Paul A. Kvale

Mortality Results from a Randomized Prostate-Cancer Screening Trial

BACKGROUND The effect of screening with prostate-specific-antigen (PSA) testing and digital rectal examination on the rate of death from prostate cancer is unknown. This is the first report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality. METHODS From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained. RESULTS In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings. CONCLUSIONS After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. (ClinicalTrials.gov number, NCT00002540.)

Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up

BACKGROUND The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was undertaken to determine whether there is a reduction in prostate cancer mortality from screening using serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE). Mortality after 7-10 years of follow-up has been reported previously. We report extended follow-up to 13 years after the trial. METHODS A total of 76 685 men, aged 55-74 years, were enrolled at 10 screening centers between November 1993 and July 2001 and randomly assigned to the intervention (organized screening of annual PSA testing for 6 years and annual DRE for 4 years; 38 340 men) and control (usual care, which sometimes included opportunistic screening; 38 345 men) arms. Screening was completed in October 2006. All incident prostate cancers and deaths from prostate cancer through 13 years of follow-up or through December 31, 2009, were ascertained. Relative risks (RRs) were estimated as the ratio of observed rates in the intervention and control arms, and 95% confidence intervals (CIs) were calculated assuming a Poisson distribution for the number of events. Poisson regression modeling was used to examine the interactions with respect to prostate cancer mortality between trial arm and age, comorbidity status, and pretrial PSA testing. All statistical tests were two-sided. RESULTS Approximately 92% of the study participants were followed to 10 years and 57% to 13 years. At 13 years, 4250 participants had been diagnosed with prostate cancer in the intervention arm compared with 3815 in the control arm. Cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10 000 person-years, respectively, resulting in a relative increase of 12% in the intervention arm (RR = 1.12, 95% CI = 1.07 to 1.17). After 13 years of follow-up, the cumulative mortality rates from prostate cancer in the intervention and control arms were 3.7 and 3.4 deaths per 10 000 person-years, respectively, resulting in a non-statistically significant difference between the two arms (RR = 1.09, 95% CI = 0.87 to 1.36). No statistically significant interactions with respect to prostate cancer mortality were observed between trial arm and age (P(interaction) = .81), pretrial PSA testing (P(interaction) = .52), and comorbidity (P(interaction) = .68). CONCLUSIONS After 13 years of follow-up, there was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing.

Bacterial Pneumonia in Persons Infected with the Human Immunodeficiency Virus

BACKGROUND Patients with human immunodeficiency virus (HIV) infection are at increased risk for bacterial pneumonia in addition to opportunistic infection. However, the risk factors for bacterial pneumonia and its incidence in this population are not well defined. METHODS In a multicenter, prospective, observational study, we monitored 1130 HIV-positive and 167 HIV-negative participating adults for up to 64 months for pulmonary disease. The HIV-positive group comprised 814 homosexual or bisexual men, 261 injection-drug users, and 55 female partners of HIV-infected men. RESULTS There were 237 episodes of bacterial pneumonia among the HIV-positive participants (rate, 5.5 per 100 person-years), as compared with 6 episodes among the HIV-negative participants (rate, 0.9 per 100 person-years; P < 0.001). The rate of bacterial pneumonia increased with decreasing CD4 lymphocyte counts (2.3, 6.8, and 10.8 episodes per 100 person-years in the strata with more than 500, 200 to 500, and fewer than 200 cells per cubic millimeter, respectively; P < or = 0.022 for each comparison). Injection-drug users had a higher rate of bacterial pneumonia than did homosexual or bisexual men or female partners. In the stratum with the fewest CD4 lymphocytes, cigarette smoking was associated with an increased rate of pneumonia. Mortality was almost four times higher among participants with an episode of pneumonia than among the others. Prophylaxis with trimethoprim-sulfamethoxazole was associated with a 67 percent reduction in confirmed episodes of bacterial pneumonia (P = 0.007). CONCLUSIONS Bacterial pneumonia is more frequent in HIV-positive persons than in seronegative controls, and the risk is highest among those with CD4 lymphocyte counts below 200 per cubic millimeter and among injection-drug users.

Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines

Recognition of the importance of cough in clinical medicine was the impetus for the original evidence-based consensus panel report on “Managing Cough as a Defense Mechanism and as a Symptom,” published in 1998,1 and this updated revision. Compared to the original cough consensus statement, this revision (1) more narrowly focuses the guidelines on the diagnosis and treatment of cough, the symptom, in adult and pediatric populations, and minimizes the discussion of cough as a defense mechanism; (2) improves on the rigor of the evidence-based review and describes the methodology in a separate section; (3) updates and expands, when appropriate, all previous sections; and (4) adds new sections with topics that were not previously covered. These new sections include nonasthmatic eosinophilic bronchitis (NAEB); acute bronchitis; nonbronchiectatic suppurative airway diseases; cough due to aspiration secondary to oral/pharyngeal dysphagia; environmental/occupational causes of cough; tuberculosis (TB) and other infections; cough in the dialysis patient; uncommon causes of cough; unexplained cough, previously referred to as idiopathic cough; an empiric integrative approach to the management of cough; assessing cough severity and efficacy of therapy in clinical research; potential future therapies; and future directions for research.

