Mayo Clinic Gastroenterology and Hepatology Board Review, Second Edition

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Mayo Clinic Gastroenterology and Hepatology Board Review Second Edition

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Mayo Clinic Gastroenterology and Hepatology Board Review Second Edition

Editor

Stephen C. Hauser, M.D. Co-Editors

Darrell S. Pardi, M.D. John J. Poterucha, M.D. MAYO CLINIC SCIENTIFIC PRESS TAYLOR & FRANCIS GROUP

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ISBN 0849370183 The triple-shield Mayo logo and the words MAYO, MAYO CLINIC, and MAYO CLINIC SCIENTIFIC PRESS are marks of Mayo Foundation for Medical Education and Research. ©2006 by Mayo Foundation for Medical Education and Research. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means—electronic, mechanical, photocopying, recording, or otherwise—without the prior written consent of the copyright holder, except for brief quotations embodied in critical articles and reviews. Inquiries should be addressed to Scientific Publications, Plummer 10, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. For order inquiries, contact Taylor & Francis Group, 6000 Broken Sound Parkway NW, Suite #300, Boca Raton, FL 33487. www.taylorandfrancis.com Catalog record is available from the Library of Congress. Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, express or implied, with respect to the contents of the publication. This book should not be relied on apart from the advice of a qualified health care provider. The authors, editors, and publisher have exerted efforts to ensure that drug selection and dosage set forth in this text are in accordance with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new or infrequently employed drug. Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings. It is the responsibility of the health care providers to ascertain the FDA status of each drug or device planned for use in their clinical practice.

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DEDICATION

To the many persons who have taught, encouraged, and inspired us.

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PREFACE

The specialty of gastroenterology and hepatology encompasses a vast anatomical assortment of organs with diverse structure and function, potentially afflicted by a multiplicity of disease processes. To assist physicians in training preparing for the gastroenterology board examination as well as a growing number of gastroenterologists awaiting recertification, we designed the Mayo Clinic Gastroenterology and Hepatology Board Review course and produced the second edition of this book. The book is not intended to replace the many more encyclopedic textbooks of gastroenterology, hepatology, pathology, endoscopy, nutrition, and radiology now available, nor is it intended to serve as an update to physicians looking for the newest advances in the science and art of gastroenterology and hepatology. Instead, this book provides a core of essential knowledge in gastroenterology, hepatology, and integral related areas of pathology, endoscopy, nutrition, and radiology. Clinical knowledge related to diagnostic and therapeutic approaches to patient management is emphasized. Case-based presentations and multiple board-examination–type, single-best–answer questions with annotated answers are featured. As such, this text also is intended to be used by medical students and residents for their clerkships on internal medicine and gastroenterology rotations and by gastroenterology fellows in training. Physicians in practice should find this book to be a practical review to consolidate their knowledge in gastroenterology and hepatology. The book is organized along subspecialty topics, including esophageal disorders, gastrointestinal disorders, small-bowel disease and nutrition, miscellaneous disorders, colonic disorders, liver disease, and pancreaticobiliary disease. Many color and black-and-white figures are included in the text. Each subspecialty section concludes with questions and answers (materials in the questions and answers are not included in the index). The faculty responsible for this book are all Mayo Clinic gastroenterologists and hepatologists who spend the majority of their time caring for patients and have a commitment to teaching medical students, house officers, fellows, nurses, and physicians. The faculty’s particular interests in subspecialty areas of clinical gastroenterology and hepatology provide broad expertise to the book’s content. We thank the staffs of the Section of Scientific Publications, Media Support Services, and Mayo School of Continuing Medical Education at Mayo Clinic for their contributions. The support of the publisher, Taylor & Francis Group, also is greatly appreciated. We give special thanks to our secretaries and to Keith Lindor, M.D., for his ongoing enthusiasm and support for our faculty and teaching mission.

Stephen C. Hauser, M.D.

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LIST OF CONTRIBUTORS

Jeffrey A. Alexander, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Assistant Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Gregory J. Gores, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Professor of Medicine and of Physiology, Mayo Clinic College of Medicine; Rochester, Minnesota

Todd H. Baron, Sr., M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

John B. Gross, Jr., M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Associate Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Adil E. Bharucha, M.B.B.S., M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Associate Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Gavin C. Harewood, M.D. Senior Associate Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Associate Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Lisa A. Boardman, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Assistant Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Stephen C. Hauser, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Assistant Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

David J. Brandhagen, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Assistant Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

J. Eileen Hay, M.B.,Ch.B. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Michael Camilleri, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Atherton and Winifred W. Bean Professor, and Professor of Medicine and of Physiology, Mayo Clinic College of Medicine; Rochester, Minnesota

Patrick S. Kamath, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Suresh T. Chari, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Associate Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Darlene G. Kelly, M.D., Ph.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Associate Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Michael R. Charlton, M.B.B.S. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Associate Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Mark V. Larson, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Assistant Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Albert J. Czaja, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Paul J. Limburg, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Assistant Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota ix

