1991
`
`Volume 115
`
`Number 10
`
`Published Twice Monthly by the American College of Physicians
`
`Letters 830
`
`Myonecrosis and Myofibrosis in
`Sickle Cell Anemia
`
`Mu scle Infarction in Sickle Cell
`Anemia
`Oral Quinolone Treatment for
`Osteomyelitis
`
`Qui nolone Prophylaxis during
`Neutropenia
`
`Diagnosis of Pulmonary
`Embolism
`
`The Cardiac Conduction System
`in Unexplained Sudden Death
`
`The Literature
`of Medicine 835
`
`For complete contents, see pages
`I-3 and 1-5
`
`All\lEAS 115(10)753-836 (1991)
`US ISSN 0003-4819
`
`,.
`.....
`;
`,-
`:::
`;T;
`::: C
`•;_
`r-\
`:;.: 1..i(cid:173)
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`i7j
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`L;':
`__ ,
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`._.
`
`ARTICLES
`Increasing the Dietary Potassium Intake Reduces the Need
`for Antihypertensive Medication
`
`753 Siani, Strazzullo,
`Giacco , and others
`
`Treatment for Cerebral Toxoplasmosis Protects against
`Pneumocystis carinii Pneumonia in Patients with AIDS
`
`760 Heald, Flepp, Chave,
`Malinverni , and others
`
`Heterosexual Co-transmission of Hepatitis C Virus (HCV)
`and Human Immunodeficiency Virus (HIV)
`
`764 Eyster, Alter, Aledort,
`Quan, and others
`
`Reversible Renal Failure Associated with Angiotensin(cid:173)
`Converting Enzyme Inhibitors in Polycystic Kidney Disease
`
`769 Chapman , Gabow ,
`Schrier -
`
`Screening for Alcohol Abuse Using CAGE Scores and
`Likelihood Ratios
`
`Thoracoscopic Talc Poudrage Pleurodesis for Chronic
`Recurrent Pleural Effusions
`
`BRIEF REPORTS
`Combined Endoscopic Sphincterotomy and Laparoscopic
`Cholecystectomy in Patients with Choledocholithiasis
`and Cholecystolithiasis
`
`Recovery of Adrenal Function after Failure Resulting
`from Traumatic Bilateral Adrenal Hemorrhages
`
`REVIEWS
`Risk for Serious Gastrointestinal Complications Related
`to Use of Nonsteroidal Anti-inflammatory Drugs:
`A Meta-analysis
`
`774 Buchsbaum, Buchanan,
`Centor, and others
`
`778 Aelony, King , Boutin
`
`783 Aliperti,
`Edmundowicz, Soper,
`Ashley
`
`785 Feuerstein, Streeten
`
`787 Gabriel, Jaakkimainen,
`Bombardier
`
`Cocaine-induced Myocardial Infarction in Patients with
`Normal Coronary Arteries
`
`797 Minor, Scott, Brown,
`Winniford
`
`MEDICINE AND PUBLIC ISSUES
`Cost Effectiveness of Colorectal Cancer Screening in
`the Elderly
`
`PERSPECTIVE
`How Should Results from Completed Studies Influence
`Ongoing Clinical Trials?
`
`ON BEING A DOCTOR
`A Job Well Done?
`EDITORIALS
`Treatment of Rheumatoid Arthritis: Challenges to
`Traditional Paradigms
`
`807 Wagner, Herdman ,
`Wadhwa
`
`818 Laupacis, Connolly,
`Gent, and others
`
`823 Curtis
`
`825 Pincus, Wolfe
`
`Human Immunodeficiency Virus Infection in Women
`
`827 Spence, Reboli
`
`Page 1 of 15
`
`Patent Owner Ex. 2012
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`15 November 1991
`
`Annals of Internal Medicine Table of Contents
`
`Volume 115 Number 10 AIMEAS 115(10)753-836 (1991) US ISSN 0003-4819
`
`Articles
`
`Increasing the Dietary Potassium Intake Reduces
`the Need for Antihypertensive Medication
`A. Siani, P. Strazzullo, A. Giacco, D. Pacioni,
`E. Celentano, and M. Mancini
`
`753
`
`Increasing the dietary potassium intake from natural foods is a
`feasible and effective measure to reduce antihypertensive drug
`treatment. By the end of the study, blood pressure could be
`controlled using Jess than 50% of the initial therapy in 81 % of
`the patients who increased their potassium intake compared
`with 29% of the controls.
