Epidemiology and Biostatistics: An Introduction to Clinical Research

Preface
Contents
Part I: Epidemiology
	Chapter 1: Causal Relationships in€Health and€Disease
		1.1 Inferring Causation from€Epidemiologic Studies
		1.2 Factors Favoring an€Inference of€Causation
			1.2.1 Evidence Arising from€Randomized Studies
			1.2.2 Strength of€Association
			1.2.3 Temporal Relationship
			1.2.4 Exposure-Varying Association
			1.2.5 Biological Plausibility
		References
	Chapter 2: Basic Measures of€Disease Frequency
		2.1 Prevalence
			2.1.1 Definition of€Prevalence
			2.1.2 Applications of€Prevalence Data
			2.1.3 Limitation of€Prevalence Measures
		2.2 Incidence
			2.2.1 Definitions of€Incidence
			2.2.2 Applications of€Incidence Data
		2.3 Relationship Between Prevalence and€Incidence
		2.4 Stratification of€Disease Frequencies by Person, Place, and€Time
			2.4.1 Measures of€Disease Frequency Stratified by€Characteristics of€Person
			2.4.2 Measures of€Disease Frequency Stratified by€Characteristics of€Place
			2.4.3 Measures of€Disease Frequency Stratified by€Characteristics of€Time
		References
	Chapter 3: General Considerations in€Epidemiologic€Research
		3.1 Interventional Versus Observational Study Designs
			3.1.1 Interventional Studies Can Isolate the€Causal Impact of€Specific Treatments
			3.1.2 Interventional Studies Are Limited to€Evaluation of€Specific Treatments and€Diseases
			3.1.3 The Results of€Interventional Studies May Have Limited Applicability
		3.2 Study Population
			3.2.1 Source Population
			3.2.2 Exclusion Criteria
				3.2.2.1 Exclusion of€People Who Have Prevalent Disease
				3.2.2.2 Exclusion of€People Who Have Another Strong Risk Factor for€the€Disease
				3.2.2.3 Exclusion of€People Who Cannot Provide Reliable Study Data
				3.2.2.4 Exclusion of€People Who Cannot Complete the€Study Safely
			3.2.3 Where to€Find Information About the€Study Population in€a€Research Article
		3.3 Exposure and€Outcome
			3.3.1 Definition
			3.3.2 Measuring the€Study Data
			3.3.3 Where to€Find Information About the€Exposure and€Outcome in€a€Research Article
		3.4 Internal and€External Validity
		3.5 Summary of€Common Research Study Designs
		Reference
	Chapter 4: Case Reports and€Case Series
		References
	Chapter 5: Cross-Sectional Studies
		Reference
	Chapter 6: Cohort Studies
		6.1 Cohort Study Design
			6.1.1 Exclusion for€Prevalent Disease
			6.1.2 Creation of€the€Cohorts
			6.1.3 Determination of€the€Outcome
		6.2 Quality of€the€Exposure Measurements
			6.2.1 Are the€Measurements Accurate?
			6.2.2 Are the€Measurements Precise?
			6.2.3 Are the€Measurements Applied Impartially to€the€Study Population?
			6.2.4 Are the€Measurements Performed at the€Right Time?
			6.2.5 Retrospective Versus Prospective Data Collection
		6.3 Pharmacoepidemiology Studies
		6.4 Analysis of€Cohort Study Data
			6.4.1 Calculation of€Disease Incidences Among the€Cohorts
			6.4.2 Comparison of€Disease Incidences Among the€Cohorts
				6.4.2.1 Relative Risk
				6.4.2.2 Attributable Risk
				6.4.2.3 Population Attributable Risk
				6.4.2.4 Other Measures of€Risk
		6.5 Advantages of€Cohort Studies
			6.5.1 Ability to€Discern Temporal Relationships Between Exposure and€Disease
			6.5.2 Ability to€Study Multiple Outcomes
		6.6 Limitations of€Cohort Studies
			6.6.1 Confounding
			6.6.2 Inefficient Design for€Rare Diseases and€Those with€a€Long Latency Period
		References
	Chapter 7: Case-Control Studies
		7.1 Case-Control Study Design
		7.2 Selection of€Cases and€Controls
			7.2.1 Select Case Individuals Using a€Specific Definition of€the€Disease
			7.2.2 Select Case Individuals Close to€the€Time of€Initial Disease Development
			7.2.3 Select Control Individuals from€the€Same Underlying Population as€the€Cases
			7.2.4 Select Control Individuals Who Have the€Same Opportunity to€Be€Counted as€a€Case
			7.2.5 Nested Case-Control Studies
			7.2.6 Matching
			7.2.7 Number of€Controls
		7.3 Analysis of€Case Control Study Data
			7.3.1 Concept of€the€Odds Ratio
			7.3.2 Practical Calculation of€the€Odds Ratio
			7.3.3 Odds Ratios and€Relative Risk
		7.4 Advantages of€Case Control Studies
			7.4.1 Ideal for€Studying Rare Diseases and€Those with€a€Long Latency Period