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Keith D. Lindor, M.D. Chair, Division of Gastroenterology and Hepatology, Mayo Clinic; Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Yvonne Romero, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Assistant Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

G. Richard Locke III, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Associate Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

William J. Sandborn, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Edward V. Loftus, Jr., M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Associate Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

John A. Schaffner, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Associate Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Thomas F. Mangan, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Assistant Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Vijay H. Shah, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Associate Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Joseph A. Murray, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Nicholas J. Talley, M.D., Ph.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Darrell S. Pardi, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Assistant Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

William J. Tremaine, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Randall K. Pearson, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Assistant Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Santhi S. Vege, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Bret T. Petersen, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Assistant Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Thomas R. Viggiano, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

John J. Poterucha, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Associate Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

Kenneth K. Wang, M.D. Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic; Associate Professor of Medicine, Mayo Clinic College of Medicine; Rochester, Minnesota

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TABLE OF CONTENTS

1. Study Design and Statistics for the Boards Gavin C. Harewood, M.D. . . . . . . . . . . . . . . . . . . . . . . 1

Esophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2. Gastroesophageal Reflux Disease Joseph A. Murray, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3. Barrett’s Esophagus Yvonne Romero, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4. Esophageal Cancer Kenneth K. Wang, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 5. Normal and Abnormal Esophageal Motility Nicholas J. Talley, M.D., Ph.D. . . . . . . . . . . . . . . . . . 35 Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 6. Peptic Ulcer Disease Thomas F. Mangan, M.D. . . . . . . . . . 7. Gastritis Thomas F. Mangan, M.D. . . . . . . . . . . . . . . . . 8. Gastric Neoplasms Mark V. Larson, M.D. . . . . . . . . . . . . 9. Gastrointestinal Motility Disorders Michael Camilleri, M.D. Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Small Bowel and Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 10. Malabsorption John A. Schaffner, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 11. Small-Bowel Disease and Bacterial Overgrowth John A. Schaffner, M.D. . . . . . . . . . . . . . . . . . . . 99 12. Vitamins and Minerals Stephen C. Hauser, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 13. Nutrition Disorders and Parenteral and Enteral Nutrition Darlene G. Kelly, M.D., Ph.D. . . . . . . . .111 Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

Miscellaneous Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 14. Gastrointestinal Manifestations of Human Immunodeficiency Virus Infection Stephen C. Hauser, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 15. Gastrointestinal Infections and Diverticulitis Darrell S. Pardi, M.D. . . . . . . . . . . . . . . . . . . . . . 131 16. Gastrointestinal Endocrine Tumors Thomas R. Viggiano, M.D. . . . . . . . . . . . . . . . . . . . . . . . . 141 17. Nonvariceal Gastrointestinal Tract Bleeding Jeffrey A. Alexander, M.D. . . . . . . . . . . . . . . . . . . . 151 18. Vascular Disorders of the Gastrointestinal Tract Stephen C. Hauser, M.D. . . . . . . . . . . . . . . . . . 159 19. Gastrointestinal Manifestations of Systemic Disease Stephen C. Hauser, M.D. . . . . . . . . . . . . . . .167 Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

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Colon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 20. Inflammatory Bowel Disease: Clinical Aspects William J. Tremaine, M.D. . . . . . . . . . . . . . . . . . 185 21. Inflammatory Bowel Disease: Therapy William J. Sandborn, M.D. . . . . . . . . . . . . . . . . . . . . . . 191 22. Inflammatory Bowel Disease: Extraintestinal Manifestations and Cancer Edward V. Loftus, Jr., M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 23. Microscopic Colitis and Clostridium difficile-Associated Disease Darrell S. Pardi, M.D. . . . . . . . . . 211 24. Colorectal Neoplasms Lisa A. Boardman, M.D.; Paul J. Limburg, M.D. . . . . . . . . . . . . . . . . . . . . 219 25. Irritable Bowel Syndrome G. Richard Locke III, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 26. Constipation and Disorders of Pelvic Floor Function Adil E. Bharucha, M.D. . . . . . . . . . . . . . . . 233 Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

Liver I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 27. Approach to the Patient With Abnormal Liver Tests and Fulminant Liver Failure John J. Poterucha, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 28. Chronic Viral Hepatitis John J. Poterucha, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 29. Liver Mass Lesions Gregory J. Gores, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 30. Alcoholic Liver Disease Vijay H. Shah, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 31. Vascular Diseases of the Liver Patrick S. Kamath, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 32. Portal Hypertension-Related Bleeding Patrick S. Kamath, M.D. . . . . . . . . . . . . . . . . . . . . . . . . 307 33. Ascites, Hepatorenal Syndrome, and Encephalopathy Patrick S. Kamath, M.D. . . . . . . . . . . . . . . 313

