Clinical Epidemiology Glossary

A

Absolute risk: The observed or calculated probability of an event in the population under study.

Absolute risk difference (ARD): The difference in the risk for disease or death between an exposed population and an unexposed population.

Absolute risk reduction (ARR): The difference in the absolute risk (rates of adverse events) between study and control populations.

Allocation concealment: Occurs when the person who is enrolling a participant into a clinical trial is unaware whether the next participant to be enrolled will be allocated to the intervention or control group.

Adjustment: A summarizing procedure in which the effects of differences in composition of the populations being compared have been minimized by statistical methods.

Adverse Reaction (Adverse Event): An unwanted effect caused by the administration of drugs. Onset may be sudden or develop over time

Advocacy Support Groups: Organizations and groups that actively support participants and their families with valuable resources, including self-empowerment and survival tools.

Approved Drugs: The Food and Drug Administration (FDA) must approve a substance as a drug, before it can be marketed in USA. The approval process involves several steps including pre-clinical laboratory and animal studies, clinical trials for safety and efficacy, filing of a New Drug Application by the manufacturer of the drug, FDA review of the application, and FDA approval/rejection of application.

Arm: Any of the treatment groups in a randomized trial. Most randomized trials have two “arms,” but some have three “arms,” or even more.

Association: Statistical dependence between two or more events, characteristics, or other variables. An association may be fortuitous or may be produced by various other circumstances; the presence of an association does not necessarily imply a causal relationship.

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B

Baseline: 1. Information gathered at the beginning of a study from which variations found in the study are measured. 2. A known value or quantity with which an unknown is compared when measured or assessed. 3. The initial time point in a clinical trial, just before a participant starts to receive the experimental treatment which is being tested. At this reference point, measurable values such as CD4 count are recorded. Safety and efficacy of a drug are often determined by monitoring changes from the baseline values.

Bias (systematic error): Deviation of results, inferences from the truth, or processes leading to such deviation.

Blind/Blinding/Masking: A randomized trial is “Blind”if the participant is not told which arm of the trial he is on. A clinical trial is “Blind” if participants are unaware on whether they are in the experimental or control arm of the study; also called masked.

Blind assessment: An outcome evaluation is made without the evaluator knowing which results are from the test under study and which are from the control or “gold standard.”

Blinded study (masked study): A study in which observer(s) and/or subjects are kept ignorant of the group to which the subjects are assigned, as in an experimental study, or of the population from which the subjects come, as in a non-experimental or observational study. Where both observer and subjects are kept ignorant, the study is termed a double-blind study. If the statistical analysis is also done in ignorance of the group to which subjects belong, the study is sometimes described as triple blind. The purpose of “blinding” is to eliminate sources of bias.

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C

Case-control study: Retrospective comparison of exposures of persons with disease (cases) with those of persons without the disease (controls). A study which involves identifying patients who have the outcome of interest (cases) and patients without the same outcome (controls), and looking back to see if they had the exposure of interest.

Case Definition: The set of history, clinical signs and laboratory findings that are used to classify an individual as a case or not, for an epidemiological study. Case definitions are needed to exclude individuals with the other conditions that occur at an endemic background rate in a population or other characteristics that will confuse or reduce the precision of a clinical study.

Case series: A report on a series of patients with an outcome of interest. No control group is involved.

Causality: The relating of causes to the effects they produce. Most of epidemiology concerns causality and several types of causes can be distinguished. It must be emphasized, however, that epidemiological evidence by itself is insufficient to establish causality, although it can provide powerful circumstantial evidence.

Clinical: Pertaining to or founded on observation and treatment of participants, as distinguished from theoretical or basic science.

Clinical Investigator: A medical researcher in charge of carrying out a clinical trial's protocol.

Clinical outcome: Measures patient health or wellbeing. Ideally, it should be credible, comprehensive, sensitive to change, accurate, sensible, and biologically sensible.

Clinical Practice Guideline: A systematically developed statement designed to assist clinician and patient decisions about appropriate health care for specific clinical circumstances.

Co-interventions: Interventions other than the treatment under study that may have been applied differently to the study and control groups. Co-intervention is a serious problem when double-blinding is absent or when the use of very effective non-study treatments is permitted.

Cohort: In epidemiology, a group of individuals with some characteristics in common. A group of individuals identified on the basis of a common experience or characteristic that is usually monitored over time from the point of assembly.