Screening by chest radiograph and lung cancer mortality: The Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial

CONTEXT The effect on mortality of screening for lung cancer with modern chest radiographs is unknown. OBJECTIVE To evaluate the effect on mortality of screening for lung cancer using radiographs in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial that involved 154,901 participants aged 55 through 74 years, 77,445 of whom were assigned to annual screenings and 77,456 to usual care at 1 of 10 screening centers across the United States between November 1993 and July 2001. The data from a subset of eligible participants for the National Lung Screening Trial (NLST), which compared chest radiograph with spiral computed tomographic (CT) screening, were analyzed. INTERVENTION Participants in the intervention group were offered annual posteroanterior view chest radiograph for 4 years. Diagnostic follow-up of positive screening results was determined by participants and their health care practitioners. Participants in the usual care group were offered no interventions and received their usual medical care. All diagnosed cancers, deaths, and causes of death were ascertained through the earlier of 13 years of follow-up or until December 31, 2009. MAIN OUTCOME MEASURES Mortality from lung cancer. Secondary outcomes included lung cancer incidence, complications associated with diagnostic procedures, and all-cause mortality. RESULTS Screening adherence was 86.6% at baseline and 79% to 84% at years 1 through 3; the rate of screening use in the usual care group was 11%. Cumulative lung cancer incidence rates through 13 years of follow-up were 20.1 per 10,000 person-years in the intervention group and 19.2 per 10,000 person-years in the usual care group (rate ratio [RR]; 1.05, 95% CI, 0.98-1.12). A total of 1213 lung cancer deaths were observed in the intervention group compared with 1230 in usual care group through 13 years (mortality RR, 0.99; 95% CI, 0.87-1.22). Stage and histology were similar between the 2 groups. The RR of mortality for the subset of participants eligible for the NLST, over the same 6-year follow-up period, was 0.94 (95% CI, 0.81-1.10). CONCLUSION Annual screening with chest radiograph did not reduce lung cancer mortality compared with usual care. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00002540.

Selection Criteria for Lung-Cancer Screening

BACKGROUND The National Lung Screening Trial (NLST) used risk factors for lung cancer (e.g., ≥30 pack-years of smoking and <15 years since quitting) as selection criteria for lung-cancer screening. Use of an accurate model that incorporates additional risk factors to select persons for screening may identify more persons who have lung cancer or in whom lung cancer will develop. METHODS We modified the 2011 lung-cancer risk-prediction model from our Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to ensure applicability to NLST data; risk was the probability of a diagnosis of lung cancer during the 6-year study period. We developed and validated the model (PLCO(M2012)) with data from the 80,375 persons in the PLCO control and intervention groups who had ever smoked. Discrimination (area under the receiver-operating-characteristic curve [AUC]) and calibration were assessed. In the validation data set, 14,144 of 37,332 persons (37.9%) met NLST criteria. For comparison, 14,144 highest-risk persons were considered positive (eligible for screening) according to PLCO(M2012) criteria. We compared the accuracy of PLCO(M2012) criteria with NLST criteria to detect lung cancer. Cox models were used to evaluate whether the reduction in mortality among 53,202 persons undergoing low-dose computed tomographic screening in the NLST differed according to risk. RESULTS The AUC was 0.803 in the development data set and 0.797 in the validation data set. As compared with NLST criteria, PLCO(M2012) criteria had improved sensitivity (83.0% vs. 71.1%, P<0.001) and positive predictive value (4.0% vs. 3.4%, P=0.01), without loss of specificity (62.9% and. 62.7%, respectively; P=0.54); 41.3% fewer lung cancers were missed. The NLST screening effect did not vary according to PLCO(M2012) risk (P=0.61 for interaction). CONCLUSIONS The use of the PLCO(M2012) model was more sensitive than the NLST criteria for lung-cancer detection.

