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Book Details
Abstract
This practical guide speaks to two audiences: those who read and those who conduct research. Clinicians are medical detectives by training. For each patient, they assemble clinical clues to establish causes of signs and symptoms. The task involves both clinical acumen and knowledge of medical research. This book helps guide clinicians through this detective work, by enabling them to make sense of research and to review medical literature critically. It will also be invaluable to researchers who conduct clinical research, particularly randomized controlled trials.
Building on previously published, peer-reviewed articles from The Lancet, this handbook is essential for busy clinicians and active researchers interested in research methods.
- Written by leaders in the field of clinical research who have published extensively with authorship of hundreds of articles in medical journals.
- The authorship includes one of the three authors of the CONSORT guidelines for the reporting of randomized controlled trials.
- The book presents the essential concepts to a wide array of topics including randomized control trials, descriptive studies, cohort studies, case-control studies, bias, and screening tests.
- The book utilises a readable and humorous prose style, lightening what can be a difficult area for clinical readers.
- Derived from decades of teaching clinical research in seminar settings the book will empower clinicians to make sense of, and critically appraise, current medical research and will enable researchers to enrich the quality of their work.
The updated new edition includes six new chapters:
- Surrogate endpoints
- Limitations of observational epidemiology
- Participant recruitment
- Practicalities of double-blinding
- Randomized trials in the context of a prospective meta-analysis
- Reporting studies in medical journals: CONSORT
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front Cover | Cover | ||
| Inside Front Cover | ES2 | ||
| Essential Concepts in Clinical Research: Randomised Controlled Trials and Observational Epidemiology | iii | ||
| Copyright | iv | ||
| Contents | v | ||
| Foreword | vii | ||
| Preface | ix | ||
| Chapter 1: An Overview of Clinical Research: The Lay of the Land | 1 | ||
| A Taxonomy of Clinical Research | 2 | ||
| What Studies Can and Cannot Do | 4 | ||
| Descriptive study | 4 | ||
| Cross-sectional study: a snapshot in time | 4 | ||
| Cohort study: looking forward in time | 5 | ||
| Case-control study: thinking backwards | 5 | ||
| Variations on these themes | 6 | ||
| Nested Case-Control Studies | 6 | ||
| Case-Cohort Studies | 6 | ||
| Case-Crossover Studies | 7 | ||
| Case-Time-Control Studies | 7 | ||
| Nonrandomised trial: penultimate design? | 7 | ||
| Randomised controlled trial: gold standard | 7 | ||
| Measurement of Outcomes | 8 | ||
| Confusing fractions | 8 | ||
| Measures of association: risky business | 9 | ||
| Conclusion | 10 | ||
| References | 10 | ||
| Chapter 2: Descriptive Studies: What They Can and Cannot Do | 13 | ||
| The Descriptive Triad—Or Pentad? | 14 | ||
| Five ‘W’ questions | 14 | ||
| Who Has the Disease in Question? | 14 | ||
| What Is the Condition or Disease Being Studied? | 14 | ||
| Why Did the Condition or Disease Arise? | 14 | ||
| When Does the Condition Occur? | 14 | ||
| Where Does or Does Not the Disease or Condition Arise? | 15 | ||
| So What? | 15 | ||
| Types of Descriptive Studies | 15 | ||
| Case report | 16 | ||
| Case-series report | 16 | ||
| Cross-sectional (prevalence) studies | 16 | ||
| Surveillance | 17 | ||
| Ecological correlational studies | 18 | ||
| Uses of Descriptive Studies | 18 | ||
| Trend analysis | 18 | ||
| Planning | 19 | ||
| Clues about cause | 19 | ||
| Advantages and Disadvantages | 19 | ||
