Resources for "Who Was Left Out"

This page lists some references I have used to help develop Chapter 2 of "Statistical Evidence."

Attrition

Article makes simple errors and could cause unnecessary deaths. C. Baigent, R. Collins, R. Peto. British Medical Journal 2002: 324(7330); 167. (An interesting critical review of a large randomized study and a meta-analysis.) "The worldwide meta-analysis of antiplatelet trials shows that low dose aspirin (or some other effective antiplatelet regimen) reduces non-fatal myocardial infarction, non-fatal stroke, and vascular death in a wide range of patients who are at high risk of occlusive vascular disease. A paper disputing this was published concurrently in the For Debate section of the journal, but the arguments in it (some of which the author also published on the same date in an editorial in the Lancet) depend strongly on quite simple mistakes about the randomised evidence and could cause unnecessary deaths." [Medline] [Full text] [PDF]

Statistical issues in randomized trials of cancer screening. S. G. Baker, B. S. Kramer, P. C. Prorok. BMC Med Res Methodol 2002: 2(1); 11. BACKGROUND: The evaluation of randomized trials for cancer screening involves special statistical considerations not found in therapeutic trials. Although some of these issues have been discussed previously, we present important recent and new methodologies. METHODS: Our emphasis is on simple approaches. RESULTS: We make the following recommendations:(1) Use death from cancer as the primary endpoint, but review death records carefully and report all causes of death(2) Use a simple "causal" estimate to adjust for nonattendance and contamination occurring immediately after randomization(3) Use a simple adaptive estimate to adjust for dilution in follow-up after the last screen CONCLUSION: The proposed guidelines combine recent methodological work on screening endpoints and noncompliance/contamination with a new adaptive method to adjust for dilution in a study where follow-up continues after the last screen. These guidelines ensure good practice in the design and analysis of randomized trials of cancer screening. [Abstract] [Full text] [PDF]

Quantification of the completeness of follow-up. T. G. Clark, D. G. Altman, B. L. De Stavola. Lancet 2002: 359(9314); 1309-10. Completeness of follow-up is important, especially in clinical trials, since unequal follow-up in the treatment groups can bias the analysis of results. In survival studies, information on participants who do not complete the study is often omitted because their data can be included up to the time at which they were lost to follow-up. We propose a simple measure of completeness that is the ratio of the total observed person-time and the potential person-time of follow-up in a study. Our measure is easy to calculate, can be illustrated pictorially, and can be used to identify subgroups with especially poor follow-up.

Hold the Lard! The Atkins Diet still doesn't work.. Michael Fumento. Accessed on 2002-12-06. A careful analysis of the recent research on the Atkins diet shows that there was a much higher drop out rate in that group, which could partially explain the promising results of this diet. www.reason.com/hod/mf120502.shtml

Attrition in prevention research. W. B. Hansen, L. M. Collins, C. K. Malotte, C. A. Johnson, J. E. Fielding. J Behav Med 1985: 8(3); 261-75. Selective attrition can detract from the internal and external validity of longitudinal research. Four tests of selective attrition applicable to longitudinal prevention research were conducted on data bases from two recent studies. These tests assessed (1) differences between dropouts and stayers in terms of pretest indices of primary outcome variables (substance use), (2) differences in change scores for dropouts and stayers, (3) differences in rates of attrition among experimental conditions, and (4) differences in pretest indices for dropouts among conditions. Results of these analyses indicate that cigarette smokers, alcohol drinkers, and marijuana users are more likely to drop out than nonusers, limiting the external validity of both studies. For one project, differential rates of attrition among conditions suggested a possible attrition artifact which will interfere with interpretation of outcome results, possibly masking true program effectiveness. Recommendations for standardizing reports of attrition and for avoiding attrition through second efforts are made.

Tracking and follow-up of 16,915 adolescents: minimizing attrition bias. T. C. Morrison, D. R. Wahlgren, M. F. Hovell, J. Zakarian, S. Burkham-Kreitner, C. R. Hofstetter, D. J. Slymen, K. Keating, S. Russos, J. A. Jones. Control Clin Trials 1997: 18(5); 383-96. This paper reports a multi-dimensional approach to minimize drop-outs from a two-year follow-up of a clinical trial designed to reduce initiation of tobacco use in 16,915 adolescent orthodontic patients. A hierarchical approach to data collection and tracking was employed. Seventy percent of participants were reached and interviewed at home by telephone. Strategies used to survey remaining participants included calling parents' work numbers and directory assistance, reviewing orthodontists' charts, sending surveys by mail, offering incentives, and using reverse telephone directories. More than 92% of the participants completed follow-up surveys. Multivariate analyses showed that baseline tobacco and alcohol use predicted loss to follow-up. Similarly, the number of procedures used to track each participant predicted presence of risk behaviors at post-test, demonstrating that an organized tracking hierarchy curtailed even greater compromises to internal and external validity. Evaluation and costs of individual strategies are discussed.

Tracking and attrition in longitudinal school-based smoking prevention research. P. L. Pirie, S. J. Thomson, S. L. Mann, A. V. Peterson, Jr., D. M. Murray, B. R. Flay, J. A. Best. Prev Med 1989: 18(2); 249-56. Research in the development of school-based smoking prevention programs has resulted in a set of approaches of known short-term efficacy. Further evaluation of these approaches now requires long-term follow-up of participants. To minimize the problems caused by attrition in these longitudinal studies, investigators have developed techniques for tracking study participants. Based primarily on the use of the telephone, mail, and public documents, these methods require good background information on both the study participants and their parents. This article summarizes the experience of three teams of researchers engaged in such follow-up studies. These investigators have identified the types of background information most useful in long-term follow-up of participants, have developed a set of strategies to obtain such background information, and have developed methods for successfully tracking participants after a lapse of several years.

Sample size slippages in randomised trials: exclusions and the lost and wayward. K. F. Schulz, D. A. Grimes. Lancet 2002: 359(9308); 781-5. Proper randomisation means little if investigators cannot include all randomised participants in the primary analysis. Participants might ignore follow-up, leave town, or take aspartame when instructed to take aspirin. Exclusions before randomisation do not bias the treatment comparison, but they can hurt generalisability. Eligibility criteria for a trial should be clear, specific, and applied before randomisation. Readers should assess whether any of the criteria make the trial sample atypical or unrepresentative of the people in which they are interested. In principle, assessment of exclusions after randomisation is simple: none are allowed. For the primary analysis, all participants enrolled should be included and analysed as part of the original group assigned (an intent-to-treat analysis). In reality, however, losses frequently occur. Investigators should, therefore, commit adequate resources to develop and implement procedures to maximise retention of participants. Moreover, researchers should provide clear, explicit information on the progress of all randomised participants through the trial by use of, for instance, a trial profile. Investigators can also do secondary analyses on, for instance, per-protocol or as-treated participants. Such analyses should be described as secondary and non-randomised comparisons. Mishandling of exclusions causes serious methodological difficulties. Unfortunately, some explanations for mishandling exclusions intuitively appeal to readers, disguising the seriousness of the issues. Creative mismanagement of exclusions can undermine trial validity. [Medline] [Abstract]

Intention to Treat Analysis in Clinical Trials When There are Missing Data. Streiner, D, J Geddes. Evid Based Ment Health 2001: 4(3); 70-71.