Cohort study: Involves identification of two groups (cohorts) of patients, one which received the exposure of interest, and one which did not, and following these cohorts forward for the outcome of interest. A study begins with gathering two matched groups (the cohorts)/ one which has been exposed to a prognostic/risk factor and the other which has not been exposed. The groups are then followed forward in time (prospective) to measure the development of different outcomes. In a retrospective cohort study, cohorts are identified at a point of time in the past and information is collected on their subsequent outcomes. An inception cohort is a group identified at the onset of a disorder or a first exposure to a potential risk factor, and followed forward in time.

Community-Based Clinical Trial (CBCT): A clinical trial conducted primarily through primary-care physicians rather than academic research facilities.

Compassionate use: A method of providing experimental therapeutics prior to final FDA approval for use in humans. This procedure is used with very sick individuals who have no other treatment options. Often, case-by-case approval must be obtained from the FDA for "compassionate use" of a drug or therapy.

Complementary and alternative therapy: Broad range of healing philosophies, approaches, and therapies that Western (conventional) medicine does not commonly use to promote well-being or treat health conditions. Examples include acupuncture, herbs, etc.

Comparison group: Any group to which the index group is compared (usually synonymous with control group).

Co-morbidity: Coexistence of a disease or diseases in a study participant in addition to the index condition that is the subject of study.

Confidence interval (CI): “The CI gives a measure of the precision (or uncertainty) of study results for making inferences about the population of all such patients”. The 95% CI is the range of values within which we can be 95% sure that the true value lies for the whole population of patients from whom the study patients were selected. Wide confidence intervals indicate less precise estimates of effect. CI is affected by sample size and by variability among subjects. The larger the trial's sample size is, the larger the number of outcome events and the greater the confidence that the true relative risk reduction is close to the value stated: the confidence intervals narrow and "precision" is increased. Quantifies the uncertainty in measurement. It is usually reported as a 95% CI which is the range of values within which we can be 95% sure that the true value for the whole population lies. For example, for an NNT of 10 with a 95% CI of 5 to 15, we would have 95% confidence that the true NNT value lies between 5 and 15.

Confidentiality regarding trial participants: Refers to maintaining the confidentiality of trial participants including their personal identity and all personal medical information. The trial participants' consent to the use of records for data verification purposes should be obtained prior to the trial and assurance must be given that confidentiality will be maintained.

Confounding variable (confounder): A characteristic that may be distributed differently between the study and control groups and that can affect the outcome being assessed. Confounding may be due to chance or bias.

Contraindication: A specific circumstance when the use of certain treatments could be harmful.

Control: Control is the nature of the intervention control.

Control group: The standard by which experimental observations are evaluated. In many clinical trials, one group of patients will be given an experimental drug or treatment, while the control group is given either a standard treatment for the illness or a placebo.

Controlled trials: Control is a standard against which experimental observations may be evaluated. In clinical trials, one group of participants is given an experimental drug, while another group (i.e., the control group) is given either a standard treatment for the disease or a placebo.

Control event rate (CER): The percentage of the control/ non-exposed group who experience outcome.

Cost-benefit analysis: Assesses whether the cost of an intervention is worth the benefit by measuring both in the same units; monetary units are usually used.

Cost-effectiveness analysis: Measures the net cost of providing intervention as well as the outcomes obtained. Outcomes are reported in a single unit of measurement.

Cost-minimization analysis: If health effects are known to be equal, only costs are analyzed and the least costly alternative is chosen.

Cost-utility analysis: Converts health effects into personal preferences (or utilities) and describes how much it costs for some additional quality gain (e.g. cost per additional quality-adjusted life-year, or QALY).

Crossover study design: The administration of two or more experimental therapies one after the other in a specified or random order to the same group of patients.

Cross-sectional study: The observation of a defined population at a single point in time or time interval. Exposure and outcome are determined simultaneously.

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D

Data safety and monitoring committee/ board (DSMB): An independent committee, composed of community representatives and clinical research experts, that reviews data while a clinical trial is in progress to ensure that participants are not exposed to undue risk. A DSMB may recommend that a trial be stopped if there are safety concerns or if the trial objectives have been achieved.

Diagnostic trials: Refers to trials that are conducted to find better tests or procedures for diagnosing a particular disease or condition. Diagnostic trials usually include people who have signs or symptoms of the disease or condition being studied.

Decision analysis (or clinical decision analysis): The application of explicit, quantitative methods that quantify prognoses, treatment effects, and patient values in order to analyze a decision under conditions of uncertainty.

Determinant: Any definable factor that affects a change in a health condition or other characteristic.

Dose-ranging study: A clinical trial in which two or more doses of an agent (such as a drug) are tested against' each other to determine which dose works best and is least harmful.

Dose-response relationship: A relationship in which a change in amount, intensity, or duration of exposure is associated with a change-either an increase or decrease-- in frequency or intensity of a specified outcome.

