethnicity affecting COVID-19 - Predict *occurrence/distribution* of various dz and health states ----> Ex: covid occurrence peaking again - Determining factors that ____ dz ----> Ex: wearing mask for covid

Disabilities; frequency; prevent

*Clinical trials: Phases I-IV* What is the difference between Efficacy and Effectiveness? - _____ is the *biological effect* of a treatment (ex: health benefit) - _____ is the *effect of a treatment* when widely used in practice (ex: clinical benefit)

Efficacy; Effectiveness

*Clinical trials: Phases I-IV* Identify the participating parties in a clinical trial. - *Patient/healthy volunteer* serves as subject - *Investigator* conducts clinical trial and reports adverse events - *Institution where trials are held* provide all facilities - ____ *committee* supervises and monitors every step, safeguards the welfare and rights of the participants - *Sponsor* pays for all expenses, appoints competent investigators, files papers to legal/regulatory authorities - *Regulatory authorities* are the legal authority on the outcomes of the trial

Ethical

*Ethical issues in clinical research* What are some of the major events that have shaped the rules and regulations that guide clinical research today? 1) *Tuskegee Syphilis Study* (1930-1970's): people who had syphilis were withheld from tx because they wanted to see the progression of the dz, even though penicillin was available 2) *Nuremberg Code of 1949*: states person has to voluntarily consent - ____ formal guideline of voluntary consent; also states "scientifically qualified persons" must perform the study 3) *Declaration of Helsinki* - Adopted 1964: World Medical Association (revised until 1989) - The research has to come under *independent review of individuals NOT associated with project* so that we have the pt's health considered first and foremost - If research does not include they followed declaration in M/M section, you may not be able to publish 4) *National Research Act* (established 1974) - National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research - *DHHS and FDA* establish the rules and regulations that govern conduct of ____ research in USA today - *Office for Protection from Research Risks* implement the regulations 5) _____ = Health Insurance Portability and Accountability Act of 1996 - Maintain patient's confidentiality - Sign form in physician's office

First; human; HIPPA

*Clinical trials: Phases I-IV* What is an IND? - ____ ____ ____ application Who does it get filed to and when does that happen? - It is filed to the *FDA during preclinical trials*, and becomes effective if FDA doesn't disapprove within *30 days* What must it contain? - Application for permission to administer a new drug to ____; includes *Animal Pharmacology and Toxicology Studies, Manufacturing Information, Clinical Protocols and Investigator Information*

Investigational New Drug Application; humans

*Systematic reviews and meta-analysis* What are the rating scales used for a systematic review? - Rating scales: criteria used and resultant ratings must be described so reads can evaluate the validity of the reviewer's conclusions --> No gold standard --> Most scoring systems have not been validated --> Commonly used scales: 1) _____ scale: assesses likelihood of bias - studies are scored according to the presence of three key methodological features of clinical trials, specifically: *randomization, blinding*, and *accountability of all patients* (including withdrawals) 2) _____ scale: Physiotherapy Evidence Database scale - used in *rehabilitation* and *medical literature* 3) _____ scale: review studies of *diagnostic* accuracy --> The scores of the scales are *rated* to determine the *methodological quality* ----> Note: scaling scores do not always = meaningfulness of results; (they may provide a false impression of meaningfulness)

Jadad; PEDro; QUADAS

*Epidemiology - Study of health and disease* What are the characteristics of Case-Control studies? Advantages? Disadvantages? Odds ratio used for Case-Control studies - Cases = individuals *with dz* you're interested in; controls = ppl *without the disorder* you're looking at (but may have other diseases) - Look backwards at interviews, questionnaires, and chart reviews to try to identify *potential risk factors* --> *Measure of association* expressed as ____ ____, NOT relative risk ----> Use 2x2 contingency table HIV (yes/no) vs. TB (yes/no) ----> Calculation = ( [__/__] / [__/__] ) --> OR (=/>/<) 1 odds are NOT increased --> OR (=/>/<) 1 odds are increased --> OR (=/>/<) 1 odds are reduced