Compliance

Randomised study of long term outcome after epidural versus non-epidural analgesia during labour. C. J. Howell, T. Dean, L. Lucking, K. Dziedzic, P. W. Jones, R. B. Johanson. Bmj 2002: 325(7360); 357. (This paper uses ITT analysis, but it may not be appropriate. See the rapid responses to this paper for details.) OBJECTIVE: To determine whether epidural analgesia during labour is associated with long term backache. DESIGN: Follow up after randomised controlled trial. Analysis by intention to treat. SETTING: Department of obstetrics and gynaecology at one NHS trust. PARTICIPANTS: 369 women: 184 randomised to epidural group (treatment as allocated received by 123) and 185 randomised to non-epidural group (treatment as allocated received by 133). In the follow up study 151 women were from the epidural group and 155 from the non-epidural group. MAIN OUTCOME MEASURES: Self reported low back pain, disability, and limitation of movement assessed through one to one interviews with physiotherapist, questionnaire on back pain and disability, physical measurements of spinal mobility. RESULTS: There were no significant differences between groups in demographic details or other key characteristics. The mean time interval from delivery to interview was 26 months. There were no significant differences in the onset or duration of low back pain, with nearly a third of women in each group reporting pain in the week before interview. There were no differences in self reported measures of disability in activities of daily living and no significant differences in measurements of spinal mobility. CONCLUSIONS: After childbirth there are no differences in the incidence of long term low back pain, disability, or movement restriction between women who receive epidural pain relief and women who receive other forms of pain relief. [Medline] [Abstract] [Full text] [PDF]

Intention-to-treat principle. V. M. Montori, G. H. Guyatt. Cmaj 2001: 165(10); p1339-41. [Medline] [Full text] [PDF]

Exclusions

A controlled trial of immunotherapy for asthma in allergic children. N. F. Adkinson, Jr., P. A. Eggleston, D. Eney, E. O. Goldstein, K. C. Schuberth, J. R. Bacon, R. G. Hamilton, M. E. Weiss, H. Arshad, C. L. Meinert, J. Tonascia, B. Wheeler. New England Journal of Medicine 1997: 336(5); 324-31. (Noncompliant patients were excluded prior to the start of the trial) BACKGROUND: Injections of allergens are widely prescribed for patients with asthma, but little is known about the effectiveness of immunotherapy. METHODS: We conducted a double-blind, placebo-controlled trial of multiple-allergen immunotherapy in 121 allergic children with moderate-to-severe, perennial asthma. The children, who required daily medication for their asthma, were randomly assigned to receive subcutaneous injections of either a mixture of up to seven aeroallergen extracts or a placebo. Maintenance injections were continued for 18 months or longer. Medications were adjusted every two to three weeks on the basis of peak flow rates and symptoms. The principal outcome was the daily medication score. Bronchial sensitivity to methacholine (the concentration provoking a 20 percent decrease in the forced expiratory volume in one second [PC20]) was measured twice yearly. RESULTS: The median medication score declined from 5.4 to 4.9 in the immunotherapy group (P<0.001) and from 5.2 to 5.0 in the placebo group (P<0.001), but there was no significant difference between the groups (P>0.6). The number of days on which oral corticosteroids were used was similar in the two groups. Partial or complete remission of asthma occurred in 31 percent of the immunotherapy group and in 28 percent of the placebo group (P>0.5). There was no difference between the groups in the use of medical care, symptoms, or peak flow rates. The median PC20 increased significantly in both groups, but again with no difference between the two groups. CONCLUSIONS: Immunotherapy with injections of allergens for over two years was of no discernible benefit in allergic children with perennial asthma who were receiving appropriate medical treatment. [Abstract] [Full text] [PDF]

Statistical Assumptions as Empirical Commitments. Richard A. Berk, David A. Freedman. Accessed on 2001-August. "Researchers who study punishment and social control, like those who study other social phenomena, typically seek to generalize their findings from the data they have to some larger context: in statistical jargon, they generalize from a sample to a population. Generalizations are one important product of empirical inquiry. Of course, the process by which the data are selected introduces uncertainty. Indeed, any given dataset is but one of many that could have been studied. If the dataset had been different, the statistical summaries would have been different, and so would the conclusions, at least by a little." stat-www.berkeley.edu/~census/berk2.pdf

Unjustified exclusion of elderly people from studies submitted to research ethics committee for approval: descriptive study. A. Bayer, W. Tadd. British Medical Journal 2000: 321(7267); 992-3. [Full text] [PDF]

Exclusion of elderly people from clinical research: a descriptive study of published reports. G. Bugeja, A. Kumar, A. K. Banerjee. British Medical Journal 1997: 315(7115); 1059. [Full text]

Post-randomisation exclusions: the intention to treat principle and excluding patients from analysis. D. Fergusson, S. D. Aaron, G. Guyatt, P. Hebert. Bmj 2002: 325(7365); 652-4. Abstract not available yet. [Full text] [PDF]

Participation in Research and Access to Experimental Treatments by HIV-Infected Patients. Allen L. Gifford, William E. Cunningham, Kevin C. Heslin, Ron M. Andersen, Terry Nakazono, Dale K. Lieu, Martin F. Shapiro, Samuel A. Bozzette, the HIV Cost and Services Utilization Study Consortium. N Engl J Med 2002: 346(18); 1373-1382. Background Although there is concern that minority groups and women are underrepresented in research involving patients with human immunodeficiency virus (HIV) infection, the available data are inconclusive. Methods We used nationally representative data from the HIV Cost and Services Utilization Study to determine the characteristics of the participants and nonparticipants in trials of medications for HIV infection and whether or not patients had access to experimental treatments. A probability sample of 2864 persons, representing all 231,400 adults with known HIV infection who are cared for in the contiguous United States, were interviewed on three occasions between 1996 and 1998. They were asked about participation in clinical research studies of medications and past receipt of experimental medications for HIV. Results We estimate that 14 percent of adults receiving care for HIV infection participated in a medication trial or study; 24 percent had received experimental medications; and 8 percent had tried and failed to obtain experimental treatments. According to multivariate models, non-Hispanic blacks and Hispanics were less likely to be participating in trials than non-Hispanic whites (odds ratio for participation among non-Hispanic blacks, 0.50 [95 percent confidence interval, 0.28 to 0.91]; odds ratio among Hispanics, 0.58 [95 percent confidence interval, 0.37 to 0.93]) and to have received experimental medications (odds ratios, 0.41 [95 percent confidence interval, 0.32 to 0.54] and 0.56 [95 percent confidence interval, 0.41 to 0.78], respectively). Patients who were cared for in private health maintenance organizations were less likely to participate in trials than those with fee-for-service insurance (odds ratio, 0.43 [95 percent confidence interval, 0.21 to 0.88]). Women were not underrepresented in research trials and had a similar likelihood of receiving experimental treatments. Conclusions Among patients with HIV infection, participation in research trials and access to experimental treatment is influenced by race or ethnic group and type of health insurance. [Abstract] [Full text] [PDF]

Research Fables from the Sisters Grinn, No. 11. Chicken Little.. Jeanne Grace, University of Rochester School of Nursing. Accessed on 2003-05-27. "Chicken Little was an eager young hatchling on a farm near Scholarship Forest, the home of Little Red Research Student. Little Red was attending graduate school out of town, but by chance was home visiting her trans-species Little cousins when Chicken Little was hatched. Many families of Scholarship Forest held Little Red up as a role model to their children, but Chicken Little actually imprinted on her. As a result, although poultry rarely aspire to scholarly careers, Chicken Little wanted to become an evidence-based health care provider when she grew up. She tried to practice research utilization faithfully every day." http://www.urmc.rochester.edu/SON/Fables/clittle.html

The exclusion of the elderly and women from clinical trials in acute myocardial infarction. J. H. Gurwitz, N. F. Col, J. Avorn. Jama 1992: 268(11); 1417-22. OBJECTIVE--To determine the extent to which the elderly have been excluded from trials of drug therapies used in the treatment of acute myocardial infarction, to identify factors associated with such exclusions, and to explore the relationship between the exclusion of elderly and the representation of women. DATA SOURCES--We conducted a systematic search of the English-language literature from January 1960 through September 1991 to identify all relevant studies of specific pharmacotherapies employed in the treatment of acute myocardial infarction. To accomplish this, we searched MEDLINE, major cardiology textbooks, meta-analyses, reviews, editorials, and the bibliographies of all identified articles. STUDY SELECTION--Only trials in which patients were randomly allocated to receive a specific therapeutic regimen or a placebo or nonplacebo control regimen were included for review. DATA EXTRACTION--Studies were abstracted for year of publication, source of support, performance location, drug therapies to which patients were randomized, use of invasive diagnostic tests or therapeutic procedures, exclusion criteria, size and demographic characteristics of the randomized study population, and principal outcome measures. DATA SYNTHESIS--A total of 214 trials met inclusion criteria, involving 150,920 study subjects. Over 60% of trials excluded persons over the age of 75 years. Studies published after 1980 were more likely to have age-based exclusions compared with studies published before 1980 (adjusted odds ratio, 4.92; 95% confidence interval, 2.33 to 10.54). Trials of thrombolytic therapy involving an invasive procedure were more likely to exclude elderly patients compared with other studies (adjusted odds ratio, 2.45; 95% confidence interval, 1.10 to 5.47). Studies with age-based exclusions had a smaller percentage of women compared with those without such exclusions (18% vs 23%; P = .0002), with the mean age of the study population significantly associated with the proportion of women participants (P = .0001, R2 = .29). CONCLUSIONS--Age-based exclusions are frequently used in clinical trials of medications used in the treatment of acute myocardial infarction. Such exclusions limit the ability to generalize study findings to the patient population that experiences the most morbidity and mortality from acute myocardial infarction.