Double-blind/masked study: A clinical trial design in which neither the participating individuals nor the study staff knows which participants are receiving the experimental drug and which are receiving a placebo (or another therapy). Double-blind trials are thought to produce objective results since the expectations of the doctor and the participant about the experimental drug do not affect the outcome; also called a double-masked study.

Drug-drug interaction: A modification of the effect of a drug when administered with another drug. The effect may be an increase or a decrease in the action of either substance, or it may be an adverse effect that is not normally associated with either drug.

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E

Ecological survey: A survey based on aggregate data for some population as it exists at some point or points in time; to investigate the relationship of exposure to a known or presumed risk factor for a specified outcome.

Effectiveness: A measure of the benefit resulting from an intervention administered under usual conditions of clinical care for a particular group of patients.

Efficacy: A measure of the benefit resulting from an intervention for a given health problem administered to patients under ideal conditions (i.e., perfect compliance).

Eligibility criteria: Summary criteria for participant selection; including Inclusion and Exclusion criteria.

Empirical: Based on experimental data, not on a theory.

Endpoint: Overall outcome that the protocol is designed to evaluate. Common endpoints are severe toxicity, disease progression, or death.

Enrolling: The act of signing up participants for a study. Generally, this process involves evaluating a participant with respect to the eligibility criteria of the study and going through the informed consent process.

Epidemiology: The branch of medical science that deals with the study of incidence and distribution and control of a disease in a population.

Etiology: The study of the cause or origin of a disease.

Event rate: The proportion of patients in a group in whom the event is observed. Thus, if out of 100 patients, the event is observed in 27, the event rate is 0.27. Control event rate (CER) and experimental event rate (EER) are used to refer to this in control and experimental groups of patients, respectively. The patient expected event rate (PEER) refers to the rate of events we’d expect in a patient who received no treatment or conventional treatment.

Evidence-based health care: Extends the application of the principles of evidence-based medicine to all professions associated with health care, including purchasing and management.

Evidence-based medicine (EBM): 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 requires the integration of individual clinical expertise with the best available external clinical evidence from systematic research and our patient’s unique values and circumstances.

Exclusion criteria: Stated conditions which preclude the entrance of candidates into an investigation even if they meet the inclusion criteria.

Expanded access: Refers to any of the FDA procedures, such as compassionate use, parallel track, and treatment IND that distribute experimental drugs to participants who are failing on currently available treatments for their condition and also are unable to participate in ongoing clinical trials.

Experimental drug: A drug that is not FDA licensed for use in humans, or as a treatment for a particular condition. Experimental event rate (EER): The percentage of an intervention/exposed group who experience the outcome in question.

Experimental Unit, Unit of Concern (EU): In an experiment, the experimental units are the units that are randomly selected or allocated to treatment and the unit upon which the sample size calculations and subsequent data analysis must be based. Experimental units are often a pen of animals or a cage of mice rather than the individuals themselves. Analyzing data on an individual basis when groups (herds, pens) have been the basis of random allocation is a serious error because it overestimates precision, possibly biasing the study toward a false-positive conclusion.

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F

Food and drug administration (FDA): The U.S. Department of Health and Human Services agency responsible for ensuring the safety and effectiveness of all drugs, biologics, vaccines, and medical devices, including those used in the diagnosis, treatment, and prevention of HIV infection, AIDS, and AIDS-related opportunistic infections. The FDA also works with the blood banking industry to safeguard the nation's blood supply.

Follow-up: Observation over a period of time of an individual, group, or initially defined population whose relevant characteristics have been assessed in order to observe changes in health status or health-related variables.

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G

Gold standard (also Reference standard): Ideally, the criterion used to unequivocally define the presence of a condition; or practically, the method, procedure, or measurement that is widely accepted as being the best available to detect the presence of a condition.

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H

Heterogeneity: This occurs when there is more variation between the study result (in a systematic review) than would be expected to occur by chance alone.

Hypothesis: A supposition or assumption advanced as a basis for reasoning or argument, or as a guide to experimental investigation.

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I

Inception cohort: A group of patients who are assembled near the onset of the target disorder.

Incidence: The rate of new cases of illness commencing during a specified time period in a given population. The proportion of new cases of the target disorder in the population at risk, during a specified time interval.

Inclusion/exclusion criteria: The medical or social standards determining whether a person may or may not be allowed to enter a clinical trial. These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions. It is important to note that inclusion and exclusion criteria are not used to reject people personally, but rather to identify appropriate participants and keep them safe.

Index test: The test whose diagnostic accuracy is being measured against the reference or gold standard.