`
`Treatment for Cerebral Toxoplasmosis Protects
`against Pneumocystis carinii Pneumonia in
`Patients with AIDS
`A. Heald, M. Flepp, J-P Chave, R. Malinverni,
`S. Ruttimann, V. Gabriel, C. Renold, A. Sugar,
`B. Hirsche/, and the Swiss HIV Cohort Study
`
`760
`
`Patients with cerebral toxoplasmosis have a low risk for
`subsequently developing Pneumocystis carinii pneumonia. This
`decreased risk is probably the result of chronic suppressive
`treatment with pyrimethamine and sulfonamides.
`
`Heterosexual Co-transmission of Hepatitis C
`Virus (HCV) and Human Immunodeficiency
`Virus (HIV)
`M.E. Eyster, H.J. Alter, L.M. Aledort, S. Quan,
`A. Hatzakis, and J.J. Goedert
`
`764
`
`The higher prevalence of HCV in female sexual partners of
`men with' hemophilia than in blood donor and other low-risk
`groups suggests that there is a low level of sexual
`transmission. Male to female sexual transmission of HCV
`is less efficient than that of HIV. The frequency of HCV
`transmission to female sexual partners is five times higher
`when HIV is also transmitted to the partner, suggesting that
`HIV may be a cofactor for the sexual transmission of HCV.
`
`Reversible Renal Failure Associated with
`Angiotensin-Converting Enzyme Inhibitors in
`Polycystic Kidney Disease
`A .B. Chapman , P.A. Gabow, and R. W. Schrier
`
`769
`
`The authors describe eight episodes of reversible acute renal
`deterioration in five patients with autosomal-dominant
`polycystic kidney disease, massive renal involvement, and
`chronic renal insufficiency. In all cases, angiotensin-converting
`enzyme inhibitors either predisposed the patient to or
`precipitated the acute event.
`
`Screening for Alcohol Abuse Using CAGE Scores 774
`and Likelihood Ratios
`D.G. Buchsbaum, R .G. Buchanan, R .M . Centor,
`S.H. Schnoll, and M.J. Lawton
`
`Clinicians can improve their ability to estimate a patient's risk
`for an alcohol abuse or dependence disorder using likelihood
`ratios for CAGE scores (an acronym for the four questions
`asked in the CAGE test ; Cut down, Annoyed, Guilty,
`Eye-opener).
`
`Thoracoscopic Talc Poudrage Pleurodesis for
`Chronic Recurrent Pleural Effusions
`Y. Aelony, R. King , and C. Boutin
`
`778
`
`Thoracoscopic talc poudrage is an effective pleural sclerosing
`technique and is relatively painless.
`
`Brief Reports
`
`Combined Endoscopic Sphincterotomy and
`Laparoscopic Cholecystectomy in Patients with
`Choledocholithiasis and Cholecystolithiasis
`G. Aliperti, S .A. Edmundowicz, N.J. Soper,
`and S. W. Ashley
`
`783
`
`Endoscopic sphincterotomy combined with laparoscopic
`cholecystectomy is effective in the treatment of patients with
`simultaneous gallbladder and bile duct stones. Length of
`hospital stay and degree of postoperative disability were
`significantly reduced among our patients compared with those
`having standard cholecystectomy and bile duct exploration.