ODDs ratio; a/c; b/d; =; >; <

*Systematic reviews and meta-analysis* Who is Archibald Cochrane? What is he known for and why? - A doctor who made a book stating that _____ are best (they are) - He's the father of modern clinical *epidemiology* and *evidence based* medicine - He founded the *Cochrane Collaboration*, a nonprofit organization that promotes ____ ____ *evidence* and *development* of dissemination of ____ *reviews* - The Cochrane Database of Systematic Reviews holds published *systematic reviews of research* AND *health care policies* - Types of reviews: *intervention* reviews, *diagnostic test* accuracy reviews, *methodology* reviews

RCTs; clinical trial; systematic

*Systematic reviews and meta-analysis* What are the biases that can influence the outcome or quality of a systematic review? - _____ bias: may distort treatment effects; random allocation and concealment of allocation are essential - _____ bias: systematic differences in factors related to intervention and outcome - _____ bias: systematic differences due to the way treatment groups are assembled - _____ bias: differences in provision of care to experimental and control groups in a study; blind those who receive and give care - _____ bias: differential loss of subjects across comparison groups; "intention to treat" analysis - _____ bias: outcome differs across comparison groups; quality assessment tools may provide explanations for differences in study results - _____ bias: systematic differences between reported and unreported findings

Selection; Confounding; Allocation; Performance; Attrition; Detection; Reporting

*Ethical issues in clinical research* What is an informed consent? Why is it important? - The goal of the informed consent process is to provide sufficient information to a potential participant, in a language which is easily understood by him/her, so that he/she can make the *voluntary decision* regarding "to" or "not to" participate in the research study - Important so that person can exercise personal _____ and see if they believe in the merit of the study prior to agreeing to participate

autonomy

*Epidemiology - Study of health and disease* What are the characteristics of case studies? Advantages? Limitations? - Description of *unique occurrence* or *medical condition* - Purpose is to create a *complete description* of characteristics / exposures and allows you to *hypothesize* about ____ factors - Advantage: *Catalyst* for further study - Limitations: Not enough *control*, *limited* ____ ----> Ex: first COVID-19 case in US

causal; generalizability

*Systematic reviews and meta-analysis* What is PRISMA? *P*referred *R*eported *I*tems for *S*ystematic Reviews and *M*eta *A*nalyses - A ____ for reporting of systematic reviews and meta-analyses ----> Ex: areas to check off include title, abstract, introduction, methods, results, etc. - Must include *flowchart* to see the process of review in order to be able to *replicate it* - PRISMA is the proof/evidence that a systematic review was exhaustive and that there was no bias

checklist

*Big Data in Healthcare* How can big data be used to fight disease? - Over the next decade, the greatest progress in healthcare will be made by those who have access to the deepest and most comprehensive datasets - Across healthcare, datasets are small and _____. Without an ecosystem that collects, cleanses, analyzes, and applies big data, we can't usher in the age of precision medicine.

disorganized

*Clinical trials: Phases I-IV* What are DLT and MTD? Describe. - *DLT* = _____-_____ _____; occurrence of *severe, life-threatening, or fatal side effects* that prevent any further *increase* of dose. - *MTD* = _____ _____ _____; the *highest dose* one can take before exhibiting *side effects*

dose-limiting toxicity; maximum tolerated dose

*Systematic reviews and meta-analysis* What is the purpose of a systematic review? - A systematic review summarizes the results of available *carefully designed healthcare studies* (*controlled trials*), and provides a high level of *evidence* on the ____ of healthcare *interventions* for providers or scientists to draw conclusions from - They also minimize bias when looking at studies

effectiveness;

*Epidemiology - Study of health and disease* What are the characteristics of descriptive and analytical epidemiological studies? 2) *Analytical*: used when ____ is *known* about the condition to allow for *testing of hypotheses about specific risk factors and disease* - 2 types commonly used: --> *Cohort studies* --> *Case-control studies*

enough

*Systematic reviews and meta-analysis* What is the relationship between a meta-analysis and a systematic review? - A *systematic review* refers to the entire process of selecting, evaluating, and synthesizing all available ____, while the term meta-analysis refers to the _____ approach to *combining* the data derived from a systematic-review

evidence; statistical

*Epidemiology - Study of health and disease* What are the characteristics of correlational studies? Usefulness? Limitations? - *The relationship of a disease / disorder* and *specific*_____, which then allows you to analyze patterns in a population - Used as evidence to *formulate hypotheses* for testing - Advantage: Uses info from *large databases* ----> Ex. CDC (or like tempus uses large databases (big data) to determine best treatments for tumors by mining thru literature and finding best tx while minimizing side-effects) - Limitations: No ___-___ relationship ----> Ex: cigarette sales and cardiovascular disease → High cigarette sales correlated with high CVD, but *no proof* those who purchased cigarettes develop CVD.