Informed consent: The process of learning the key facts about a clinical trial before deciding whether or not to participate. It is also a continuing process throughout the study to provide information for participants. To help someone decide whether or not to participate, the doctors and nurses involved in the trial explain the details of the study.

Informed consent document: A document that describes the rights of the study participants, and includes details about the study, such as its purpose, duration, required procedures, and key contacts. Risks and potential benefits are explained in the informed consent document. The participant then decides whether or not to sign the document. Informed consent is not a contract, and the participant may withdraw from the trial at any time.

Institutional review board (IRB): 1. A committee of physicians, statisticians, researchers, community advocates, and others that ensures that a clinical trial is ethical and that the rights of study participants are protected. All clinical trials in the U.S. must be approved by an IRB before they begin. 2. Every institution that conducts or supports biomedical or behavioral research involving human participants must, by federal regulation, have an IRB that initially approves and periodically reviews the research in order to protect the rights of human participants.

Intention to treat analysis: Individual outcomes in a clinical trial are analyzed according to the group to which they have been randomized, regardless of whether they dropped out, fully complied with the intervention or crossed over to the other treatment in order to preserve randomization. By simulating practical experience intention to treat analysis provides a better measure of effectiveness (as opposed to efficacy).

Intervention name: The generic name of the precise intervention being studied.

Interventions: Primary interventions being studied: types of interventions are Drug, Gene Transfer, Vaccine, Behavior, Device, or Procedure.

Investigational new drug: A new drug, antibiotic drug, or biological drug that is used in a clinical investigation. It also includes a biological product used in vitro for diagnostic purposes.

Interviewer bias: Systematic error due to interviewer's subconscious or conscious gathering of selective data.

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L

Lead-time bias: Overestimation of survival because of earlier diagnosis-time of death does not change, just time of diagnosis.

Likelihood ratio: The likelihood ratio for a test result compares the likelihood of that result in patients with disease to the likelihood of that result in patients without disease.

The likelihood ratio of a negative test: Ratio of the probability of a false negative result if the disease is present to the probability of a true negative result if the disease is absent.

The likelihood ratio of a positive test: Ratio of the probability of a true positive result if the disease is present to a false positive result if the disease is absent.

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M

Masked: The knowledge of intervention assignment.

Meta-analysis: Statistical synthesis of the results from several studies that address the same question.

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N

Natural history study: Study of the natural development of something (such as an organism or a disease) over a period of time.

Negative predictive value: The proportion of people who receive a negative test result who are truly free of the target disorder.

New drug application (NDA): An application submitted by the manufacturer of a drug to the FDA - after clinical trials have been completed - for a license to market the drug for a specified indication.

N-of-1 trials: In such trials, the patient undergoes pairs of treatment periods organized so that one period involves the use of the experimental treatment and the other involves the use of an alternate or placebo therapy. The patient and physician are blinded, if possible, and outcomes are monitored. Treatment periods are replicated until the clinician and patient are convinced that the treatments are definitely different or definitely not different.

Number needed to treat (NNT): The number of patients with a particular condition who must receive an intervention to prevent the occurrence of one adverse outcome. The inverse of the absolute risk reduction and the number of patients that need to be treated to prevent one bad outcome. Calculated as the inverse of the absolute risk reduction (1/ARR).

Number needed to harm (NNH): The number of patients for whom there is one additional patient who experiences a harmful outcome.

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O

Observational study (non-experimental study): Changes or differences in one characteristic (e.g. whether or not people received a specific treatment or intervention) are studied in relation to changes or differences in other(s) (e.g. whether or not they died), without the intervention of the investigator.

Off-label-use: A drug prescribed for conditions other than those approved by the FDA.

Open-label trial: A clinical trial in which doctors and participants know which drug or vaccine is being administered.

Orphan drugs: An FDA category that refers to medications used to treat diseases and conditions that occur rarely. There is little financial incentive for the pharmaceutical industry to develop medications for these diseases or conditions. Orphan drug status, however, gives the manufacturer specific financial incentives to develop and provide such medications.

Odds: A ratio between two probabilities-the probability of an event to a non-event.

Odds ratio (OR): The odds of the experimental group showing positive (or negative) effects of an intervention or exposure, in comparison to the control group.

Overview: See Systematic Overview

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P

P value: The possibility that any particular outcome would have occurred by chance. Statistical significance is usually p<0.05. P value is considered to be inferior to confidence intervals in determining significance of studies.

Peer review: Review of a clinical trial by experts chosen by the study sponsor. These experts review the trials for scientific merit, participant safety, and ethical considerations.

Pharmacokinetics: The processes (in a living organism) of absorption, distribution, metabolism, and excretion of a drug or vaccine.