Spectrum bias in the evaluation of diagnostic tests: lessons from the rapid dipstick test for urinary tract infection. M. S. Lachs, I. Nachamkin, P. H. Edelstein, J. Goldman, A. R. Feinstein, J. S. Schwartz. Ann Intern Med 1992: 117(2); 135-40. (A diagnostic test will usually perform more effectively in patients who have clear signs of illness and will preform less effectively in borderline patients. This is reflected in values of sensitivity and specificity that change depending on who is evaluated. If the patients being evaluated are similar to the patients you see in your practice, this is not a problem. But often, patients with more extreme symptoms are preferentially recruited into research studies. This leads to spectrum bias which can often overstate the effectiveness of a diagnostic test.) OBJECTIVE: To determine if the leukocyte esterase and bacterial nitrite rapid dipstick test for urinary tract infection (UTI) is susceptible to spectrum bias (when a diagnostic test has different sensitivities or specificities in patients with different clinical manifestations of the disease for which the test is intended). DESIGN: Cross-sectional study. PATIENTS: A total of 366 consecutive adult patients in whom clinicians performed urinalysis to diagnose or exclude UTI. SETTING: An urban emergency department and walk-in clinic. MEASUREMENTS: After the patient encounter, but before dipstick test or culture was done, clinicians recorded the signs and symptoms that were the basis for suspecting UTI and for performing a urinalysis and an estimate of the probability of UTI based on the clinical evaluation. For all patients who received urinalysis, dipstick tests and culture were done in the clinical microbiology laboratory by medical technologists blinded to clinical evaluation. Sensitivity for the dipstick was calculated using a positive result in either leukocyte esterase or bacterial nitrite, or both, as the criterion for a positive dipstick, and greater than 10(5) CFU/mL for a positive culture. RESULTS: In the 107 patients with a high (greater than 50%) prior probability of UTI, who had many characteristic UTI symptoms, the sensitivity of the test was excellent (0.92; 95% CI, 0.82 to 0.98). In the 259 patients with a low (less than or equal to 50%) prior probability of UTI, the sensitivity of the test was poor (0.56; CI, 0.03 to 0.79). CONCLUSIONS: The leukocyte esterase and bacterial nitrite dipstick test for UTI is susceptible to spectrum bias, which may be responsible for differences in the test's sensitivity reported in previous studies. As a more general principle, diagnostic tests may have different sensitivities or specificities in different parts of the clinical spectrum of the disease they purport to identify or exclude, but studies evaluating such tests rarely report sensitivity and specificity in subgroups defined by clinical symptoms. When diagnostic tests are evaluated, information about symptoms in the patients recruited for study should be included, and analyses should be done within appropriate clinical subgroups so that clinicians may decide if reported sensitivities and specificities are applicable to their patients. [Medline]

Comorbidity of chronic diseases in general practice. F. G. Schellevis, J. van der Velden, E. van de Lisdonk, J. T. van Eijk, C. van Weel. J Clin Epidemiol 1993: 46(5); 469-73. With the increasing number of elderly people in The Netherlands the prevalence of chronic diseases will rise in the next decades. It is recognized in general practice that many older patients suffer from more than one chronic disease (comorbidity). The aim of this study is to describe the extent of comorbidity for the following diseases: hypertension, chronic ischemic heart disease, diabetes mellitus, chronic nonspecific lung disease, osteoarthritis. In a general practice population of 23,534 persons, 1989 patients have been identified with one or more chronic diseases. Only diseases in agreement with diagnostic criteria were included. In persons of 65 and older 23% suffer from one or more of the chronic diseases under study. Within this group 15% suffer from more than one of the chronic diseases. Osteoarthritis and diabetes mellitus are the diseases with the highest rate of comorbidity. Comorbidity restricts the external validity of results from single-disease intervention studies and complicates the organization of care.

Nicotine patch therapy in adolescent smokers. T. A. Smith, R. F. House, Jr., I. T. Croghan, T. R. Gauvin, R. C. Colligan, K. P. Offord, L. C. Gomez-Dahl, R. D. Hurt. Pediatrics 1996: 98(4 Pt 1); 659-67. OBJECTIVE: To evaluate the safety, tolerance, and efficacy of 24-hour nicotine patch therapy in adolescent smokers who were trying to stop smoking. DESIGN: Nonrandomized, open-label, 6-month clinical trial. SETTING: Five public high schools in the Rochester, MN, area. SUBJECTS: Twenty-two adolescent smokers, aged 13 through 17 years, with current smoking rate of 20 or more cigarettes per day (cpd). INTERVENTION: Daily nicotine patch therapy for 8 weeks (22 mg/d for 6 weeks followed by 11 mg/d for 2 weeks). Weekly individual behavioral counseling and group support continued for 8 weeks with follow up visits at 3 and 6 months and a mailed survey at 1 year. MAIN OUTCOME MEASURES: Self-reported smoking abstinence verified by expired air carbon monoxide of 8 ppm or less, nicotine withdrawal symptoms, adverse experiences, and blood cotinine levels. RESULTS: Subjects had a mean +/- SD smoking rate of 23.3 +/- 5.0 (range, 20 to 35) cpd at study entry and 2.6 +/- 1.6 years of smoking; the mean age was 15.9 +/- 1.2 (range 13 through 17) years, and 68% were girls. Of the 22 participants, 19 (86%) completed patch therapy, 3 (14%) had biochemically validated smoking cessation at week 8, and 1 continued to be smoke free at 3 and 6 months after patch initiation. There was a significant decrease from baseline in the mean nicotine withdrawal scores for days 4 and 7 of week 1 and the mean for weeks 2 through 8. Skin reactions were the most common adverse event. As the worst skin reactions, 55% had erythema only, 5% had erythema and edema, and 9% had erythema and vesicles, whereas 32% had no skin reactions. Other reported adverse events were headaches (41%), nausea and vomiting (41%), tiredness (41%), dizziness (27%), and arm pain (23%). None of these were considered serious, life threatening, or led to the discontinuation of patch therapy. In adults with comparable smoking rates, we found that the adolescents had lower blood cotinine levels. Those smoking 20 to 25 cpd had cotinine levels of 146 +/- 84 (adolescents) vs 260 +/- 98 (adults) ng/ml, and those smoking 26 to 35 cpd had levels of 169 +/- 73 vs 276 +/- 110 ng/ml, respectively. CONCLUSION: Nicotine patch therapy seems safe in adolescent smokers. Placebo-controlled trials are needed to establish the efficacy of nicotine patch therapy in adolescents.