`
`Recovery of Adrenal Function after Failure
`Resulting from Traumatic Bilateral Adrenal
`Hemorrhages
`B. Feuerstein and D.H.P. Streeten
`
`785
`
`A 32-year-old psychotic man had severe pelvic and femoral
`injuries and hypotension associated with adrenal insufficiency
`caused by bilateral adrenal hemorrhages . Adrenocorticotropic
`hormone administration was found to cause normal increases
`in plasma cortisol concentrations at 10 and 30 months after the
`initial trauma.
`
`(Continued on page I-5)
`
`Postmaster: Send changes of address to Circulation Manager, Annals of Internal Medicine, Independence Mall West, Sixth Street at Race,
`Philadelphia, PA 19106-1572.
`
`Annals of Internal Medicine is published twice monthly and copyrighted I!:> 1991 by the American College of Physicians, Independence Mall West,
`Sixth Street at Race, Philadelphia, PA 19106-1572, USA. Basic USA subscription price is $75.00 per year. Second-class postage paid at Philadelphia,
`Pennsylvania, and at additional mailing offices. Canada Post International Publications Mail Sales Agreement #546186. GST ID#l28512159.
`
`15 November 1991 • Annals of Internal Medicine • Volume 115 • Number 10
`
`1-3
`
`Page 2 of 15
`
`Patent Owner Ex. 2012
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`(Table of Contents, continued)
`
`Reviews
`
`Editorials
`
`Risk for Serious Gastrointestinal Complications
`Related to Use of Nonsteroidal Anti-inflammatory
`Drugs. A Meta-analysis
`S.E. Gabriel, L. Jaakkimainen, and
`C. Bombardier
`
`787
`
`Treatment of Rheumatoid Arthritis : Challenges to
`Traditional Paradigms
`T. Pincus and F. Wolfe
`
`825
`
`Users of nonsteroidal anti-inflammatory drugs (NSAIDs) are at
`approximately three times greater relative risk for developing
`serious adverse gastrointestinal events than are nonusers.
`Additional risk factors include age greater than 60 years ,
`previous history of gastrointestinal events, and concomitant
`corticosteroid use. These data represent summary statistics
`from 16 studies and cannot be considered generalizable to all
`NSAID users.
`
`Cocaine-induced Myocardial Infarction in Patients
`with Normal Coronary Arteries
`R.L. Minor, Jr, B.D. Scott, D.D. Brown, and
`M.D. Winniford
`
`797
`
`Cocaine-induced myocardial infarction in patients with normal
`coronary arteries appears to involve adrenergically mediated
`increases in myocardial oxygen consumption, vasoconstriction
`of large epicardial arteries or small coronary resistance
`vessels, and coronary thrombosis.
`
`Based on a long-term observational study rather than a
`randomized controlled trial, Epstein and colleagues, in the
`15 March 1991 issue of Annals, challenged the current views
`about rheumatoid arthritis therapy . One of their conclusions
`was that gold is of no value. Possible benefits of gold may
`have been obscured by methodologic problems ; these include
`the timing of data acquisition, use of other second-line
`therapies in control patients not receiving gold , and analyses
`of patients as a group rather than as individuals.
`
`Human Immunodeficiency Virus Infection
`in Women
`M.R. Spence and A .C. Reboli
`
`827
`
`Large multidisciplinary , longitudinal studies of women infected
`with human immunodeficiency virus must be done because
`women now represent a major group of patients wit~ ~IDS.
`
`Medicine and Public Issues
`
`Letters
`
`Cost Effectiveness of Colorectal Cancer
`Screening in the Elderly
`J.L. Wagner, R.C. Herdman, and S. Wadhwa
`
`807
`
`Although colorectal cancer screening is costly, its potential
`medical benefits make it a reasonably cost-effective preventive
`intervention for the elderly . A program of annual fecal occult
`blood testing (FOBT) in the elderly would detect at least 17%
`of the expected cases of cancer and could cost $35 000 per
`year of life saved.