Phase I Trials: Initial studies to determine the metabolism and pharmacologic actions of drugs in humans, the side effects associated with increasing doses, and to gain early evidence of effectiveness; may include healthy participants and/or patients.

Phase II Trials: Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks.

Phase III Trials: Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefitrisk relationship of the drug and provide an adequate basis for physician labeling.

Phase IV Trials: Post-marketing studies to delineate additional information including the drug's risks, benefits, and optimal use.

Placebo: A placebo is the shame treatment used in a control group in place of the actual treatment. A placebo is an inactive pill, liquid, or powder that has no treatment value. In clinical trials, experimental treatments are often compared with placebos to assess the treatment's effectiveness.

Placebo-controlled study: A method of investigation of drugs in which an inactive substance (the placebo) is given to one group of participants, while the drug being tested is given to another group. The results obtained in the two groups are then compared to see if the investigational treatment is more effective in treating the condition.

Placebo effect: A physical or emotional change, occurring after a substance is taken or administered, that is not the result of any special property of the substance. The change may be beneficial, reflecting the expectations of the participant and, often, the expectations of the person giving the substance.

Preclinical: Refers to the testing of experimental drugs in the test tube or in animals - the testing that occurs before trials in humans may be carried out.

Prevention trials: Refers to trials to find better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vaccines, vitamins, minerals, or lifestyle changes.

Protocol: A study plan on which all clinical trials are based. The plan is carefully designed to safeguard the health of the participants as well as answer specific research questions. A protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study. While in a clinical trial, participants following a protocol are seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of their treatment.

Positive predictive value: Proportion of people with a positive test who have the target disorder.

Post-test odds: The odds that the patient has the target disorder after the test is carried out (calculated as the pre-test odds x likelihood ratio).

Power: The ability of a study to demonstrate an association or causal relationship between two variables, given that an association exists. For example, 80% power in a clinical trial means that the study has an 80% chance of showing a statistically significant treatment effect if there really was an important difference between outcomes. If the statistical power of a study is low, the study results will be questionable (the study might have been too small to detect any differences). By convention, 80% is an acceptable level of power.

Post-test probability: The proportion of patients with that particular test result who have the target disorder (post-test odds/[1 + post-test odds]).

Pre-test odds: The odds that the patient has the target disorder before the test is carried out (pre-test probability/ [1 – pre-test probability]).

Pre-test probability (prevalence): The proportion of people with the target disorder in the population at risk at a specific time (point prevalence) or time interval (period prevalence).

Precision (statistical precision): The range in which the best estimates of a true value approximate the true value.

Predictive value: In screening and diagnostic tests, the probability that a person with a positive test is a true positive (i.e., does have the target disease), or that a person with a negative test truly does not have the disease. The predictive value of a screening test is determined by the sensitivity and specificity of the test, and by the prevalence of the condition for which the test is used.

Prevalence: The proportion of persons with a particular disease within a given population at a given time.

Primary research: Individual studies such as randomized controlled trials, cohort studies, case-control studies, cross-sectional studies, etc.

Prognosis: The possible outcomes of a disease or condition and the likelihood that each one will occur.

Prognostic factor: A factor or indicator (such as age or gender) related to an individual’s probability of developing a disease or other outcome. Compare with risk factors. Neither prognostic nor risk factors necessarily imply a cause-and-effect relationship.

Prospective study: Study design where one or more groups (cohorts) of individuals who have not yet experienced the outcome event in question are followed forward in time and monitored for the number of such events which occur.

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Q

Quality of life trials (or Supportive Care trials): Refers to trials that explore ways to improve comfort and quality of life for individuals with a chronic illness.

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R

Randomization (or random allocation): Method analogous to tossing a coin to assign patients to treatment groups (the experimental treatment is assigned if the coin lands “heads” and a conventional, “control” or “placebo” treatment is given if the coin lands “tails”).

Randomized controlled trial: An experimental comparison study in which participants are allocated via a randomization mechanism, to either an intervention/ treatment group or a control /placebo group, and then followed over time and assessed for the outcomes of interest. Participants have an equal chance of being allocated to either group.

Recall bias: Systematic error due to the differences in accuracy or completeness of recall to memory of past events or experiences.

Recruiting: The period during which a trial is attempting to identify and enroll participants. Recruitment activities can include advertising and other ways of soliciting interest from possible participants.