The Effect of School Dropout Rates on Estimates of Adolescent Substance Use among Three Racial/Ethnic Groups. Randall C. Swaim, F Beauvais, EL Chavez, ER Oetting. American Journal of Public Health 1997: 87(1); 51-55. (A study of adolescent drug use based in a high school would leave out anyone not attending school. This could lead to a serious bias overall. Because there is an interaction with race, you might also have problems with any results that imply that one racial or ethnic group has greater or less drug use than another.) ABSTRACT: OBJECTIVES: This study examined, across three racial/ethnic groups, how the inclusion of data on drug use of dropouts can alter estimates of adolescent drug use rates. METHODS: Self-report rates of lifetime prevalence and use in the previous 30 days were obtained from Mexican American, White non-Hispanic, and Native American student (n = 738) and dropouts (n = 774). Rates for the age cohort (students and dropouts) were estimated with a weighted correction formula. RESULTS: Rates of use reported by dropouts were 1.2 to 6.4 times higher than those reported by students. Corrected rates resulted in changes in relative rates of use by different ethnic groups. CONCLUSIONS: When only in-school data are available, errors in estimating drug use among groups with high rates of school dropout can be substantial. Correction of student-based data to include drug use of dropouts leads to important changes in estimated levels of drug use and alters estimates of the relative rates of use for racial/ethnic minority groups with high dropout rates. [Medline]

Physicians' reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. K. M. Taylor, R. G. Margolese, C. L. Soskolne. N Engl J Med 1984: 310(21); p1363-7. We studied the reasons surgical principal investigators chose not to enter patients in a large, multicenter trial sponsored by a cooperative group. In 1976 the National Surgical Adjuvant Project for Breast and Bowel Cancers (NSABP) initiated a clinical trial to compare segmental mastectomy and postoperative radiation, or segmental mastectomy alone, with total mastectomy. Because the low rates of accrual were threatening to close the trial prematurely, we mailed a questionnaire to the 94 NSABP principal investigators, asking why they were not entering eligible patients in the trial. A response rate of 97 per cent was achieved. Physicians who did not enter all eligible patients offered the following explanations: (1) concern that the doctor-patient relationship would be affected by a randomized clinical trial (73 per cent), (2) difficulty with informed consent (38 per cent), (3) dislike of open discussions involving uncertainty (22 per cent), (4) perceived conflict between the roles of scientist and clinician (18 per cent), (5) practical difficulties in following procedures (9 per cent), and (6) feelings of personal responsibility if the treatments were found to be unequal (8 per cent). Further investigation into the behavioral aspects of the investigator-patient relationship is particularly pressing, since fear of change in this relationship was the most common reason given for not entering eligible patients in the trial.

Representation of older patients in cancer treatment trials. EL Trimble, CL Carter, D Cain, B Freidlin, RS Ungerleider, MA Friedman. Cancer 1994: 74(7); 2208-14. ABSTRACT: In 1990, the five leading causes of cancer death in men aged 65 and older were carcinomas of the lung, prostate, colon and rectum, and pancreas, and leukemia. For women in this age group, the five leading causes of cancer death were carcinomas of the lung, breast, colon and rectum, pancreas, and ovary. To determine the representation of the elderly in clinical trials, the 1992 accrual of the National Cancer Institute (NCI)-sponsored Clinical Cooperative Group treatment trials (which included more than 8000 elderly patients) for the aforementioned sites was compared with the 1990 incidence data from the NCI's Surveillance, Epidemiology, and End Results program. Of the male patients enrolled in the trials, an average of 39% were older than 65 (47.3% lung, 79.5% prostate, 47.5% colorectal, 45.6% pancreas, and 9.6% leukemia); whereas 25.9% of all women enrolled in trials were 65 or older (43.6% lung, 17.3% breast, 46.2% colorectal, 59.6% pancreas, and 35.4% ovary). With respect to incidence, older patients generally are underrepresented in cancer treatment trials. With the exception of the data on prostate cancer, each of the comparisons using the Z statistic gave probability values of less than 0.01. The most significant discrepancies between incidence and participation in cancer treatment protocols were noted for leukemia in males and breast cancer in females. Possible explanations for these findings include (1) a research focus on aggressive therapy, which may be unacceptably toxic to the elderly; (2) presence of comorbidity in the elderly; (3) fewer trials available specifically aimed at older patients; (4) limited expectations for long term benefits on the part of physicians, relatives, and the patients themselves; and (5) a lack of financial, logistic, and social support for the participation of elderly patients in clinical trials. Recognizing this situation, NCI recently sponsored a number of trials that specifically target the elderly. This paper describes the status of all major Phase II and III clinical trials that recently were closed, still are active, or now are in review that address the clinical care of this important segment of the U.S. population.

Nonresponse

Effect of UK national guidelines on services to treat patients with acute low back pain: follow up questionnaire survey. A. G. Barnett, M. R. Underwood, M. R. Vickers. British Medical Journal 1999: 318(7188); 919-20. (This study obtained survey response rates of 87% and 85%. Larger practices were overrepresented.) Abstract not available yet. [Full text] [PDF]

Imputing nonresponses to mail-back questionnaires. J. W. Drane. Am J Epidemiol 1991: 134(8); 908-12. Many mail-back questionnaires are expected at the outset to elicit poor response rates, perhaps as low as 15-30%. Corrections can be designed into such a survey by using either two or three mailouts of the questionnaire at regular intervals. Assuming a trend in responses as a function of the number of mailouts a person receives before filling out and mailing back the questionnaire, responses are imputed for those who do not mail back the questionnaire after the final mailout. Standard errors are derived, and an example is included. The imputation is easily programmed. A validation of this method is also included.

Non-response bias in a lifestyle survey. A. Hill, J. Roberts, P. Ewings, D. Gunnell. J Public Health Med 1997: 19(2); p203-7. BACKGROUND: Monitoring health targets is often undertaken using questionnaire surveys of lifestyle risk factors. Non-response bias is recognized but rarely quantified. METHODS: Following a questionnaire survey on a random sample of 6009 residents of Somerset with a response rate of 57.6 per cent, a telephone survey was undertaken on a random sample of 400 non-responders. A small number of the more important questions from the questionnaire were put to the non-responders over the phone. RESULTS: Fifty-nine per cent of the sample were contacted and agreed to participate. Statistically significant differences between responders and non-responders to the original questionnaire were detected for current smoking, hazardous alcohol consumption and lack of moderate or vigorous activity. CONCLUSIONS: Lifestyle questionnaire surveys need to include an assessment of the non-response bias.

A comparison on nonresponse in mail, telephone, and face-to-face surveys. J. J. Hox, D De Leeuw. Quality and Quantity 1994: 28(4); 329-344.

Do safety practices differ between responders and non-responders to a safety questionnaire? D. Kendrick, R. Hapgood, P. Marsh. Injury Prevention 2001: 7(2); 100-3. OBJECTIVE: To compare reported safety practices between responders and non-responders to a safety survey. DESIGN: Cross sectional survey at baseline compared with safety practices reported at subsequent child health surveillance checks. SUBJECTS: Parents of children aged 3-12 months registered with practices participating in a controlled trial of injury prevention in primary care that did, and did not, respond to the baseline survey and who subsequently attended child health surveillance checks. RESULTS: No difference in safety practices was found between responders and non-responders to the survey at the 6-9 month check. Responders were more likely to report owning a stair gate (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.82 to 4.16) and socket covers (OR 2.16, 95% CI 1.53 to 3.04) at the 12-15 month check, and owning socket covers (OR 2.19, 95% CI 1.34 to 3.61) at the 18-24 month check. Responders were more likely to report greater than the median number of safety practices at the 18 month check. CONCLUSIONS: Non-responders to a safety survey appear to be less likely to report owning several items of safety equipment than responders. Further work is needed to confirm these findings. Extrapolating the results of safety surveys to the population as a whole may lead to over estimation of safety equipment possession. [Medline] [Abstract] [Full text] [PDF]

Quality of response in different population groups in mail and telephone surveys. J. Siemiatycki, S. Campbell, L. Richardson, D. Aubert. Am J Epidemiol 1984: 120(2); p302-14. Mail and telephone survey methods, with follow-up by other methods, can provide high response rates. However, it is not clear whether different population groups provide responses of different quality, thus creating risk of biased comparisons. A closely related problem is whether proxy response adequately substitutes for self-response. This study addressed these issues in the context of parallel mail and telephone health surveys carried out in Montreal. In the telephone survey, proxy respondents provided lower estimates of morbidity and health care utilization than self-respondents; in the mail survey, there was no difference between proxy and self-response. Response validity was assessed by comparing reported physician visits with those recorded by the government-run universal health insurance plan. In general, mail responses were more valid than telephone responses. In both methods, there were suggestive but not persuasive differences in validity among sociodemographic subgroups. In both methods, those reporting illness or medication use had less underreporting of physician visits than those not reporting such things.