`
`Myonecrosis and Myofibrosis in Sickle Cell
`Anemia
`J. Mattana and P .C. Singha/; D. Grob and
`T.D. Schiano; R.B. Layzer; J . Valeriano-Marcet
`and L.D. Kerr
`
`Muscle Infarction in Sickle Cell Anemia
`G.J. Dennis and R.M. Keating
`
`Oral Quinolone Treatment for Osteomyelitis
`H.M. Blumberg; L.0. Gentry
`
`Quinolone Prophylaxis during Neutropenia
`P.H. Chandrasekar; A. Del Favero,
`F. Menichetti, and P. Martino
`
`818
`
`Diagnosising Pulmonary Embolism
`B.E. Ojserkis; M .A. Kelley, J.L. Carson,
`H .l . Palevsky , and J.S . Schwartz
`
`The Cardiac Conduction System in Unexplained
`Sudden Death
`M . Lev and S. Bharati
`
`The Literature of Medicine
`
`Reviews, Notes, and Listings
`
`Perspective
`
`How Should Results from Completed Studies
`Influence Ongoing Clinical Trials? The CAFA
`Study Experience
`A. Laupacis, S.J. Connolly, M. Gent,
`R.S. Roberts, J. Cairns, and C. Joyner,
`for the CAF A Study Group
`
`Seven randomized studies during the past 5 years have
`evaluated or are evaluating the efficacy of warfarin or aspirin
`or both in decreasing the risk of embolic events in patients
`with nonrheumatic atrial fibrillation. By March 1990, two of
`the studies had been published. The Steering Committee of the
`Canadian Atrial Fibrillation Anticoagulation (CAFA) study
`decided that the evidence of benefit with warfarin, from the
`two published studies, was sufficiently compelling to stop
`recruitment into CAFA without any preliminary examination of
`the CAF A data.
`
`On Being a Doctor
`
`A Job Well Done?
`J.R. Curtis
`
`823
`
`830
`
`831
`
`832
`
`833
`
`833
`
`834
`
`835
`
`This story chronicles a resident's growth through interactions
`with a person with AIDS . It concentrates on the resident's
`gradual realization that a physician's job may be well done
`despite a patient's death.
`
`Classified Services
`
`CME Bulletin Board
`
`Index to Advertisers
`
`Medical Notices
`Abstracts of Articles
`Information for Authors
`Copyright Form
`Business and Subscription Information
`
`Begins on 1-24
`Begins on 1-27
`1-9
`
`1-15
`1-104
`See Advertising Pages
`1-132
`1-136
`
`15 November 1991 • Annals of Internal Medicine • Volume 115 • Number 10
`
`1-5
`
`Page 3 of 15
`
`Patent Owner Ex. 2012
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`15 November 1991 Volume 115 Number 10 AIMEAS 115(10)753-836(1991) US ISSN 0003-4819
`
`Annals of Internal Medicine
`
`Published Twice Monthly by the American College of Physicians
`
`Editorial Policy
`
`Annals of Internal Medicine publishes original articles, reviews, clinical
`conferences, editorials, book reviews, letters, and other information relevant
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`Annals of Internal Medicine accepts no responsibility for statements made
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`Annals of Internal Medicine (ISSN 0003-4819) is issued twice monthly by
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`The Editors
`Annals of Internal Medicine
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`
`15 November 1991 • Annals of Internal Medicine • Volume 115 • Number 10
`
`1-7
`
`Publication Policy Committee,
`American College of Physicians
`John H. Holbrook, MD, Chairman
`Elizabeth Barrett-Connor, MD
`John F. Burnum, MD
`Linda Hawes Clever, MD
`Kenneth M. Ludmerer, MD
`John J. Mazza, MD
`Robert H . Moser, MD
`Eleanor Z. Wallace, MD
`
`Editors
`Editors, Robert H . Fletcher, MD, and
`Suzanne W. Fletcher, MD
`Editors Emeriti, J. Russell Elkinton, MD, and
`Edward J. Huth, MD