Liver II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 34. Metabolic Liver Disease David J. Brandhagen, M.D.; John B. Gross, Jr., M.D. . . . . . . . . . . . . . . . 321 35. Cholestatic Liver Disease: Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, and Drug-Induced Cholestasis Keith D. Lindor, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333 36. Autoimmune Hepatitis Albert J. Czaja, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337 37. Nonalcoholic Fatty Liver Disease Albert J. Czaja, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 38. Liver Disease and Pregnancy J. Eileen Hay, M.B.,Ch.B. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 39. Liver Manifestations of Human Immunodeficiency Virus Infection J. Eileen Hay, M.B.,Ch.B. . . . . . 367 40. Liver Transplantation Michael R. Charlton, M.B.B.S. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377 Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

Pancreas and Biliary Tree . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 41. Acute Pancreatitis Todd H. Baron, Sr., M.D.; Santhi S. Vege, M.D. . . . . . . . . . . . . . . . . . . . . . . 405 42. Chronic Pancreatitis Suresh T. Chari, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 43. Pancreatic Neoplasms Randall K. Pearson, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419 44. Gallstones Bret T. Petersen, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .427 Questions and Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447 xii

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CHAPTER 1

Study Design and Statistics for the Boards Gavin C. Harewood, M.D.

Placebo-control: untreated patients receive a nonactive treatment (placebo) indistinguishable from the active treatment Randomization: each patient has an equal likelihood of receiving active treatment or placebo Double blinding: neither patient nor investigator is aware of whether active treatment or placebo is given to each study subject Concealed allocation: investigator enrolling patients is unaware of treatment arm (active treatment vs. placebo) to which each recruited subject is assigned

TYPES OF STUDY DESIGN Most clinical studies fall into one of two categories: case-control study or cohort study.

Case-Control Study Two groups of patients are identified, one with the disease being studied (cases) and one without the disease (controls) (Fig. 1). Both groups are analyzed to determine whether they have a specific risk factor or exposure. For example, patients with gastroesophageal reflux disease (GERD) (cases) and patients without GERD (controls) could be analyzed to determine whether they are cigarette smokers (exposure). The findings would allow comparison of the proportion of smokers among patients with GERD and those without GERD. Case-control studies are generally retrospective.

BASIC STATISTICS The 2×2 Table The 2×2 table is the fundamental building block used to solve many statistical questions in the board examination. It requires allocation of patients in one of four boxes (Fig. 2). By convention,

Cohort Study Two groups of patients are identified, one with exposure (cases) and one without exposure (controls) (Fig. 1). Both groups are followed prospectively to determine whether a specific disease develops. For example, patients with asbestos exposure (cases) and those without asbestos exposure (controls) could be followed prospectively to determine whether pancreatic cancer develops (outcome). The findings would allow comparison of the proportion of those exposed to asbestos and those not exposed in whom pancreatic cancer develops. Cohort studies are prospective. In treatment cohort studies (i.e., clinical trials comparing disease outcomes in patients receiving a new medication [cases] vs. untreated patients [controls]), desirable features of the study design include the following:

Time zero

With disease (case)

? exposure

Without disease (control)

Cohort study

With exposure

Casecontrol study

? disease

Without exposure

Fig. 1. Comparison of case-control study and cohort study.

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Study Design and Statistics for the Boards

the two columns are used to designate patients with and without disease, and the two rows represent patients with positive and negative test results. This table allows all patients to be assigned as 1) true positive (TP), positive test result in the setting of disease; 2) true negative (TN), negative test result in the absence of disease; 3) false positive (FP), positive test result in the absence of disease; or 4) false negative (FN), negative test result in the setting of disease.

Definitions to Remember Some epidemiology and statistical definitions that may be helpful for the board examination are the following: Incidence: proportion of a population initially free of disease in whom disease subsequently develops over time Prevalence: proportion of a population with disease at a single point in time Sensitivity: proportion of patients with disease who have a positive test result, true positive/(true positive + false negative) Specificity: proportion of patients without disease who have a negative test result, true negative/(true negative + false positive) Positive predictive value (PPV): proportion of patients with a positive test result who have disease, true positive/ (true positive + false positive) Negative predictive value (NPV): proportion of patients with a negative test result without disease, true negative/ (true negative + false negative)

PPV = 40/(40+95) = 29.6% NPV = 855/(10+855) = 98.8%

Question 2 If the new test for colon cancer is now applied to a higher-risk population with a 50% risk of colon cancer, how do the PPV and NPV change? Again, a 2×2 table is constructed. However, in this case the prevalence of colon cancer has increased to 50%; that is, in our population of 1,000 people, 500 have colon cancer and 500 are cancer-free (Fig. 4). Steps 1 through 4 are applied again, yielding the following: PPV = 400/(400 + 50) = 88.9% NPV = 450/(100 + 450) = 81.8% • As prevalence of disease changes, sensitivity and specificity remain constant. However, PPV and NPV change. As prevalence increases, PPV increases and NPV decreases; as prevalence decreases, PPV decreases and NPV increases.

Other Statistical Terms Type I (alpha) error: a difference between treatment and placebo is erroneously reported when no difference actually exists. For most studies, the alpha level is set a priori at 0.05; that is, for a difference to be statistically significant, a 1 in 20 chance, no more, exists that this difference occurred by chance alone (P