Nonresponse bias and early versus all responders in mail and telephone surveys. J. Siemiatycki, S. Campbell. Am J Epidemiol 1984: 120(2); p291-301. Mail and telephone survey methods, with or without follow-up by other methods, are cost-effective alternatives to the conventional home interview approach. However, it has long been thought that they are especially susceptible to nonresponse bias. The study addressed this issue in the context of parallel mail and telephone health surveys carried out in Montreal. The mail strategy among 1,555 adults achieved 68.5% response and follow-up by telephone and home interview increased response to 80.9%. Respondents were adequately representative of the entire sample with respect to socioeconomic status, number of adults in household, and ethnic distribution. The 68.5% initial stage respondents were similar to all respondents on the above variables as well as on age, sex, education and reported health status. Odds ratios of smoking and respiratory symptoms hardly differed between initial stage and all respondents. The telephone survey among 1,595 adults achieved 72.7% response and follow-up by mail and personal interview increased response to 88.2%. Comparisons between respondents and the entire sample and between initial stage respondents and all respondents gave similar results to those found in the mail strategy, although there was some change in a symptom-smoking odds ratio from the initial stage respondents to all respondents. In both survey strategies, there was no evidence of substantial nonresponse bias and estimates of morbidity and health care would not have differed much if the fieldwork had stopped at the initial mail or telephone stage.

What are the characteristics of general practitioners who routinely do not return postal questionnaires: a cross sectional study. N. Stocks, D. Gunnell. J Epidemiol Community Health 2000: 54(12); p940-1. Abstract not available.

Representativeness and response rates from the Domestic/International Gastroenterology Surveillance Study (DIGEST). J. G. Tijssen. Scand J Gastroenterol Suppl 1999: 23115-9. BACKGROUND: The Domestic/international Gastroenterology Surveillance Study (DIGEST) examined the prevalence of upper gastrointestinal symptoms among the general population in 10 countries, and the impact of these symptoms on healthcare usage and quality of life. This report discusses the validation of the DIGEST sample and reviews the response rates from the survey. METHODS: External validation of the DIGEST sample was conducted by comparing the age, age by gender and annual household incomes of the sample with census-derived data. A comparison was also made between Psychological General Well-Being Index (PGWBI) scores from study subjects in the Scandinavian countries and the USA and the total sample population norms. RESULTS: Under- and oversampling, defined as > or =5% difference from the population norms, was evident in eight out of 10 countries, but no systematic bias was evident. The final distribution of the sample by gender was 51% female and 49% male. Although differences in PGWBI scores were noted between DIGEST subjects and population norms, these differences were <0.30 standard deviations--markedly below the difference considered as relevant for the PGWBI. Response for the survey in individual countries ranged from 17% in the USA to 61% in Norway, with a survey-wide rate of 27%. The overall response rate, including primary non-respondents, was 13.4%. The majority of nonresponse (51.4%) was attributed to failure to establish contact with the subjects, with 41.7% of subjects declining to be interviewed and the remaining 6.9% of subjects not meeting the age and sex criteria used for the survey. CONCLUSIONS: The DIGEST sample exhibited good external validity, providing a foundation for comparison between data derived from individual countries in the survey.

Outliers

Ozone Depletion, History and politics. Brien Sparling. Accessed on 2002-11-27. "Ground based measurements of Ozone were first started in 1956, in at Halley Bay, Antarctica. Satellite measurements of ozone started in the early 70's, but the first comprehensive worldwide measurements started in 1978 with the Nimbus-7 satellite. Nimbus-7 carried a TOMS (total ozone mapping spectrometer, and a SBUV(solar backscatter UV meter). The TOMS finally broke on May 7th,1993, but today there are several different satellites measuring concentrations of ozone and other atmosheric gases. Gases in the troposphere and lower stratosphere are sampled by weather balloons or by airplanes such as the ER-2 managed by NASA." www.nas.nasa.gov/About/Education/Ozone/history.html

Some Remarks on Wild Observations. William H. Kruskal. Accessed on 2002-11-27. "The purpose of these remarks is to set down some non-technical thoughts on apparently wild or outlying observations. These thoughts are by no means novel, but do not seem to have been gathered in one convenient place." www.tufts.edu/~gdallal/out.htm

Volunteers

Selection bias in observational and experimental studies. J. H. Ellenberg. Stat Med 1994: 13(5-7); 557-67. There has been a heightened awareness of the dangers of selection bias over the past two decades. Certainly coverage in statistical and 'statistics for medicine', and epidemiology textbooks have allocated pages to warn investigators and readers of investigations to be aware of its presence. The scientific community has not, however, yet accepted the necessity for critical assessment of the method of sample selection in the planning and execution of studies as a fundamental underpinning of observational and experimental studies. To wit, we are faced with a plethora of research studies receiving funding, being published in peer-reviewed journals and influencing future studies, that may be reporting entirely spurious associations. It is the intent of this paper to present examples of selection bias in a variety of areas which have resulted in misleading or entirely incorrect results. We hope to help make such research scientifically 'politically incorrect' to the degree that the scientific community 'just says no' to such studies, either proposed or reported.

A comparison of cigarette smokers recruited through the Internet or by mail. J. F. Etter, T. V. Perneger. Int J Epidemiol 2001: 30(3); 521-5. OBJECTIVES: To compare smokers recruited by mail or through the Internet. METHODS: A questionnaire was mailed to 19,352 inhabitants of Switzerland in 1998, in an effort to enroll them in a smoking cessation trial. The same questionnaire was also available on the Internet. Furthermore, we mailed a survey to a representative sample (n = 1000) of the population of Geneva, Switzerland, in 1996. In this study, we compare three groups: 1027 smokers recruited through the Internet, 2961 volunteer trial participants recruited by mail (response rate 16%), and 211 smokers in the representative sample also recruited by mail (response rate 75%). RESULTS: Smokers self-recruited through the Internet were younger, more educated, more motivated to quit smoking and smoked more cigarettes per day than smokers in the other samples. Compared to trial participants, Internet participants had more negative attitudes towards smoking, higher self-efficacy scores, and were more addicted to tobacco. The strength of associations between smoking-related variables was similar in Internet and trial participants. CONCLUSION: As expected, the three groups of smokers differed on several characteristics. However, bias in distributions of variables did not imply bias in associations between variables. Thus, Internet recruitment is a potentially useful method for analytical studies that focus on associations between variables.

Uptake of screening and prevention in women at very high risk of breast cancer. D. Evans, F. Lalloo, A. Shenton, C. Boggis, A. Howell. Lancet 2001: 358(9285); 889-90. Management of women at high lifetime risk of familial breast cancer is hampered because of limited data concerning the appropriateness of treatment options. Over the past 8 years women at very high (>40%) lifetime risk of breast cancer have had the option of entering two chemoprevention treatment trials, a magnetic resonance imaging (MRI) breast screening study, or a risk-reducing mastectomy (RRM) study. Only 10% of eligible women have entered one of the chemotherapy trials with a similar proportion opting for RRM (>50% in mutation carriers) compared with 60% opting for MRI screening. Future chemotherapy trials will have to be designed to address this poor recruitment.