exposure; cause-effect;

*Epidemiology - Study of health and disease* What are cross-sectional studies? Usefulness? Limitations? - "Snapshot" of population @ one point in time and tells you how to intervene to curve who it impacts the most - Purpose is to describe the ____ of a disorder within a defined group/population - Advantage: *Efficient method* - Limitations: Cannot determine ____ (exposure and dz), insensitive to duration of disorder (long, like alzheimer's, or short dz, like covid), so then you may *under-representation of disease frequency* due to deaths ----> Ex: Covid antibody prevalence in large school community subject to covid

frequency; causality

*Ethical issues in clinical research* In reviewing an IRB proposal, there are 3 different types of reviews. What are they and know the circumstances for each type of review. 1) ____ review --> Circumstances: invasive procedures, at-risk subjects, non-routine procedures (novel) 2) ____ review = faster, only requires the *chair* and *1 IRB member* for approval --> Circumstances: simply recording data (HR, BP), adult subjects, non-invasive procedures (making someone run), routine procedures (less risk) ----> Ex: moderate exercise by health adults: monitor resp rate, HR, BP, etc. - choose measurements that can be done in non-invasive manner, this is why it can be ^^^ 3) ____ review = even faster, only involves the *chair* to approve --> Circumstances: surveys, interviews, secondary analyses of coded data, database ----> Ex: retrospective study - only looking at info in medical documents/file that has been collected already, therefore the use of this info has already been approved (?) - Overall ratings: · Approve · Requires modifications · Disapprove (start over)

full; expedited;

*Clinical trials: Phases I-IV* What are SAD and MAD studies? 1) *SAD* = *S*ingle *A*scending *D*ose studies - Used for *phase 1A trials* - A group of 3-6 people are given a small dose of the drug and observed for a specific period of time - If they do not exhibit any adverse side effects, a new group of patients is then given a ____ dose - This is continued until *intolerable side effects occur*, at which the drug is said to have reached *MTD*, AKA ____ _____ _____ 2) *MAD* = *M*ultiple *A*scending *D*ose studies - A group of people receive a low dose of the drug - The dose is *subsequently elevated* to a pre-____ level - Blood and other fluid samples are collected at various time points to better understand how the drug is processed within the body

higher; maximum tolerated dose; determined

*Systematic reviews and meta-analysis* What are the 3 types of systematic reviews published in Cochrane Reviews? 1) _____ reviews - looks at medical interventions to disease states, etc. assess the benefits and harms of medical interventions used in *healthcare* and *health policy* 2) _____ test _____ reviews - assess how well a *diagnostic test* performs in *diagnosing and detecting* a particular disease 3) _____ reviews - address issues relevant to how *systematic reviews* and *clinical trials* are *conducted and reported* (a look at research protocol, propose a new test or procedure, etc.)

intervention; Diagnostic; accuracy; Methodology

*Epidemiology - Study of health and disease* What are the characteristics of descriptive and analytical epidemiological studies? 1) *Descriptive*: used when ____ is *known* about the *occurrence or determinants* of health conditions and disease states ----> Ex: when we first heart ab covid in china, there were a lot of descriptive studies to understand what caused the onset - *Purpose* is to determine who ____ disorder (covid is multi-generational), where *frequency* of disease is *highest/lowest* (covid is highest in highly populated areas), *when it occurs* most/least (flu occurs most during fall) - *Use*: to set priorities for health care planning (orders put in place for covid to allow for more hospital beds for covid pts, warp speed vaccine development, ventilator manufacturing increased) and *generate hypothesis* - *Classifications*: --> *Case report/case series* --> *Correlational studies* --> *Cross-sectional studies*

little; experiences;