			7.4.2 Efficiency
			7.4.3 Evaluation of€Multiple Exposures
		7.5 Limitations of€Case Control Studies
			7.5.1 Confounding
			7.5.2 Requires Ascertainment of€Previous Exposures in€Retrospect
			7.5.3 Inability to€Directly Determine the€Incidence of€Disease
		References
	Chapter 8: Randomized Trials
		8.1 Rationale for€Randomized Trials
		8.2 General Design of€Randomized Trials
		8.3 Trial Populations
			8.3.1 Definition of€the€Target Condition
			8.3.2 Exclusion of€People Suspected to€Have Difficulty Adhering to€the€Study Treatments
			8.3.3 Exclusion of€People Who Have Comorbid Conditions
			8.3.4 Exclusion of€People Who Are Already Receiving the€Study Treatment
			8.3.5 Exclusion for€Safety
			8.3.6 Broadly Inclusive Healthcare Settings Promote Applicability of€Trial Results
		8.4 Interventions and€Control Procedures
			8.4.1 Intervention
			8.4.2 Control Procedures
				8.4.2.1 Placebo
				8.4.2.2 Delayed Treatment
				8.4.2.3 Pre-existing Standard of€Care
				8.4.2.4 No Treatment
		8.5 Outcomes of€Trials
			8.5.1 Capture Important Benefits and€Harms of€the€Intervention
			8.5.2 Types of€Outcomes
			8.5.3 Mortality Outcomes
			8.5.4 Surrogate Outcomes
			8.5.5 Premature Termination of€Trials
		8.6 Procedures to€Promote Internal Validity of€Trials
			8.6.1 Randomization
			8.6.2 Blinding
			8.6.3 Concealment of€Treatment Allocation
			8.6.4 Efficacy and€Effectiveness
			8.6.5 Trial Reporting
		8.7 Specific Trial Designs
			8.7.1 Factorial Trials
			8.7.2 Crossover Trials
			8.7.3 Phases of€Drug Development
				8.7.3.1 Phase I€Studies
				8.7.3.2 Phase II Studies
				8.7.3.3 Phase III Studies
				8.7.3.4 Phase IV Studies
		8.8 Analysis of€Clinical Trial Data
			8.8.1 Measures of€Effect
				8.8.1.1 Relative Risk
				8.8.1.2 Attributable Risk
				8.8.1.3 Number Needed to€Treat or Harm
				8.8.1.4 Changes in€Quantitative Outcomes
			8.8.2 Intention-To-Treat Analysis
			8.8.3 Subgroup Analyses
		8.9 Limitations of€Randomized Trials
			8.9.1 Limited External Validity (Applicability) of€the€Trial Population
			8.9.2 Limited External Validity (Applicability) of€the€Trial Environment
			8.9.3 Narrow Study Question
			8.9.4 Randomized Design Accounts Only for€Confounding
			8.9.5 Negative Trials
		References
	Chapter 9: Misclassification
		9.1 Definition of€Miscalculation
		9.2 Non-differential Miscalculation
			9.2.1 Non-differential Misclassification of€the€Exposure
			9.2.2 Non-differential Misclassification of€the€Outcome
			9.2.3 Summary of€Non-differential Misclassification
		9.3 Differential Misclassification
			9.3.1 Differential Misclassification of€the€Exposure
			9.3.2 Differential Misclassification of€the€Outcome
			9.3.3 Summary of€Differential Misclassification
		9.4 Assessment of€Misclassification in€Research Articles
		Reference
	Chapter 10: Confounding
		10.1 Confounding Obscure Understanding of€Causal Relationships
		10.2 Evaluation of€a€Potential Confounding Characteristic
			10.2.1 Confounding Characteristic Associated with€the€Exposure
			10.2.2 Confounding Characteristic Associated with€the€Outcome
			10.2.3 Confounding Characteristic Not on€the€Causal Pathway of€Association
			10.2.4 Evaluation of€Confounding Characteristics in€Research Articles
		10.3 Residual Confounding
		10.4 Confounding by Indication
		10.5 Methods to€Control for€Confounding
			10.5.1 Method of€Restriction
			10.5.2 Method of€Stratification plus Adjustment
			10.5.3 Method of€Matching
			10.5.4 Method of€Regression
		10.6 Interpreting Results After Adjustment for€Confounding
		Reference
	Chapter 11: Effect Modification
		11.1 Concept of€Effect Modification
		11.2 Evaluation of€Effect Modification
			11.2.1 Criteria for€Assessing the€Presence of€Effect Modification
			11.2.2 Statistical Considerations for€Evaluating Effect Modification
				11.2.2.1 Confidence Intervals
				11.2.2.2 P-value for€Interaction
				11.2.2.3 Multiple Testing
		11.3 Effect Modification and€Confounding Are Distinct Concepts
		11.4 Effect Modification on€the€Relative and€Absolute Scales
		References
	Chapter 12: Screening and€Diagnosis
		12.1 General Principles of€Screening and€Diagnosis
		12.2 Utility of€Testing
		12.3 Qualities of€Diseases Appropriate for€Screening