The healthy control subject in psychiatric research: impulsiveness and volunteer bias. J. P. Gustavsson, M. Asberg, D. Schalling. Acta Psychiatr Scand 1997: 96(5); 325-8. Exciting and demanding biomedical experiments may attract a specific subgroup of people as volunteers. In the present study of selection bias, subjects volunteering in a psychobiological study that included a potentially painful procedure (lumbar puncture) were compared with those who declined to participate, with regard to scores on personality scales administered during a previous investigation of the same subjects. Significant differences were found on the Eysenck Personality Questionnaire and Karolinska Scales of Personality Impulsiveness scale, suggesting an over-representation of impulsive individuals among the volunteers. If the specific subject of investigation has implications for the type of individual who will participate as a healthy volunteer in biomedical research, variation will be introduced, affecting the independent variable, and the conclusions that can be drawn from such research may be questionable.

Are Subjects in Pharmacological Treatment Trials of Depression Representative of Patients in Routine Clincal Practice. M. Zimmerman, J.I. Mattia, Michael A. Posternak. American Journal of Psychiatry 2002: 159(3); 469-473. (A nice overview appears in the Lancet at http://www.thelancet.com/journal/vol359/iss9308/full/llan.359.9308.news.20219.2) OBJECTIVE: The methods used to evaluate the efficacy of antidepressants differ from treatment for depression in routine clinical practice. The rigorous inclusion/exclusion criteria used to select subjects for participation in efficacy studies potentially limit the generalizability of these trials' results. It is unknown how much impact these criteria have on the representativeness of subjects in efficacy trials. This study estimated the proportion of depressed patients treated in routine clinical practice who would meet standard inclusion/exclusion criteria for an efficacy trial. METHOD: A total of 803 individuals, aged 16--65 years, who were seen at intake at an outpatient practice underwent a thorough diagnostic evaluation, including the administration of semistructured diagnostic interviews; 346 patients had current major depression. Common inclusion/exclusion criteria used in efficacy studies of antidepressants were applied to the depressed patients to determine how many would have qualified for an efficacy trial. RESULTS: Approximately one-sixth of the 346 depressed patients would have been excluded from an efficacy trial because they had a bipolar or psychotic subtype of depression. The presence of a comorbid anxiety or substance use disorder, insufficient severity of depressive symptoms, or current suicidal ideation would have excluded 86.0% (N=252) of the remaining 293 outpatients with nonpsychotic unipolar major depressive disorder from an antidepressant efficacy trial. CONCLUSIONS: Subjects treated in antidepressant trials represent a minority of patients treated for major depression in routine clinical practice. These results show that antidepressant efficacy trials tend to evaluate a subset of depressed individuals with a specific clinical profile.

A genetic bias in clinical trials? Cytochrome P450-2D6 (CYP2D6) genotype in general vs selected healthy subject populations [letter]. S. Chen, S. Kumar, W. H. Chou, J. S. Barrett, P. J. Wedlund. Br J Clin Pharmacol 1997: 44(3); 303-4.

Older references (check for inclusion among newer references)

Unjustified exclusion of elderly people from studies submitted to research ethics committee for approval: descriptive study. A. Bayer and W. Tadd. British Medical Journal 2000:321(7267);992-3. Abstract not available yet. [Medline] [Full text] [PDF]

Exclusion of elderly people from clinical research: a descriptive study of published reports. G. Bugeja, A. Kumar and A. K. Banerjee. British Medical Journal 1997:315(7115);1059. Abstract not available yet. [Medline] [Full text]

Hold the Lard! The Atkins Diet still doesn't work.. Michael Fumento. Accessed on 2002-12-06. A careful analysis of the recent research on the Atkins diet shows that there was a much higher drop out rate in that group, which could partially explain the promising results of this diet. www.reason.com/hod/mf120502.shtml

Participation in Research and Access to Experimental Treatments by HIV-Infected Patients. Allen L. Gifford, William E. Cunningham, Kevin C. Heslin, Ron M. Andersen, Terry Nakazono, Dale K. Lieu, Martin F. Shapiro, Samuel A. Bozzette and the HIV Cost and Services Utilization Study Consortium. N Engl J Med 2002:346(18);1373-1382. Background Although there is concern that minority groups and women are underrepresented in research involving patients with human immunodeficiency virus (HIV) infection, the available data are inconclusive. Methods We used nationally representative data from the HIV Cost and Services Utilization Study to determine the characteristics of the participants and nonparticipants in trials of medications for HIV infection and whether or not patients had access to experimental treatments. A probability sample of 2864 persons, representing all 231,400 adults with known HIV infection who are cared for in the contiguous United States, were interviewed on three occasions between 1996 and 1998. They were asked about participation in clinical research studies of medications and past receipt of experimental medications for HIV. Results We estimate that 14 percent of adults receiving care for HIV infection participated in a medication trial or study; 24 percent had received experimental medications; and 8 percent had tried and failed to obtain experimental treatments. According to multivariate models, non-Hispanic blacks and Hispanics were less likely to be participating in trials than non-Hispanic whites (odds ratio for participation among non-Hispanic blacks, 0.50 [95 percent confidence interval, 0.28 to 0.91]; odds ratio among Hispanics, 0.58 [95 percent confidence interval, 0.37 to 0.93]) and to have received experimental medications (odds ratios, 0.41 [95 percent confidence interval, 0.32 to 0.54] and 0.56 [95 percent confidence interval, 0.41 to 0.78], respectively). Patients who were cared for in private health maintenance organizations were less likely to participate in trials than those with fee-for-service insurance (odds ratio, 0.43 [95 percent confidence interval, 0.21 to 0.88]). Women were not underrepresented in research trials and had a similar likelihood of receiving experimental treatments. Conclusions Among patients with HIV infection, participation in research trials and access to experimental treatment is influenced by race or ethnic group and type of health insurance. [Abstract]

The exclusion of the elderly and women from clinical trials in acute myocardial infarction. J. H. Gurwitz, N. F. Col and J. Avorn. Jama 1992:268(11);1417-22. OBJECTIVE--To determine the extent to which the elderly have been excluded from trials of drug therapies used in the treatment of acute myocardial infarction, to identify factors associated with such exclusions, and to explore the relationship between the exclusion of elderly and the representation of women. DATA SOURCES--We conducted a systematic search of the English-language literature from January 1960 through September 1991 to identify all relevant studies of specific pharmacotherapies employed in the treatment of acute myocardial infarction. To accomplish this, we searched MEDLINE, major cardiology textbooks, meta-analyses, reviews, editorials, and the bibliographies of all identified articles. STUDY SELECTION--Only trials in which patients were randomly allocated to receive a specific therapeutic regimen or a placebo or nonplacebo control regimen were included for review. DATA EXTRACTION--Studies were abstracted for year of publication, source of support, performance location, drug therapies to which patients were randomized, use of invasive diagnostic tests or therapeutic procedures, exclusion criteria, size and demographic characteristics of the randomized study population, and principal outcome measures. DATA SYNTHESIS--A total of 214 trials met inclusion criteria, involving 150,920 study subjects. Over 60% of trials excluded persons over the age of 75 years. Studies published after 1980 were more likely to have age-based exclusions compared with studies published before 1980 (adjusted odds ratio, 4.92; 95% confidence interval, 2.33 to 10.54). Trials of thrombolytic therapy involving an invasive procedure were more likely to exclude elderly patients compared with other studies (adjusted odds ratio, 2.45; 95% confidence interval, 1.10 to 5.47). Studies with age-based exclusions had a smaller percentage of women compared with those without such exclusions (18% vs 23%; P = .0002), with the mean age of the study population significantly associated with the proportion of women participants (P = .0001, R2 = .29). CONCLUSIONS--Age-based exclusions are frequently used in clinical trials of medications used in the treatment of acute myocardial infarction. Such exclusions limit the ability to generalize study findings to the patient population that experiences the most morbidity and mortality from acute myocardial infarction.