*Epidemiology - Study of health and disease* What are measurements of disease frequency? What information is gathered from these measurements? What is their usefulness? Limitations? - Tells you the *degree of frequency or magnitude* of disease in a given population - Measure using the population *size* (in thousands or multiple of thousands), in a given period of time, using *whole* numbers (NOT *fractions*) --> *Reflects risk for disease in given group* ----> Ex: 35 cases/3200 ppl/1 year = 10.94/1000 - so instead of fraction, frequency reported as 1094 cases/100,000 individuals - Measures: 2) *Incidence* = ____ cases in a specific time - Estimates risk of developing dz during that period of time; but it *discounts the duration of illness* - 2 expressions: a. _____ _____ = *#of new cases (given time period)/total population at risk* --> *Concerns*: need to specify time period of observation, and the number of people at risk for developing dz *may vary over time* (summer - ppl outside more, reducing number of cases bc far away; now ppl inside, and now increasing cases), competing risk factors may contribute to dz (HTN, ethnicity, etc. for covid) - so, the impact of behavior contributes; assume all subjects are available --> *Limitations*: f/up period not uniform for all participants -----> Ex: new cases of covid compared to previous day b. _____ _____ = *# of new cases/total person-time* --> Total person-time = *sum* of the time periods of observation; can account for death/attrition --> Usefulness: *more efficient that CI* bc no data needs to be eliminated since time period not specified

new; cumulative incidence (CI); incidence rate (IR)

*Systematic reviews and meta-analysis* How do you read a Forest Plot? - Solid line at *1.0 on the x-axis* = tells you there is ____ significant difference between intervention and comparison groups - The farther *away from 1.0* (the larger the numbers) = the *stronger the odds* are that the *effect* was due to the _____ - The number that the square is placed at for each article is the ___ ____, and the lines extending from the square is the ____ ____ - The *size* of the square tells you *how many subjects* were in each study - The *diamond* is a *summary measure of the odds ratio and confidence interval of all the studies together*. How is it constructed? - Forest plots are constructed by *comparing variables within each study* and building a graph based on ____ size and *confidence intervals* What is its purpose? - The purpose is to *visualize the homogeneity between studies*

no; intervention; odds ratio; confidence interval; effect

*Clinical trials: Phases I-IV* What are the elements of a clinical trial application? - Title page - Statement of ____ - Background info - Protocol: study design - Investigator information - Evaluation parameters - Statistical plan - Additional documents Who is the Data Safety Monitoring Board and what is their purpose? - An independent committee required for ____ sponsored studies, and studies that are *double-blinded, large, multi-center, long duration, or have an endpoint of death or stroke* - They protect *safety of subjects*, propose appropriate *analysis*, and ensure *integrity* of the study

objectives; NIH

*Epidemiology - Study of health and disease* What are the classifications of epidemiological studies? 1) ______ --> Descriptive (case report, correlational, cross-sectional) or Analytical 2) _____

observational; Experimental (or quasi-experimental)

*Systematic reviews and meta-analysis* What are the two stages in a meta-analysis? 2) 2nd stage: *calculation* of _____ *average result* across all studies - Apply statistical methods to calculate combined estimates of effects to provide more *confidence* in the outcome --> *Effect size*: an estimate of the magnitude of _____ between the groups OR the effect of the *intervention* (independent of sample size) ----> _____ data = means and correlations ----> _____ data: odds ratio and relative risks --> *Effect size index*: is created for the data in each study that allows for comparison across studies ----> *Continuous* data: mean difference between groups/the pooled standard deviation of the 2 groups -----> *Proportions*: ratio itself --> *Weighting effect size*: adjustments in the calculation of the effect size used to weigh the _____ of each individual study (based on sample size)

pooled; difference; Continuous; binary; contribution

*Clinical trials: Phases I-IV* Where does animal research occur relative to Clinical Trials? - This occurs during _____ trials What is the importance of animal and cell culture-based experimental studies? - Using *animals* (in vivo) provides *preliminary* information regarding a drug's effect on _____ *changes* to *blood counts, electrolytes, liver function, immune function, and cholesterol levels* --> May provide info on potential adverse effects (disturbances in sleep, appetite, activity) - *Cell cultures* (in vitro) allow you to evaluate solubility, stability, hERG inhibition, protein binding, CYP450 interactions

preclinical; physiological;