Recruitment status: Indicates the current stage of a trial, whether it is planned, ongoing, or completed. Possible values include:

a. Not yet recruiting: participants are not yet being recruited or enrolled

b. Recruiting: participants are currently being recruited and enrolled

c. Enrolling by invitation: participants are being (or will be) selected from a predetermined population

d. Active, not recruiting: study is ongoing (i.e., patients are being treated or examined), but enrollment has completed

e. Completed: the study has concluded normally; participants are no longer being examined or treated (i.e., last patient's last visit has occurred)

f. Suspended: recruiting or enrolling participants has halted prematurely but potentially will resume

g. Terminated: recruiting or enrolling participants has halted prematurely and will not resume; participants are no longer being examined or treated

h. Withdrawn: study halted prematurely, prior to enrollment of first participant

Reference standard: See Gold Standard.

Referral bias: The sequence of referrals that may lead patients from primary to tertiary centers raises the proportion of more severe or unusual cases, thus increasing the likelihood of adverse or unfavorable outcomes. Physicians and medical centers may attract individuals with specific disorders or exposures.

Relative risk (RR): The ratio of the probability of developing, in a specified period of time, an outcome among those receiving the treatment of interest or exposed to a risk factor, compared with the probability of developing the outcome if the risk factor or intervention is not present.

Relative risk reduction (RRR): The extent to which a treatment reduces a risk, in comparison with patients not receiving the treatment of interest.

Reproducibility (repeatability, reliability): The results of a test or measure are identical or closely similar each time it is conducted.

Retrospective study: Study design in which cases where individuals who had an outcome event in question are collected and analyzed after the outcomes have occurred.

Risk-benefit ratio: The risk to individual participants versus the potential benefits. The risk/benefit ratio may differ depending on the condition being treated.

Risk factor: Patient characteristics or factors associated with an increased probability of developing a condition or disease in the first place. Compare with prognostic factor. Neither risk nor prognostic factors necessarily imply a cause-and-effect relationship.

Risk Ratio: The ratio of risk in the treated group (EER), to the risk in the control group (CER). This is used in randomized trials and cohort studies and is calculated as EER/CER. It is also called relative risk.

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S

Sample size: This is the size of the sample. Larger samples usually mean more precise results. Sample size usually depends on the purpose of the study, the population size from which the sample will be pulled, as well as the level of precision and the level of confidence or risk that is acceptable, and the degree of variability in the attributes being measured.

Sample Selection / Allocation Procedures:

• a. Matching: When confounding cannot be controlled by randomization, individual cases are matched with individual controls that have similar confounding factors, such as age, to reduce the effect of the confounding factors on the association being investigated in analytic studies. Most commonly seen in case-control studies.
• b. Restriction (Specification): Eligibility for entry into an analytic study is restricted to individuals within a certain range of values for a confounding factor, such as age, to reduce the effect of the confounding factor when it cannot be controlled by randomization. Restriction limits the external validity (generalizability) to those with the same confounder values.
• c. Census: A sample that includes every individual in a population or group (e.g., entire herd, all known cases). A census not feasible when group is large relative to the costs of obtaining information from individuals.
• d. Haphazard, Convenience, Volunteer, Judgmental Sampling: Any sampling not involving a truly random mechanism. A hallmark of this form of sampling is that the probability that a given individual will be in the sample is unknown before sampling. The theoretical basis for statistical inference is lost and the result is inevitably biased in unknown ways. Despite their best intentions, humans cannot choose a sample in a random fashion without a formal randomizing mechanism.
• e. Consecutive (Quota) Sampling: Sampling individuals with a given characteristic as they are presented until enough with that characteristic are acquired. This method is okay for descriptive studies but unfortunately not much better than haphazard sampling for analytical observational studies.
• f. Random Sampling: Each individual in the group being sampled has a known probability of being included in the sample obtained from the group before the sampling occurs.
• g. Simple Random Sampling / Allocation: Sampling conducted such that each eligible individual in the population has the same chance of being selected or allocated to a group. This sampling procedure is the basis of the simpler statistical analysis procedures applied to sample data. Simple random sampling has the disadvantage of requiring a complete list of identified individuals making up the population (the list frame) before the sampling can be done.
• h. Stratified Random Sampling: The group from which the sample is to be taken is first stratified on the basis of a important characteristic related to the problem at hand (e.g., age, parity, weight) into subgroups such that each individual in a subgroup has the same probability of being included in the sample but the probabilities are different between the subgroups or strata. Stratified random sampling assures that the different categories of the characteristic that is the basis of the strata are sufficiently represented in the sample but the resulting data must be analyzed using more complicated statistical procedures (such as Mantel-Haenszel) in which the stratification is taken into account.
• i. Cluster Sampling: Staged sampling in which a random sample of natural groupings of individuals (houses, herds, kennels, households, stables) are selected and then sampling all the individuals within the cluster. Cluster sampling requires special statistical methods for proper analysis of the data and is not advantageous if the individuals are highly correlated within a group (a strong herd effect).
• j. Systematic Sampling: From a random start in first n individuals, sampling every nth animal as they are presented at the sampling site (clinic, chute). Systematic sampling will not produce a random sample if a cyclical pattern is present in the important characteristics of the individuals as they are presented. Systematic sampling has the advantage of requiring only knowledge of the number of animals in the population to establish n and that anyone presenting the animals is blind to the sequence so they cannot bias it.