Randomised study of long term outcome after epidural versus non-epidural analgesia during labour. C. J. Howell, T. Dean, L. Lucking, K. Dziedzic, P. W. Jones and R. B. Johanson. Bmj 2002:325(7360);357. OBJECTIVE: To determine whether epidural analgesia during labour is associated with long term backache. DESIGN: Follow up after randomised controlled trial. Analysis by intention to treat. SETTING: Department of obstetrics and gynaecology at one NHS trust. PARTICIPANTS: 369 women: 184 randomised to epidural group (treatment as allocated received by 123) and 185 randomised to non-epidural group (treatment as allocated received by 133). In the follow up study 151 women were from the epidural group and 155 from the non-epidural group. MAIN OUTCOME MEASURES: Self reported low back pain, disability, and limitation of movement assessed through one to one interviews with physiotherapist, questionnaire on back pain and disability, physical measurements of spinal mobility. RESULTS: There were no significant differences between groups in demographic details or other key characteristics. The mean time interval from delivery to interview was 26 months. There were no significant differences in the onset or duration of low back pain, with nearly a third of women in each group reporting pain in the week before interview. There were no differences in self reported measures of disability in activities of daily living and no significant differences in measurements of spinal mobility. CONCLUSIONS: After childbirth there are no differences in the incidence of long term low back pain, disability, or movement restriction between women who receive epidural pain relief and women who receive other forms of pain relief. [Medline]

Do safety practices differ between responders and non-responders to a safety questionnaire? D. Kendrick, R. Hapgood and P. Marsh. Injury Prevention 2001:7(2);100-3. OBJECTIVE: To compare reported safety practices between responders and non-responders to a safety survey. DESIGN: Cross sectional survey at baseline compared with safety practices reported at subsequent child health surveillance checks. SUBJECTS: Parents of children aged 3-12 months registered with practices participating in a controlled trial of injury prevention in primary care that did, and did not, respond to the baseline survey and who subsequently attended child health surveillance checks. RESULTS: No difference in safety practices was found between responders and non-responders to the survey at the 6-9 month check. Responders were more likely to report owning a stair gate (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.82 to 4.16) and socket covers (OR 2.16, 95% CI 1.53 to 3.04) at the 12-15 month check, and owning socket covers (OR 2.19, 95% CI 1.34 to 3.61) at the 18-24 month check. Responders were more likely to report greater than the median number of safety practices at the 18 month check. CONCLUSIONS: Non-responders to a safety survey appear to be less likely to report owning several items of safety equipment than responders. Further work is needed to confirm these findings. Extrapolating the results of safety surveys to the population as a whole may lead to over estimation of safety equipment possession. [Medline]

Spectrum bias in the evaluation of diagnostic tests: lessons from the rapid dipstick test for urinary tract infection. M. S. Lachs, I. Nachamkin, P. H. Edelstein, J. Goldman, A. R. Feinstein and J. S. Schwartz. Ann Intern Med 1992:117(2);135-40. OBJECTIVE: To determine if the leukocyte esterase and bacterial nitrite rapid dipstick test for urinary tract infection (UTI) is susceptible to spectrum bias (when a diagnostic test has different sensitivities or specificities in patients with different clinical manifestations of the disease for which the test is intended). DESIGN: Cross-sectional study. PATIENTS: A total of 366 consecutive adult patients in whom clinicians performed urinalysis to diagnose or exclude UTI. SETTING: An urban emergency department and walk-in clinic. MEASUREMENTS: After the patient encounter, but before dipstick test or culture was done, clinicians recorded the signs and symptoms that were the basis for suspecting UTI and for performing a urinalysis and an estimate of the probability of UTI based on the clinical evaluation. For all patients who received urinalysis, dipstick tests and culture were done in the clinical microbiology laboratory by medical technologists blinded to clinical evaluation. Sensitivity for the dipstick was calculated using a positive result in either leukocyte esterase or bacterial nitrite, or both, as the criterion for a positive dipstick, and greater than 10(5) CFU/mL for a positive culture. RESULTS: In the 107 patients with a high (greater than 50%) prior probability of UTI, who had many characteristic UTI symptoms, the sensitivity of the test was excellent (0.92; 95% CI, 0.82 to 0.98). In the 259 patients with a low (less than or equal to 50%) prior probability of UTI, the sensitivity of the test was poor (0.56; CI, 0.03 to 0.79). CONCLUSIONS: The leukocyte esterase and bacterial nitrite dipstick test for UTI is susceptible to spectrum bias, which may be responsible for differences in the test's sensitivity reported in previous studies. As a more general principle, diagnostic tests may have different sensitivities or specificities in different parts of the clinical spectrum of the disease they purport to identify or exclude, but studies evaluating such tests rarely report sensitivity and specificity in subgroups defined by clinical symptoms. When diagnostic tests are evaluated, information about symptoms in the patients recruited for study should be included, and analyses should be done within appropriate clinical subgroups so that clinicians may decide if reported sensitivities and specificities are applicable to their patients. [Medline]

Comorbidity of chronic diseases in general practice. F. G. Schellevis, J. van der Velden, E. van de Lisdonk, J. T. van Eijk and C. van Weel. J Clin Epidemiol 1993:46(5);469-73. With the increasing number of elderly people in The Netherlands the prevalence of chronic diseases will rise in the next decades. It is recognized in general practice that many older patients suffer from more than one chronic disease (comorbidity). The aim of this study is to describe the extent of comorbidity for the following diseases: hypertension, chronic ischemic heart disease, diabetes mellitus, chronic nonspecific lung disease, osteoarthritis. In a general practice population of 23,534 persons, 1989 patients have been identified with one or more chronic diseases. Only diseases in agreement with diagnostic criteria were included. In persons of 65 and older 23% suffer from one or more of the chronic diseases under study. Within this group 15% suffer from more than one of the chronic diseases. Osteoarthritis and diabetes mellitus are the diseases with the highest rate of comorbidity. Comorbidity restricts the external validity of results from single-disease intervention studies and complicates the organization of care.

Sample size slippages in randomized trials: exclusions and the lost and wayward. K. F. Schulz and D.A. Grimes. Lancet 2002:359(781-785. Proper randomisation means little if investigators cannot include all randomised participants in the primary analysis. Participants might ignore follow-up, leave town, or take aspartame when instructed to take aspirin. Exclusions before randomisation do not bias the treatment comparison, but they can hurt generalisability. Eligibility criteria for a trial should be clear, specific, and applied before randomisation. Readers should assess whether any of the criteria make the trial sample atypical or unrepresentative of the people in which they are interested. In principle, assessment of exclusions after randomisation is simple: none are allowed. For the primary analysis, all participants enrolled should be included and analysed as part of the original group assigned (an intent-to-treat analysis). In reality, however, losses frequently occur. Investigators should, therefore, commit adequate resources to develop and implement procedures to maximise retention of participants. Moreover, researchers should provide clear, explicit information on the progress of all randomised participants through the trial by use of, for instance, a trial profile. Investigators can also do secondary analyses on, for instance, per-protocol or as-treated participants. Such analyses should be described as secondary and non-randomised comparisons. Mishandling of exclusions causes serious methodological difficulties. Unfortunately, some explanations for mishandling exclusions intuitively appeal to readers, disguising the seriousness of the issues. Creative mismanagement of exclusions can undermine trial validity.

Nonresponse bias and early versus all responders in mail and telephone surveys. J. Siemiatycki and S. Campbell. Am J Epidemiol 1984:120(2);p291-301. Mail and telephone survey methods, with or without follow-up by other methods, are cost-effective alternatives to the conventional home interview approach. However, it has long been thought that they are especially susceptible to nonresponse bias. The study addressed this issue in the context of parallel mail and telephone health surveys carried out in Montreal. The mail strategy among 1,555 adults achieved 68.5% response and follow-up by telephone and home interview increased response to 80.9%. Respondents were adequately representative of the entire sample with respect to socioeconomic status, number of adults in household, and ethnic distribution. The 68.5% initial stage respondents were similar to all respondents on the above variables as well as on age, sex, education and reported health status. Odds ratios of smoking and respiratory symptoms hardly differed between initial stage and all respondents. The telephone survey among 1,595 adults achieved 72.7% response and follow-up by mail and personal interview increased response to 88.2%. Comparisons between respondents and the entire sample and between initial stage respondents and all respondents gave similar results to those found in the mail strategy, although there was some change in a symptom-smoking odds ratio from the initial stage respondents to all respondents. In both survey strategies, there was no evidence of substantial nonresponse bias and estimates of morbidity and health care would not have differed much if the fieldwork had stopped at the initial mail or telephone stage.