*Big Data in Healthcare* What are the benefits of using big data in healthcare? - Allows for the right care, the right innovations, the right care provider, and right values How can big data be used to direct patient care? - Through _____ databases and data analytics platforms --> TEMPA: a centralized database that is able to collect aggregated data from any source across all major disease types What big databases are available to the public? - *GTex portal, TCGA, Ensembl, PubMed, MEDLINE, Cochrane library, Clinicaltrials.gov*

private

*Systematic reviews and meta-analysis* What is the process of conducting a systematic review? 1. State the *study objective* → define a specific ____ and define variables 2. Develop the *protocol* → set ____ and ____ criteria; define evaluation method 3. Develop search *strategy* → select ____ words and identify relevant resources that include relevant informatiton 4. *Conduct the search* → search databases and review other relevant reesources 5. Retrieve ____ *papers* 6. *Screen and select papers* that meet established ____ 7. Evaluate *methodologic* ____ of selected studies 8. ____ and *synthesize* findings 9. *Determine* if statistical data is *sufficient for further analysis*, conduct a ____-____; if not, *report the results* of the systematic review (note: systematic reviews and meta-analyses are same up until this point when you ask "do I have enough data to do a meta-analysis?", if you don't, then you do report the results of the systematic review) --> If you DO have have sufficient data, then you go on to analyze effect size estimates and report the results of meta-analysis

question; inclusion; exclusion; key; relevant; criteria; quality; Analyze; meta-analysis

*Epidemiology - Study of health and disease* What are the characteristics of Cohort studies? Advantages? Disadvantages? - Follow to "see" if disorder develops, look backward to determine differences, can be descriptive or analytic --> *Measure of association* expressed as ____ ___, NOT odds ratio ----> Use 2x2 contigency table ----> Exposure (yes/no) vs. Disease (yes/no) ----> Calculation = [__/ (__+__)] / [__ (__/__)] --> RR (=/>/<) 1 exposure doesn't increase risk of disease --> RR (=/>/<) 1 exposure does increase risk of disease --> RR (=/>/<) 1 exposure reduces risk of disease

relative risk (RR); a/a+b; c/c+d; =; >; <

*Clinical trials: Phases I-IV* Detail the goals of clinical trials. - Clinical trials are trials done on actual people - Goals include: --> Assess the ____ and ____ of a *new investigational drug, device,* or *intervention in clinical practice* --> Establish the ____ of a *new investigational drug, device,* or *intervention in clinical practice* - Overall, the results should be unambiguous and should improve patient care and outcomes

safety; efficacy; role

*Big Data in Healthcare* What pipelines does Tempus use to collect and structure patient data? - *Molecular* ____ data - *Structured clinical* data - *Structured* _____ data - _____ *modeling* data How does Tempus use artificial intelligence to provide clinical recommendations? - Artificial intelligence is used along with data aggregated into the tempus library to guide clinical decisions and support tools and analytic tools

sequencing; imaging; predictive

*Clinical trials: Phases I-IV* What are Parallel and Cross-over designs? What are the characteristics of each? 1) *Parallel designs*: separate groups receiving different treatments - Overall, ____ duration than crossover, but you need a *larger sample size*, doesn't have carryover effects - typically use this for acute, not chronic diseases - "____" = a subject is matched with a similar subject to *reduce the chance that other variables* obscure the primary comparison of interest - "____" = tests the effects of 2+ tx simultaneously - attractive when the interventions are thought to have *independent* effects or when effects are thought to be *complimentary* - Types: a. ____ _____ = simplest, just two groups of patients, one with a condition and one without - both groups are separated to receive test drug vs placebo ----> Ex: HTN group given amlodipine or placebo, and normotensive group given amlodipine or placebo b. ______ = partitioning of subjects by factor other than the treatment given (gender, age, race) ----> Ex: HTN group broken into males vs. females, each group given amlodipine or placebo, and normotensive group broken into males vs. females, each group given amlodipine or placebo 2) *Cross over designs*: the participants cross over from one treatment to another over the course of a clinical trial - Overall, _____ duration than parallel, *smaller* sample size, carryover effect, used for chronic, stable conditions