Screening Trials: Refers to trials which test the best way to detect certain diseases or health conditions.

Selection bias: A bias in assignment or a confounding variable that arises from study design rather than by chance. These can occur when the study and control groups are chosen so that they differ from each other by one or more factors that may affect the outcome of the study.

Sensitivity (of a diagnostic test): The proportion of truly diseased persons, as measured by the gold standard, who are identified as diseased by the test under study.

Sensitivity Analysis (economic studies): A technique for testing the robustness of a decision analysis by repeating the analysis with a range of probability and utility estimates.

Side effects: Any undesired actions or effects of a drug or treatment. Negative or adverse effects may include headache, nausea, hair loss, skin irritation, or other physical problems. Experimental drugs must be evaluated for both immediate and long-term side effects.

Single-blinded study: A study in which one party, either the investigator or participant, is unaware of what medication the participant is taking; also called singlemasked study.

SnNout: When a sign/test/symptom has a high Sensitivity, a Negative result can help rule out the diagnosis. For example, the sensitivity of a history of ankle swelling for diagnosing ascites is 93%; therefore if a person does not have a history of ankle swelling, it is highly unlikely that the person has ascites.

Specificity (of a diagnostic test): The proportion of truly non-diseased persons, as measured by the gold standard, who are so identified by the diagnostic test under study.

SpPin: What a sign/test/symptom has a high Specificity, a Positive result rules in the diagnosis. For example, the specificity of a fluid wave for diagnosing ascites is 92%; therefore if a person does have a fluid wave, it rules in the diagnosis of ascites.

Standard treatment: A treatment currently in wide use and approved by the FDA, considered to be effective in the treatment of a specific disease or condition.

Standard of care: Treatment regimen or medical management based on state-of-the-art participant care.

Statistical significance: How likely the result is due to chance. The probability that an event or difference occurred by chance alone. In clinical trials, the level of statistical significance depends on the number of participants studied and the observations made, as well as the magnitude of differences observed.

Stratification: Division into groups. Stratification may also refer to a process to control for differences in confounding variables, by making separate estimates for groups of individuals who have the same values for the confounding variable.

Strength of inference: The likelihood that an observed difference between groups within a study represents a real difference rather than mere chance or the influence of confounding factors based on both p values and confidence intervals. Strength of inference is weakened by various forms of biases and by small sample sizes.

Study endpoint: A primary or secondary outcome used to judge the effectiveness of a treatment.

Study type: The primary investigative techniques used in an observational protocol; types are Purpose, Duration, Selection, and Timing

Surrogate outcome/endpoint: Intended to capture the treatment effect of an important clinical endpoint but does not directly measure the clinical benefit of the intervention, substitutes something we can measure for something we want to measure. Compare with clinical outcome.

Survival curve: A graph of the number of events occurring over time or the chance of being free of these events over time. The events must be discrete and the time at which they occur must be precisely known. In most clinical situations, the chance of an outcome changes with time. In most survival curves the earlier follow-up periods usually include results from more patients than the later periods and are therefore more precise.

Systematic review: A summary of the medical literature that uses explicit methods to perform a comprehensive literature search and critical appraisal of individual studies and that uses appropriate statistical techniques to combine these valid studies.

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T

Test/treatment thresholds: The probability of disease above which we treat for the disease and below which we do not treat. The treatment threshold is determined by the costs and benefits of the treatment. Values can be assigned to these thresholds from data on the reliability and potential risks of the diagnostic test and the benefits and risks of the diagnostic test and the benefits and risks of a specific treatment. Treatment should be withheld if the probability of disease is smaller than the testing threshold, and treatment should be given without further testing if the probability of the disease is greater than the test-treatment threshold. The test should be performed (with treatment depending on the test outcome) only if the probability of disease is between the two thresholds. The method exposes important principles of decisionmaking and helps the clinician develop a rational, quantitative approach to the use of diagnostic tests. The probability at which one should be indifferent between testing and treating.

Toxicity: An adverse effect produced by a drug that is detrimental to the participant's health. The level of toxicity associated with a drug will vary depending on the condition which the drug is used to treat.