`Associate Editors, Elias Abrutyn, MD,
`John L. Abruzzo, MD, E. Victor Adlin, MD,
`Martin Black, MD, Leonard E. Braitman, PhD,
`Paul E. Epstein, MD,
`Steven N. Goodman, MD, PhD, MHS,
`Daniel G. Haller, MD, Warren Laskey, MD
`Book Review Editor, Edward J . Huth, MD
`Executive Editor, Kathleen Case
`Managing Editor, Pamela Fried
`
`Editorial Board
`James 0. Armitage, MD, Omaha
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`Laurence H. Beck, MD, Dan ville
`John D. Cantwell, MD, Atlanta
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`Michael A. Geheb, MD, Detroit
`Norlin M. Hadler, MD, Chapel Hill
`Thomas S. lnui, MD, Seattle
`Mark A. Kelley , MD, Philadelphia
`Shirley A.P. Levine, MD, San Antonio
`Diane E . Meier, MD, New York
`Richard K. Root , MD, Seattle
`Arthur H. Rubenstein , MD, Chicago
`Laurence Z. Rubenstein, MD, Sepulveda
`Jeremy N. Ruskin, MD, Boston
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`
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`Information for Authors (Short Form*)
`
`DISTRIBUTION
`Annals has over 93 000 subscribers. about 86 000 in the United States and
`Canada and 7000 in other countries.
`In the United States, abou t 42% of subscribers are physicians in general
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`cine, and 10% are physicians in other fields: about 16% are residents or
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`schools.
`
`CONTENT
`The editorial emphasis is on reports of original clinical research, reviews.
`and commentaries pertinent to internal medicine.
`
`Articles
`Studies of the causes , diagnosis. course, and treatment of disease and its
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`Literature of Medicine
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`History of Medicine
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`
`On Being a Doctor
`
`Short essays on the human experience of being a doct0r. Maximum text
`length , 2500 words.
`
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`
`Opinions on current topics and commentary o n papers published else(cid:173)
`where in the issue. Text length, no more than 1200 words; no more than
`20 references; no tables or figures. Most editorials are solicited by the
`Editors.
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`
`15 November 1991 • A1111i1/s ,f /11temlll Medicine • Volume 115 • Number 10
`
`1-9
`
`Page 5 of 15
`
`Patent Owner Ex. 2012
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`REVIEWS
`
`Risk for Serious Gastrointestinal Complications Related
`to Use of Nonsteroidal Anti-inflammatory Drugs
`A Meta-analysis
`
`Sherine E. Gabriel , MD, MSc ; Liisa Jaakkimainen, MSc; and Claire Bombardier, MD
`
`• Objective: To describe the relative risk for serious
`gastrointestinal complications due to nonaspirin non(cid:173)
`steroidal anti-inflammatory drug (NSAID) exposure
`among NSAID users as well as in selected subgroups.
`• Design: Overview and meta~analysis.
`• Data Identification: A literature search of English(cid:173)
`language studies examining the association between
`NSAIDs and adverse gastrointestinal events for the pe(cid:173)
`riod 1975 to 1990 identified using MEDLINE and commu(cid:173)
`nicating with three internationally recognized experts.
`• Data Analysis: A qualitative summary of study char(cid:173)
`acteristics and a critical appraisal of study quality were
`done. The results of 16 primary studies were selected
`and combined statistically. Summary estimates were
`weighted by sample size and quality score.