shorter; no stratification; stratification; Longer

*Clinical trials: Phases I-IV* Understand both the potential benefits and risks of participation in clinical research 1) *Benefits:* - *Early access* to investigational medicine and tests (good for if you have cancer) - Obtain *expert medical care* at leading health care facilities during trial - *Free* lab work and trial medicines - Frequent monitoring of health ___ and *early detection of complications* - Play an active role in their own health care - *Help others* by contributing to medical research - Help with taking medicines correctly - Some studies show that those who participate in clinical trials *do better* than those who don't 2) *Risks:* - There may be *unpleasant* (blood draws), *serious,* or even *life-threatening* side effects of experimental treatment - The experimental treatment may *not be effective* for participant - The protocol may require *more of time and attention* than would a non-protocol treatment (more trips to study site, more tx, more hospital stays, complex dosage requirements, etc.) - Feeling of being a guinea pig :( - Lack of *treatment* ____ - May limit future tx options - Privacy

status; flexibility

*Systematic reviews and meta-analysis* What are the differences between a Systematic Review and a Narrative Review? - *Narrative reviews* are qualitative summaries of evidence on a given topic. They are *informal*, _____, and written by an *expert* of the field - *Systematic reviews* are research studies set to *identify*, _____, and *synthesize* all the empirical data that meets pre-specified *eligibility criteria* to answer a *specific research* question. Explicit methods (flow chart showing how data was collected and reviewed, see PRISMA) are used to *eliminate* _____ --> Types of reviews: effectiveness of *interventions*, accuracy of *diagnostic tools*, identification of *prognostic factors*, and *methodological factors*

subjective; appraise; bias

*Clinical trials: Phases I-IV* What are Biodistribution studies? - Biodistribution studies confirm the drug reaches the ____ ____ and *does not accumulate* in target sites of potential *toxicity* --> Performed in animals and humans What are Pharmacokinetic studies? - Pharmacokinetic (PK) studies determine how the drug _____ *changes* as it moves throughout the body --> ADME --> Bioavailability --> 1st pass effect results in *active* and *inactive* metabolites

target tissue; concentration

*Clinical trials: Phases I-IV* Differentiate between the various phases of clinical research. Understand the objectives, outcomes/endpoints, inclusion/exclusion criteria, average time to complete, number of participants, success rate, and use of a placebo. 1) *Preclinical*: identify the ____ and find the "hit" ____ - Includes... a. *In vitro and in vivo preclinical and nonclinical studies* to examine *biological effect, pharmacology, metabolism, uptake, exposure, and potential toxicities* of the drug b. *SAR* (structure activity relationship) *studies* to improve *in vitro physiochemical* and *ADME* (absorption, distribution, metabolism, excretion) properties c. *Selectivity* and *safety* screens d. *In* ____ *studies* used to determine *physiological effects* of drug on small animal (including toxicology and biodistribution studies) - IND (investigational new drug) paperwork must be completed, (becomes effective if FDA doesn't disapprove within 30 days) --> This paperwork contains info about *animal pharmacology and toxicology studies* (determines if its safe to test in humans), *manufacturing information (info pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance), and *clinical protocols and investigator information* - Takes ___-___ years

target; compound; vivo; 3-6

*Big Data in Healthcare* What is big data? - Large volume of complex and variable information that requires advanced _____ and *analytics* to *capture, store, manage, and analyze* What are the challenges to using big data in healthcare? - Data collection *obstacles* (with EMR systems, physician notes, pdfs) - ____ of multiple data sources (lack of standard protocol to compile data into useful formats, difficulty managing and storing data in accessible databases) - Data analysis and clinical insights (poor data quality, lack of tools, accessibility to tools)

technology; Integration

*Big Data in Healthcare* What 'healthcare ecosystems' does Tempus serve? - Several *precise* _____ and types of *data extraction* in order to provide *personalized and data-driven treatments* --> These include *clinical data, molecular therapy, immunotherapy, CRISPR therapy, AI-assisted analysis,* etc.