| Overstepping the Data | 20 | ||
| Conclusion | 20 | ||
| References | 21 | ||
| Chapter 3: Bias and Causal Associations in Observational Research | 25 | ||
| Internal and External Validity | 26 | ||
| Bias | 26 | ||
| Selection Bias | 27 | ||
| Are the groups similar in all important respects? | 27 | ||
| Information Bias | 28 | ||
| Has information been gathered in the same way? | 28 | ||
| Is the information bias random or in one direction? | 29 | ||
| Confounding | 29 | ||
| Is an extraneous factor blurring the effect? | 29 | ||
| Oral contraceptives and myocardial infarction (and smoking) | 29 | ||
| IUDs and infertility (and sexually transmitted disease) | 29 | ||
| Directed Acyclic Graphs | 30 | ||
| Control for Confounding | 30 | ||
| Restriction | 31 | ||
| Matching | 31 | ||
| Stratification | 31 | ||
| Multivariable analysis | 32 | ||
| Propensity scores | 32 | ||
| Sensitivity analysis | 33 | ||
| Instrumental variables | 33 | ||
| Chance | 33 | ||
| Judging Associations | 34 | ||
| Bogus, indirect, or real? | 34 | ||
| Conclusion | 35 | ||
| References | 35 | ||
| Chapter 4: Cohort Studies: Marching Towards Outcomes | 39 | ||
| Data Collection: Forwards and Backwards | 40 | ||
| Advantages of Cohort Studies | 41 | ||
| Disadvantages of Cohort Studies | 42 | ||
| What to Look for in Cohort Studies | 43 | ||
| Who is at risk? | 43 | ||
| Who is exposed? | 43 | ||
| Who is an appropriate control? | 43 | ||
| Have outcomes been assessed equally? | 44 | ||
| Tracking Participants Over Time | 44 | ||
| Have losses been minimised? | 44 | ||
| Reporting Cohort Studies | 44 | ||
| Variations on the Cohort Theme | 47 | ||
| Before-after studies | 47 | ||
| Nested case-control studies | 47 | ||
| Conclusion | 48 | ||
| References | 48 | ||
| Chapter 5: Case-Control Studies: Research in Reverse | 51 | ||
| Basic Case-Control Study Design | 52 | ||
| Advantages and Disadvantages | 53 | ||
| Selection of Case and Control Groups | 54 | ||
| Case group | 54 | ||
| Control group | 54 | ||
| Measurement of Exposure Information | 56 | ||
| Control for Confounding | 56 | ||
| Conclusion | 57 | ||
| References | 57 | ||
| Chapter 6: Compared to What? Finding Controls for Case-Control Studies | 59 | ||
| Aim of Controls | 60 | ||
| Where to Find Controls? | 62 | ||
| Controls From a Known Group | 62 | ||
| Random-digit dialling | 63 | ||
| Controls From an Unknown Group | 64 | ||
| Neighbourhood controls | 64 | ||
| Hospital controls | 65 | ||
| Friend or associate controls | 65 | ||
| Relative controls | 66 | ||
| How Many Control Groups? | 66 | ||
| How Many Controls Per Case? | 66 | ||
| What to Look for in Controls | 67 | ||
| Conclusion | 67 | ||
| References | 67 | ||
| Chapter 7: The Limitations of Observational Epidemiology | 71 | ||
| False Claims | 71 | ||
| Amateurs at Work | 72 | ||
| Administrative Databases | 74 | ||
| Weak Associations: Size Matters | 75 | ||
| Porous Peer Review | 76 | ||
| Fraud | 77 | ||
| Conclusion | 78 | ||
| References | 78 | ||
| Chapter 8: Uses and Abuses of Screening Tests | 83 | ||
| Ethical Implications | 85 | ||
| What are the potential harms of screening? | 85 | ||
| Criteria for Screening | 86 | ||
| If a test is available, should it be used? | 86 | ||
| Assessment of Test Effectiveness | 87 | ||
| Is the test valid? | 87 | ||
| Trade-Offs Between Sensitivity and Specificity | 89 | ||
| Where should the cut-off for abnormal be? | 89 | ||
| Prevalence and Predictive Values | 89 | ||
| Can test results be trusted? | 89 | ||
| Tests in Combination | 90 | ||
| Should a follow-up test be done? | 90 | ||
| Benefit or Bias? | 91 | ||
| Does a screening programme really improve health? | 91 | ||
| Lead-time bias | 91 | ||
| Length bias | 91 | ||
| Guidelines for test evaluations | 92 | ||
| Conclusion | 92 | ||
| References | 92 | ||