`• Main Results: The overall odds ratio of the risk for
`adverse gastrointestinal events related to NSAID use,
`summarized from 16 studies (9 case-control and 7
`cohort) was 2.74 (95% Cl, 2.54 to 2.97). The summary
`odds ratios were as follows: elderly patients, (aged
`~ 60 years), 5.52 (Cl, 4.63 to 6.60); patients under 65
`years of age, 1.65 (Cl, 1.08 to 2.53); women, 2.32 (Cl,
`1.91 to 2.82); and men, 2.40 (Cl, 1.85 to 3.11 ). The
`summary odds ratio for NSAID users receiving concom(cid:173)
`itant corticosteroids compared with NSAID users nor
`receiving corticosteroids was 1.83 (Cl, 1.20 to 2. 78). The
`summary odds ratio for the first gastrointestinal event
`was 2.39 (Cl, 2.16 to 2.65). The relative risk for a
`subsequent or unspecified gastrointestinal event was
`4.76 (Cl, 4.05 to 5.59). The summary odds ratio for less
`than 1 month of NSAID exposure was 8.00 (Cl, 6.37 to
`10.06); for more than 1 month but less than 3 months of
`exposure, the summary odds ratio was 3.31 (Cl, 2.27 to
`4.82); and for more than 3 months of exposure, the
`summary odds ratio was 1.92 (Cl, 1.19 to 3.13).
`• Conclusions: Users of NSAIDs are at approximately
`three times greater relative risk for developing serious
`adverse gastrointestinal events than are nonusers. Ad(cid:173)
`ditional risk factors include age greater than 60 years,
`previous history of, gastrointestinal events, and con(cid:173)
`comitant corticosteroid use. Another possible risk fac(cid:173)
`tor is the first 3 months of NSAID therapy. The risk for
`serious gastrointestinal events appears to be equal
`among men and women. These data represent sum(cid:173)
`mary statistics from 16 studies and cannot be consid-
`ered generalizable to all NSAID users.
`·
`
`Annals of Internal Medicine. 1991 ;IIS:787-796.
`
`From the Mayo Clinic and Mayo Foundation , Rochester, Min(cid:173)
`nesota; and Wellesley Hospital, Toronto; Ontario. For current
`author addresses, see end of text.
`
`N onsteroidal anti-inflammatory drugs (NSAIDs) are
`the most widely used agents for the treatment of mus(cid:173)
`culoskeletal and arthritic syndromes (l). Use of these
`agents has been increasingly associated with gastroin(cid:173)
`testinal toxicity , including mild dyspepsia, as well as
`more serious gastrointestinal reactions such as bleeding,
`perforation, and other events leading to hospitalization
`or death. Although researchers agree that an increased
`risk for gastrointestinal toxicity exists with NSAID use,
`the size of the reported risk has varied markedly , and
`there is little agreement on the definition of "high risk"
`groups (2-19).
`We reviewed the literature on NSAID-related adverse
`gastrointestinal events. First, we summarized study
`characteristics and appraised study quality. We then did
`a meta-analysis of all controlled trials that examined
`the risks for serious gastrointestinal events among
`NSAID users. Our primary objective was to estimate a
`summary odds ratio or relative risk for serious gastro(cid:173)
`intestinal complications due to nonaspirin NSAID expo(cid:173)
`sure.
`
`Methods
`
`A comprehensive search of the English-language literature
`from 1975 to 1990 was conducted using MEDLINE and search(cid:173)
`ing the following terms: anti-inflammatory agents, non-steroi-·
`dal ; gastropathy, toxicity, adverse effects, or side effects; pep(cid:173)
`tic ulcer or dyspepsia; gastric erosion, gastritis, gastric ulcer,
`gastric mucosa, endoscopy; and human. We also searc hed fo r
`specific NSAIDs by name .
`Five hundred twenty-six references were obtained. These
`were reviewed by one of the authors, and any citation that
`mentioned NSAlD-related gastrointestinal events was selected
`(Figure I). One hundred forty-two articles met this criterion
`and were entered into "Reference Manager" (20). Five addi(cid:173)
`tional articles were identified by communicatio n with three
`investigators (Marie Griffin, MD; Michael Langman, MD; and
`Richard Hunt, MD) from the United States, United Kingdom ,
`and Canada, respectively. These 5 articles were added to the
`data set, for a total of 147 articles.