therapies

*Systematic reviews and meta-analysis* How is the research question for a systematic review defined? 1) Precise statement of the *primary objective* (below) - The question guides the review process; assists with determining: *eligibility criteria*, *searching* for studies, collecting *data* from included studies, and presenting the findings - Types of questions: --> *Diagnostic* ____ - specificy the test, reference standard, outcomes --> *Causation* (example: smoking causes cancer?) --> *Prognosis* - prognostic factors, outcomes of interest --> _____ - delineate the treatment, outcome measures, population characteristics 2) *Identify and define variables* that are being used 3) When you have a *primary objective*, you can develop a *secondary objective*, relating to different aspects of the PICO question --> ____ objective: *directly ties to the PICO question* (to assess the effects of [intervention or comparison] for [health problem] in [types of people, disease/problem, and setting, if specified]) ----> Ex: to compare the effect of drug XYZ, relative to placebo, on changes in serum total cholesterol from baseline to week 12, in patients with moderate HLD --> ____ objectives (can be multiple): *related to the PICO question*, which may involve different variables or the same variables at different time points or in different subsets of the study population. ----> Ex: to compare the effect of drug XYZ, relative to placebo, on changes in serum total cholesterol AND serum triglycerides from baseline to weeks 4 and 8, in patients with moderate HLD 4) Define inclusion/exclusion criteria (study designs, participants, interventions, outcomes): develop the protocol - Define the evaluation method

tools; Intervention; Primary; secondary

*Epidemiology - Study of health and disease* What are measurements of disease frequency? What information is gathered from these measurements? What is their usefulness? Limitations? - Tells you the *degree of frequency or magnitude* of disease in a given population - Measure using the population *size* (in thousands or multiple of thousands), in a given period of time, using ____ numbers --> *Reflects risk for disease in given group* ----> Ex: 35 cases/3200 ppl/1 year = 10.94/1000 - so instead of fraction, frequency reported as 1094 cases/100,000 individuals - Measures: 1) *Prevalence* = probability individual will have dz in a defined ____ of ____ (gives you an idea of the *impact of dz* on population and allows health community to *plan accordingly* for this population) -----> Ex: ICU units cleared, pts not needed in hospital discharged, etc. for COVID - Tells you *# of existing cases/total pop. at specific time* --> ____ *prevalence* = single point in time --> ____ *prevalence* = over a period of time (usually 1 yr) - Limitatoitns: doesn't tell you cause, just the *amount of cases* (so, if you have a *long* disease, you will show a *large* prevalence; vs *short* disease, it'll be *low* prevalence, even if # was high)

whole (not fractions); period; time; point; period;

*Ethical issues in clinical research* What comprises an informed consent? What does it contain? 2) *Consent elements* - "own free will" - Vulnerable subjects include: --> Children --> Prisoners --> Students --> Nursing home residents What are the subject's rights with regards to an informed consent and clinical trial? - Freedom to ____ at *any time, for any reason, before/during/after the study, and can say their safety/comfort was compromised* --> It is a non-binding contract agreement What is provided in the consent protion of an informed consent --> Requires ____ signatures: *pt/subject, researcher, witness* ----> Note: CANNOT be a free-standing piece of paper that doesn't describe what is taking place, because it could be incorporated into ANY type of document - needs to be within context of the document When is informed consent required? Not required? - These standards of informed consent are required for *all procedures, even standard ones*, to ensure that the pt understands alternatives - *Retrospective studies ____ require informed consent, but they ____ require IRB approval*

withdraw; 3; don't; do

*Ethical issues in clinical research* What comprises an informed consent? What does it contain? 1) *Information elements* - *How is the subject informed?* --> Subjects must be *fully informed* - important so that person can exercise personal autonomy and see if they believe in the merit of the study prior to agreeing to participate --> They get a ____ explanation of the procedures, stating: o What is being performed o How is it being performed o What is the expected outcome o What are the side-effects --> The investigators can't withhold why the individuals was selected, reasonably foreseeable risks/side effects, and potential benefits - *How is the information kept confidential?* --> Pt's given a code as their identifier (info used to link the code to the individual is stored in a locked compartment within another locked compartment wherein only ONE individual can access) --> Pts need to be informed of any video/photography --> Subjects can review info --> Subjects can _____ any time - non-binding contractual agreement - *How is the document worded?* --> Lay language (clear, basic, lowest education level) - *How are the pt's questions addressed?* --> Researcher is available 24/7 to pt for any concerns

written; withdraw;

*Systematic reviews and meta-analysis* Are PICO questions used in systematic reviews? - Y/N? What databases are searched when conducting a systematic review? - *MEDLINE, EMBASE, CINAHL, Web of Science, EBM Reviews (Cochrane Central Register of Controlled Trials)*

y (P = population / condition, I = intervention, C = comparison, O = outcome, T = Type of study (sometimes))