| Chapter 9: Refining Clinical Diagnosis With Likelihood Ratios | 95 | ||
| Likelihood Ratios for Tests With Two Outcomes | 96 | ||
| Why Bother? | 97 | ||
| Shift Happens | 98 | ||
| Choosing Cut Points | 98 | ||
| Fagan Nomogram | 99 | ||
| Two-Step Fagan Nomogram | 100 | ||
| Nomogram Alternatives | 100 | ||
| Size Matters | 100 | ||
| Some Large Likelihood Ratios | 102 | ||
| Likelihood Ratios for Tests With Multiple Outcomes | 102 | ||
| The Importance of Accurate Pretest Probability | 103 | ||
| Diagnostic Thresholds | 103 | ||
| Limitations of Likelihood Ratios | 104 | ||
| Conclusion | 105 | ||
| References | 105 | ||
| Chapter 10: Boosting Recruitment to Randomised Controlled Trials | 107 | ||
| Scope of the Problem | 108 | ||
| Consequences of Poor Recruitment | 108 | ||
| Trial abandonment | 108 | ||
| Power | 108 | ||
| External validity | 108 | ||
| Ethical Concerns | 109 | ||
| Great expectations? | 109 | ||
| Recruitment Terminology | 109 | ||
| Keeping tabs | 111 | ||
| Alternatives to the Traditional Randomised Trial | 111 | ||
| Single randomised consent | 111 | ||
| Double randomised consent | 111 | ||
| Partially randomised patient-preference trial | 112 | ||
| Cohort multiple randomised controlled trial | 113 | ||
| Special Populations: Reaching the Hard-to-Reach | 114 | ||
| Language and cultural barriers | 114 | ||
| What Works? | 114 | ||
| The Way Ahead | 116 | ||
| Conclusion | 116 | ||
| References | 117 | ||
| Chapter 11: Sample Size Calculations in Randomised Trials: Mandatory and Mystical | 121 | ||
| Components of Sample Size Calculations | 122 | ||
| Effect of Selecting α Error and Power | 123 | ||
| Estimation of Population Parameters | 125 | ||
| Low Power With Limited Available Participants | 126 | ||
| Sample Size Samba | 127 | ||
| Sample Size Modification | 127 | ||
| Futility of post hoc Power Calculations | 127 | ||
| What Should Readers Look for in Sample Size Calculations? | 128 | ||
| Conclusion | 128 | ||
| References | 129 | ||
| Chapter 12: Generation of Allocation Sequences in Randomised Trials: Chance, Not Choice | 131 | ||
| What to Look for With Sequence Generation | 133 | ||
| Nonrandom methods masquerading as random | 133 | ||
| Method of generation of an allocation sequence | 133 | ||
| Simple (Unrestricted) Randomisation | 134 | ||
| Restricted Randomisation | 135 | ||
| Blocking | 135 | ||
| Random allocation rule | 136 | ||
| Biased coin and urn randomisation | 136 | ||
| Replacement randomisation | 137 | ||
| Stratified Randomisation | 137 | ||
| Separation of Generation and Implementation | 138 | ||
| Conclusion | 138 | ||
| References | 139 | ||
| Chapter 13: Generation of Allocation Sequences in Non-Double-Blinded Randomised Trials: Guarding Against Guessing | 141 | ||
| Forcing Cosmetic Credibility | 142 | ||
| Unequal Group Sizes in Restricted Trials | 143 | ||
| Alternatives in Non-Double-Blinded Trials | 144 | ||
| Mixed Randomisation | 145 | ||
| Full Disclosure in the Protocol? | 149 | ||
| Conclusion | 149 | ||
| References | 149 | ||
| Chapter 14: Allocation Concealment in Randomised Trials: Defending Against Deciphering | 153 | ||
| Allocation Concealment | 154 | ||
| Importance of Allocation Concealment | 154 | ||
| Personal Accounts of Deciphering | 155 | ||
| What to Look for with Allocation Concealment | 156 | ||
| Baseline Comparisons | 159 | ||
| What to Look for with Baseline Characteristics | 160 | ||
| Conclusion | 160 | ||
| References | 160 | ||
| Chapter 15: Exclusions and Losses in Randomised Trials: Retention of Trial Participants | 163 | ||
| Exclusions Before Randomisation | 164 | ||
| What to look for in exclusions before randomisation | 164 | ||
| Exclusions After Randomisation | 164 | ||
| What to look for in exclusions after randomisation | 166 | ||
| Discovery of Participant Ineligibility | 166 | ||
| Post-Randomisation, Pretreatment Outcome | 166 | ||