`From the 147 articles in the data set, 40 studies were se(cid:173)
`lected that examined the association between NSAIDs and
`adverse gastrointestinal events . Specific inclusion and exclu(cid:173)
`sion criteria were applied to these studies independently by
`two of the authors. All studies that contained a comparison
`group and provided an estimate of risk for serious gastrointes(cid:173)
`tinal complications (defined as bleeding, perforation , or other
`adverse gastrointestinal events resulting in hospitalization or
`death) in NSAID users compared with nonusers, regardless of
`underlying disease, were included in
`the meta-analysis. A
`study was excluded if its primary objective was to assess
`effectiveness, if it involved the treatment of children (under 18
`years of age), if it described fewer than ten patients, if the only
`NS~ID studied was salicylate, or if the outcome examined was
`
`© 1991 American College of Physicians
`
`787
`
`Page 6 of 15
`
`Patent Owner Ex. 2012
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`SELECTION OF STUDIES AND REVIEWS
`
`Search strategy
`
`I. Comprehensive medllne
`search and review of
`bibliographies of selected articles
`
`11. Mention of NSAID(cid:173)
`related GI adverse
`event (by citation review)
`
`Number of citations r 142 l
`
`Ill. Additional artl~::~~~:~:::~ ~
`by 3 Intern•::,.::::--
`"-.,.
`
`Reviews or commentaries
`(by citation review)
`35
`I
`Re;~~~=h~f!~::r0 ::~~:• J~ta
`from 2 rrimary studies
`
`Studies examining the association
`between NSAIDa and adverse GI events
`40
`I
`5st'::~!~ru:f::~~ierla
`l
`
`Stln~~u
`
`10
`Review articles selected
`for critical appraisal
`
`16
`Primary studies selected
`for met&-analyals
`
`Figure 1. Selection of studies and reviews.
`
`the identification of ulcer rather than the presence of serious
`gastrointestinal complications. Disagreements between the two
`reviewe rs were resolved by consensus. Sixteen studies were
`selected (21-36) for meta-analysis (see Figure I) .
`
`Meta-analysis
`
`The following criteria were used to evaluate the quality of
`the studies included in the meta-analysis: blinding, definition of
`outcome, case selection, control selection, matching technique ,
`definition of exposure , and control for confounders (Appendix
`A). The Methods section of each study was photocopied, with
`care taken to exclude any mention of the authors' names,
`study results , or journal title . Study quality was evaluated in a
`blinded fashion by two of the investigators. Quality scores
`were assigned to each criterion according to its relative impor(cid:173)
`tance. A quality score of O indicated poor definitions and no
`attempt to avoid bias, and a score of 46 indicated the con(cid:173)
`verse . The average score (between the two readers) among the
`first six categories constituted the baseline score for the study.
`For every 5 confounders identified in a primary study, I bonus
`point was awarded, to a maximum of 5 points for studies that
`identified more than 25 confounders. Thus , the maximum qual(cid:173)
`ity score attainable was 51. Agreement between the two read(cid:173)
`ers regarding the quality score was evaluated using the kappa
`statistic (37).
`Data from all articles were abstracted in duplicate to avoid
`errors. The two observers met, discussed each item, and resolved
`all disagreements and errors. A final copy of the completed data
`collection forms was then created and entered into a database
`(ORACLE, Oracle Corporation, Belmont, California) (38).
`The results of the 16 primary studies were combined statis(cid:173)
`tically using two different techniques . First , overall point esti(cid:173)
`mates of the odds ratios and 95% confidence intervals (Cls)
`were calculated from the raw data of the 16 selected studies
`using the Mantel-Haenszel statistic (39). The second technique
`involved combining the published odds ratios and Cls directly
`across studies to produce an overall estimate of the odds ratio
`and 95% CI (40). The latt~r will hereafter be referred to as tlie
`" direct" method . The direct method was the primary statisti(cid:173)
`cal analysis technique used , and all results were calculated
`using this method unless otherwise stated.
`The purpose of this analysis was not to estimate a common
`parameter, but rather to compute an average or summary sta(cid:173)
`tistic across the 16 selected st