			12.3.1 Early Recognition of€the€Disease Should Provide Meaningful Benefit
			12.3.2 Screening Tests Should Target Diseases that Have Potentially Serious Consequences
			12.3.3 Diseases Targeted by Screening Require a€Preclinical Phase
		12.4 Qualities of€Tests Appropriate for€Screening or Diagnosis
			12.4.1 Validity
				12.4.1.1 Sensitivity and€Specificity
				12.4.1.2 Positive and€Negative Predictive Values
				12.4.1.3 Likelihood Ratios
			12.4.2 Reliability
				12.4.2.1 Coefficient of€Variation
				12.4.2.2 Kappa
		12.5 Defining Cut Points for€Continuous Tests
		12.6 Types of€Biases in€Screening Studies
			12.6.1 Confounding (Referral Bias)
			12.6.2 Lead Time Bias
			12.6.3 Length Bias Sampling
		12.7 Levels of€Prevention
			12.7.1 Primary Prevention
			12.7.2 Secondary Prevention
			12.7.3 Tertiary Prevention
		12.8 Association Is Not Sufficient for€Prediction
		References
Part II: Biostatistics
	Chapter 13: Summary Measures in€Statistics
		13.1 Types of€Variables
		13.2 Univariate Statistics
			13.2.1 Histograms
			13.2.2 Measures of€Location and€Spread
			13.2.3 Quantiles
			13.2.4 Univariate Statistics for€Binary Data
		13.3 Bivariate Statistics
			13.3.1 Tabulation Across Categories
			13.3.2 Correlation
			13.3.3 Quantile-Continuous Variable Plots
	Chapter 14: Introduction to€Statistical Inference
		14.1 Definition of€a€Population and€a€Sample
		14.2 External Validity
		14.3 Statistical Inference
		14.4 Confidence Intervals
		14.5 Hypothesis Testing
			14.5.1 Construction of€Statistical Hypotheses
			14.5.2 P-Values
		Reference
	Chapter 15: Hypothesis Tests in€Practice
		15.1 Two-Sample Hypothesis Tests
			15.1.1 T-Test
			15.1.2 Chi-Square Test
			15.1.3 Hypothesis Tests for€Other Types of€Study Data
			15.1.4 Multiple Sample Hypothesis Tests
		15.2 An Imperfect System
			15.2.1 Type I€Error
			15.2.2 Type II Error
		15.3 Power
			15.3.1 Sample Size (N)
			15.3.2 Effect Size (μ)
			15.3.3 Variability (σ)
			15.3.4 Significance Level (α)
	Chapter 16: Linear Regression
		16.1 Describing the€Association Between Two Variables
		16.2 Univariate Linear Regression
			16.2.1 The Linear Regression Equation
			16.2.2 Residuals and€the€Sum of€Squares
			16.2.3 Interpreting Continuous Covariates from€a€Linear Regression Model
			16.2.4 Interpreting Binary Covariates from€Linear Regression Equations
		16.3 Diagnostics
			16.3.1 Absolute Versus Relative Fit
			16.3.2 Nonlinear Associations
			16.3.3 Influential Points
			16.3.4 Extrapolating the€Regression Equation Beyond the€Observed Data
		16.4 Multiple Linear Regression
			16.4.1 Definition of€the€Multiple Regression Model
			16.4.2 Interpreting Results from€the€Multiple Regression Model
				16.4.2.1 Obtaining Estimated Values for€a€Particular Set of€Data
				16.4.2.2 Obtaining Relative Differences in€the€Outcome Variable by a€Covariate
				16.4.2.3 Interpreting Multiple Regression Results in€Research Articles
				16.4.2.4 P-Values and€Confidence Intervals for€Regression Coefficients
		16.5 Confounding and€Effect Modification in€Multiple Regression Models
			16.5.1 Confounding
			16.5.2 Effect Modification
	Chapter 17: Log-Link and€Logistic Regression
		17.1 Regression for€Ratios
			17.1.1 Log-Link Regression
			17.1.2 Interpretation of€Log-Link Regression Models
			17.1.3 Hypothesis Testing for€Log-Link Regression Results
		17.2 Logistic Regression
			17.2.1 Definition and€Interpretation of€the€Logistic Regression Model
			17.2.2 Interpreting Logistic Regression Results from€Research Articles
	Chapter 18: Survival Analysis
		18.1 Motivation for€Survival Data
		18.2 Interpretation of€Survival Data
			18.2.1 Description of€the€Survivor Function
			18.2.2 Estimating Time-Specific and€Median Survival from€S(t)
			18.2.3 Statistical Testing of€Survival Data
		18.3 Estimation of€the€Survivor Function
			18.3.1 Definitions of€Outcomes and€Censoring
			18.3.2 Kaplan-Meier Estimation of€the€Survivor Function for€Uncensored Data
			18.3.3 Kaplan-Meier Estimation of€the€Survivor Function for€Censored Data
		18.4 Cox’s Proportional Hazards Model
		18.5 Interpreting Survival Data
			18.5.1 Interpreting Hazard Ratios
			18.5.2 Interpreting Survival Versus Hazard Ratio Data
		Reference
Glossary of€Terms
Index