| Protocol Deviations | 167 | ||
| Loss to Follow-Up and Retention | 168 | ||
| Conclusion | 170 | ||
| References | 170 | ||
| Chapter 16: Blinding in Randomised Trials: Hiding Who Got What | 173 | ||
| Potential Effects of Blinding | 174 | ||
| Lexicon of Blinding | 175 | ||
| Masking or Blinding? | 176 | ||
| Placebos and Blinding | 177 | ||
| Does Blinding Prevent Bias? | 178 | ||
| What to Look for in Descriptions of Blinding | 178 | ||
| Conclusion | 180 | ||
| References | 181 | ||
| Chapter 17: Implementation of Treatment Blinding in Randomised Trials | 183 | ||
| Introduction | 184 | ||
| Single Blinding: Participants, Investigators, or Assessors | 184 | ||
| Participants | 185 | ||
| Investigators | 185 | ||
| Assessors | 185 | ||
| Implementation issues: participants | 185 | ||
| Sham procedures | 186 | ||
| Implementation issues: assessors | 187 | ||
| Double Blinding: Participants, Investigators, and Assessors | 187 | ||
| Implementation issues: if no effective treatment exists | 188 | ||
| Implementation issues: if an accepted effective treatment exists | 188 | ||
| Implementation Issues: Challenging Double-Dummy Situations | 190 | ||
| The Importance of Placebos | 190 | ||
| Conclusion | 191 | ||
| References | 191 | ||
| Chapter 18: Surrogate Endpoints and Composite Outcomes: Shortcuts to Unknown Destinations | 193 | ||
| What is a Surrogate Endpoint? | 193 | ||
| Advantages of Surrogate Endpoints | 194 | ||
| Disadavantages of Surrogate Endpoints | 194 | ||
| Validation of Surrogate Endpoints | 196 | ||
| Terminological Tangles | 196 | ||
| Levels of Evidence | 198 | ||
| The Way Forward | 199 | ||
| Composite Outcomes | 200 | ||
| Advantages of Composite Outcomes | 200 | ||
| Disadvantages of Composite Outcomes | 201 | ||
| Composite Outcomes in Contemporary Research | 202 | ||
| Conclusion | 202 | ||
| References | 203 | ||
| Chapter 19: Multiplicity in Randomised Trials I: Endpoints and Treatments | 205 | ||
| The Issue | 206 | ||
| A Proposed Statistical Solution | 207 | ||
| Multiple Endpoints | 207 | ||
| Composite Endpoints | 208 | ||
| Multiple Treatments (Multiarm Trials) | 209 | ||
| The Issue of multiplicity adjustment in multiarm trials | 210 | ||
| The Role of Adjustments for Multiplicity | 211 | ||
| What Readers Should Look for | 212 | ||
| Conclusion | 212 | ||
| References | 213 | ||
| Chapter 20: Multiplicity in Randomised Trials II: Subgroup and Interim Analyses | 215 | ||
| Subgroup Analyses | 216 | ||
| What readers should look for with subgroup analyses | 218 | ||
| Interim Analyses | 219 | ||
| Early termination and biased estimates of treatment effects | 221 | ||
| Stopping for harm or futility | 222 | ||
| Other statistical stopping methods | 223 | ||
| What readers should look for with interim analyses | 223 | ||
| Conclusion | 223 | ||
| References | 224 | ||
| Chapter 21: Conducting a Randomised Trial as Part of a Prospective Meta-Analysis | 227 | ||
| Introduction | 228 | ||
| Multicentre Randomised Controlled Trial | 228 | ||
| Prospective Meta-Analysis | 228 | ||
| Some Disadvantages of Multicentre Randomised Trials | 229 | ||
| Some Potential Disadvantages of PMAs | 231 | ||
| Basic Steps in a PMA | 232 | ||
| Conclusion | 233 | ||
| References | 233 | ||
| Chapter 22: Reporting Studies in Medical Journals: CONSORT and Other Reporting Guidelines | 235 | ||
| Introduction | 236 | ||
| Reporting of Randomised Controlled Trials | 236 | ||
| Deficient Reporting | 236 | ||
| Selective Reporting | 237 | ||
| The CONSORT Statement: A Reporting Guideline for Randomised Trials | 238 | ||
| Reporting using the CONSORT statement | 241 | ||
| Other than a two-group, parallel randomised trial | 241 | ||
| Studies Other Than RCTs | 241 | ||
| Conclusion | 242 | ||
| References | 244 | ||
| Index | 247 | ||
| Inside Back Cover | ES3 |