Ozone Depletion, History and politics. Brien Sparling. Accessed on 2002-11-27. "Ground based measurements of Ozone were first started in 1956, in at Halley Bay, Antarctica. Satellite measurements of ozone started in the early 70's, but the first comprehensive worldwide measurements started in 1978 with the Nimbus-7 satellite. Nimbus-7 carried a TOMS (total ozone mapping spectrometer, and a SBUV(solar backscatter UV meter). The TOMS finally broke on May 7th,1993, but today there are several different satellites measuring concentrations of ozone and other atmosheric gases. Gases in the troposphere and lower stratosphere are sampled by weather balloons or by airplanes such as the ER-2 managed by NASA." www.nas.nasa.gov/About/Education/Ozone/history.html

Applying evidence to the individual patient. S. E. Straus and D. L. Sackett. Ann Oncol 1999:10(1);29-32. Abstract not available yet. [Medline]

The Effect of School Dropout Rates on Estimates of Adolescent Substance Use among Three Racial/Ethnic Groups. Randall C. Swaim, F Beauvais, EL Chavez and ER Oetting. American Journal of Public Health 1997:87(1);51-55. ABSTRACT: OBJECTIVES: This study examined, across three racial/ethnic groups, how the inclusion of data on drug use of dropouts can alter estimates of adolescent drug use rates. METHODS: Self-report rates of lifetime prevalence and use in the previous 30 days were obtained from Mexican American, White non-Hispanic, and Native American student (n = 738) and dropouts (n = 774). Rates for the age cohort (students and dropouts) were estimated with a weighted correction formula. RESULTS: Rates of use reported by dropouts were 1.2 to 6.4 times higher than those reported by students. Corrected rates resulted in changes in relative rates of use by different ethnic groups. CONCLUSIONS: When only in-school data are available, errors in estimating drug use among groups with high rates of school dropout can be substantial. Correction of student-based data to include drug use of dropouts leads to important changes in estimated levels of drug use and alters estimates of the relative rates of use for racial/ethnic minority groups with high dropout rates.

Physicians' reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. K. M. Taylor, R. G. Margolese and C. L. Soskolne. N Engl J Med 1984:310(21);p1363-7. We studied the reasons surgical principal investigators chose not to enter patients in a large, multicenter trial sponsored by a cooperative group. In 1976 the National Surgical Adjuvant Project for Breast and Bowel Cancers (NSABP) initiated a clinical trial to compare segmental mastectomy and postoperative radiation, or segmental mastectomy alone, with total mastectomy. Because the low rates of accrual were threatening to close the trial prematurely, we mailed a questionnaire to the 94 NSABP principal investigators, asking why they were not entering eligible patients in the trial. A response rate of 97 per cent was achieved. Physicians who did not enter all eligible patients offered the following explanations: (1) concern that the doctor-patient relationship would be affected by a randomized clinical trial (73 per cent), (2) difficulty with informed consent (38 per cent), (3) dislike of open discussions involving uncertainty (22 per cent), (4) perceived conflict between the roles of scientist and clinician (18 per cent), (5) practical difficulties in following procedures (9 per cent), and (6) feelings of personal responsibility if the treatments were found to be unequal (8 per cent). Further investigation into the behavioral aspects of the investigator-patient relationship is particularly pressing, since fear of change in this relationship was the most common reason given for not entering eligible patients in the trial.

Representation of older patients in cancer treatment trials. EL Trimble, CL Carter, D Cain, B Freidlin, RS Ungerleider and MA Friedman. Cancer 1994:74(7);2208-14. ABSTRACT: In 1990, the five leading causes of cancer death in men aged 65 and older were carcinomas of the lung, prostate, colon and rectum, and pancreas, and leukemia. For women in this age group, the five leading causes of cancer death were carcinomas of the lung, breast, colon and rectum, pancreas, and ovary. To determine the representation of the elderly in clinical trials, the 1992 accrual of the National Cancer Institute (NCI)-sponsored Clinical Cooperative Group treatment trials (which included more than 8000 elderly patients) for the aforementioned sites was compared with the 1990 incidence data from the NCI's Surveillance, Epidemiology, and End Results program. Of the male patients enrolled in the trials, an average of 39% were older than 65 (47.3% lung, 79.5% prostate, 47.5% colorectal, 45.6% pancreas, and 9.6% leukemia); whereas 25.9% of all women enrolled in trials were 65 or older (43.6% lung, 17.3% breast, 46.2% colorectal, 59.6% pancreas, and 35.4% ovary). With respect to incidence, older patients generally are underrepresented in cancer treatment trials. With the exception of the data on prostate cancer, each of the comparisons using the Z statistic gave probability values of less than 0.01. The most significant discrepancies between incidence and participation in cancer treatment protocols were noted for leukemia in males and breast cancer in females. Possible explanations for these findings include (1) a research focus on aggressive therapy, which may be unacceptably toxic to the elderly; (2) presence of comorbidity in the elderly; (3) fewer trials available specifically aimed at older patients; (4) limited expectations for long term benefits on the part of physicians, relatives, and the patients themselves; and (5) a lack of financial, logistic, and social support for the participation of elderly patients in clinical trials. Recognizing this situation, NCI recently sponsored a number of trials that specifically target the elderly. This paper describes the status of all major Phase II and III clinical trials that recently were closed, still are active, or now are in review that address the clinical care of this important segment of the U.S. population.

Are Subjects in Pharmacological Treatment Trials of Depression Representative of Patients in Routine Clincal Practice. M. Zimmerman, J.I. Mattia and Michael A. Posternak. American Journal of Psychiatry 2002:159(3);469-473. OBJECTIVE: The methods used to evaluate the efficacy of antidepressants differ from treatment for depression in routine clinical practice. The rigorous inclusion/exclusion criteria used to select subjects for participation in efficacy studies potentially limit the generalizability of these trials' results. It is unknown how much impact these criteria have on the representativeness of subjects in efficacy trials. This study estimated the proportion of depressed patients treated in routine clinical practice who would meet standard inclusion/exclusion criteria for an efficacy trial. METHOD: A total of 803 individuals, aged 16--65 years, who were seen at intake at an outpatient practice underwent a thorough diagnostic evaluation, including the administration of semistructured diagnostic interviews; 346 patients had current major depression. Common inclusion/exclusion criteria used in efficacy studies of antidepressants were applied to the depressed patients to determine how many would have qualified for an efficacy trial. RESULTS: Approximately one-sixth of the 346 depressed patients would have been excluded from an efficacy trial because they had a bipolar or psychotic subtype of depression. The presence of a comorbid anxiety or substance use disorder, insufficient severity of depressive symptoms, or current suicidal ideation would have excluded 86.0% (N=252) of the remaining 293 outpatients with nonpsychotic unipolar major depressive disorder from an antidepressant efficacy trial. CONCLUSIONS: Subjects treated in antidepressant trials represent a minority of patients treated for major depression in routine clinical practice. These results show that antidepressant efficacy trials tend to evaluate a subset of depressed individuals with a specific clinical profile.

What are the characteristics of general practitioners who routinely do not return postal questionnaires: a cross sectional study. Nigel Stocks, David Grunnell. J Epidemiol Community Health 2000; 54:940-941.

Assessing the generalizability of smoking studies. Hughes JR, Giovino RM, Flore MC. Addiction 1997; 92:469-472.

Intention-to-treat principle. Victor M. Montori, Gordon H. Guyatt. CMAJ 2001;165(10):1339-41. http://www.cma.ca/cmaj/vol-165/issue-10/1339.asp

A comparison of cigarette smokers recruited through the Internet or by mail. Jean-Francois Etter and Thomas V Perneger. International Journal of Epidemiology 2001; 30:521-525.

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