Treatment IND: IND stands for Investigational New Drug application, which is part of the process to get approval from the FDA for marketing a new prescription drug in the U.S. It makes promising new drugs available to desperately ill participants as early in the drug development process as possible. Treatment INDs are made available to participants before general marketing begins, typically during Phase III studies. To be considered for a treatment IND a participant cannot be eligible to be in the definitive clinical trial.

Treatment effects: The evidence-based journals (Evidence-Based Medicine and ACP Journal Club) have achieved consensus on some terms they use to describe both the good and bad effects of therapy. We will bring them to life with a synthesis of three randomized trials in diabetes which individually showed that several years of intensive insulin therapy reduced the proportion of patients with worsening retinopathy to 13% from 38%, raised the proportion of patients with satisfactory hemoglobin A1c levels to 60% from about 30%, and increased the proportion of patients with at least one episode of symptomatic hypoglycemia to 57% from 23%. Note that in each case the first number constitutes the “experimental event rate” (EER) and the second number the “control event rate” (CER). We will use the following terms and calculations to describe these effects of treatment:

e. g. When the experimental treatment reduces the probability of a bad outcome (Worsening diabetic retinopathy)

RRR (relative risk reduction). The proportional reduction in rates of bad outcomes between experimental and control participants in a trial, calculated as |EER – CER|/ CER, and accompanied by a 95% confidence interval (CI). In the case of worsening diabetic retinopathy, |EER – CER|/CER = |13% – 38%|/38% = 66%.

ARR (absolute risk reduction). The absolute arithmetic difference in rates of bad outcomes between experimental and control participants in a trial, calculated as |EER – CER|, and accompanied by a 95% CI. In this case, |EER – CER| =|13% – 38%| = 25%. (This is sometimes called the risk difference)

NNT (number needed to treat). The number of patients who need to be treated to achieve one additional favorable outcome, calculated as 1/ARR and accompanied by a 95% CI. In this case, 1/ARR = 1/25% = 4.

e.g. when the experimental treatment increases the probability of a good outcome (Satisfactory HbA1c levels) :

RBI (relative benefit increase). The proportional increase in rates of good outcomes between experimental and control patients in a trial, calculated as |EER – CER|/ CER, and accompanied by a 95% confidence interval (CI). In the case of satisfactory hemoglobin A1c levels, |EER – CER|/CER =|60% – 30%|/30% = 100%.

ABI (absolute benefit increase). The absolute arithmetic difference in rates of good outcomes between experimental and control patients in a trial, calculated as |EER – CER|, and accompanied by a 95% confidence interval (CI). In the case of satisfactory hemoglobin A1c levels, |EER – CER| = |60% – 30%| =30%

NNT (number needed to treat). The number of patients who need to be treated to achieve one additional good outcome, calculated as 1/ARR and accompanied by a 95% CI. In this case, 1/ARR = 1/30% = 3.

e.g. when the experimental treatment increases the probability of a bad outcome (episodes of hypoglycemia).

RRI (relative risk increase). The proportional increase in rates of bad outcomes between experimental and control patients in a trial, calculated as |EER – CER|/CER, and accompanied by a 95% confidence interval (CI). In the case of hypoglycemic episodes, |EER – CER|/CER = |57% – 23%|/23% = 148%. (RRI is also used in assessing the impact of “risk factors” for disease).

ARI (absolute risk increase). The absolute arithmetic difference in rates of bad outcomes between experimental and control patients in a trial, calculated as |EER – CER|, and accompanied by a 95% confidence interval (CI). In the case of hypoglycemic episodes, |EER – CER| = |57% – 23%| = 34%. (ARI is also used in assessing the impact of “risk factors” for disease).

NNH (number needed to harm). The number of patients who, if they received the experimental treatment, would result in one additional patient being harmed, compared with patients who received the control treatment, calculated as 1/ARI and accompanied by a 95% CI. In this case, 1/ARI = 1/34% = 3.

Treatment trials: Refers to trials which test new treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.

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V

Validity: The degree to which the results of a study are likely to be true, believable, and free of bias. This is entirely independent of the precision of the results and does not predict the results to your patients.

• The internal validity of a study refers to the integrity of the experimental design.

• The external validity of a study refers to the appropriateness by which its results can be applied to non-study patients or populations.

• Symmetry Principle: In a study, the principle of keeping all things between groups similar except for the treatment of interest. This means that the same instrument is used to measure each individual in each group, the observers know the same things about all individuals in all groups, randomization is used to obtain a similar allocation of individuals to each group, the groups are followed at the same time.

Verification bias (work-up bias): Occurs when patients with negative test results are not evaluated with the gold standard test.