INCIDENCE OF TUBERCULOSIS IN THE UNITED STATES AMONG HIV-INFECTED PERSONS. THE PULMONARY COMPLICATIONS OF HIV INFECTION STUDY GROUP

Among opportunistic pathogens associated with the acquired immunodeficiency syndrome (AIDS), Mycobacterium tuberculosis is distinguished by its relative virulence and potential for person-to-person transmission. Persons infected with human immunodeficiency virus (HIV) are particularly susceptible to tuberculosis, both from the reactivation of latent infection and from new infection with rapid progression to active disease [1-4]. The annual incidence of tuberculosis in the United States was 8.7 per 100 000 persons in 1995 [5], but rates 1000-fold higher have been reported in some HIV-seropositive populations [6-14]. Most studies have been restricted by geography, HIV-risk group, or specific high-prevalence settings; such restrictions have resulted in an inaccurate assessment of the overall effect of the HIV epidemic on the incidence of tuberculosis in the United States [15, 16]. The Pulmonary Complications of HIV Infection Study (PCHIS) [17] prospectively followed HIV-seropositive patients who had demographic variables similar to those of patients with AIDS in the United States. Participants with asymptomatic or symptomatic HIV infection were recruited from sites in the eastern, midwestern, and western United States. A previous report on this cohort [18] identified determinants of delayed-type hypersensitivity response and risk factors for tuberculin reactivity. We examined the incidence of tuberculosis among patients enrolled in the PCHIS for a median observation period of approximately 4.5 years. Methods Patients and Study Design The PCHIS was a multicenter, prospective study of the frequency and spectrum of pulmonary disorders in persons infected with HIV. From November 1988 through February 1990, 1171 HIV-seropositive persons and 182 HIV-seronegative persons were enrolled at centers in six U.S. cities: New York; Newark, New Jersey; Detroit; Chicago; San Francisco; and Los Angeles. Participants were followed through 31 March 1994. We report on 1130 HIV-infected persons from the PCHIS who were followed past baseline. Participants were recruited to represent a range of severity of HIV disease. Approximately half of the participants at each center had CD4 lymphocyte counts of 400 cells/mm3 or more and no HIV-related symptoms, and half had CD4 lymphocyte counts of less than 400 cells/mm3 or symptomatic HIV infection. Both groups included persons from one of three HIV-transmission categories: homosexual men, male and female injection drug users, and women who had acquired HIV through heterosexual contact. Exclusion criteria were AIDS, as defined by the Centers for Disease Control and Prevention (CDC) [19]; acute pulmonary processes; use of immunosuppressive therapy in the past 6 months; and treatment of tuberculosis in the past 12 months. The study was approved by the institutional review board at each site, and participants gave informed consent. At baseline and at regular intervals, clinical monitoring (including T-lymphocyte subset analysis and chest roentgenography) was done, and participants were acutely evaluated if new pulmonary symptoms occurred. Centers used the same predetermined diagnostic algorithms that were initiated if specified criteria were met. Complete details of the study design have been described elsewhere [17]. Delayed hypersensitivity was tested at baseline and then annually using purified protein derivative (PPD) tuberculin at a strength of 5 TU per 0.1-mL dose and mumps antigen (Connaught Laboratories, Inc., Swiftwater, Pennsylvania). Tests were administered by intradermal injection of 0.1 mL of antigen by the Mantoux method and read by experienced nurses 48 to 72 hours later in most cases (the interval exceeded 4 days in 18 persons). A positive response to PPD was defined as an induration at least 5 mm in diameter. Any person who was not positive when first tested but who became positive on any subsequent test was considered to be a tuberculin converter. A positive response to mumps was defined as any degree of induration (>0 mm). The criteria for anergy was nonreactivity (0 mm) to both PPD and mumps antigen. Pulmonary tuberculosis was defined by the isolation of M. tuberculosis from a respiratory tract specimen or by improvement on chest radiography in response to specific multidrug antituberculous therapy. Patients who were diagnosed with extrapulmonary tuberculosis had clinically compatible disease and response to specific therapy, with or without the isolation of the organism from a site outside the lung. Patients who were considered to have both pulmonary and extrapulmonary tuberculosis met each set of criteria. These requirements are consistent with those of the CDC for reporting cases of tuberculosis [20], except that we did not require patients to be PPD positive if they had disease that was not mycobacteriologically confirmed. Statistical Analysis Tuberculosis rates were calculated as the number of cases divided by the number of years that patients were followed multiplied by 100. Except as noted below, the length of time that patients were followed was calculated for each person starting from enrollment and continuing until one of the following occurred: diagnosis of tuberculosis, death from any cause, the last study visit, or 31 March 1994. Statistical significance for comparison of rates was determined by tests for person-time data done on the basis of binomial distribution [21]. P values were determined by an exact test when sample sizes were insufficient and by an asymptotic test when sizes were sufficient. All tests were two-sided, and a P value of 0.05 was considered significant. Exact 95% CIs were calculated for rates by assuming the numerator to be a Poisson variable [22] and for rate ratios using a modified binomial model [21]. Adjusted rate ratios for comparisons among groups defined by demographic variables were calculated by using a Mantel-Haenszel type estimator for incidence-rate data with approximate 95% confidence limits based on the tests [21]. Seventy-three participants, including women who had acquired HIV through heterosexual contact and persons were not black, white, or Hispanic, were excluded from some calculations of adjusted rates because of small sample sizes. Distributions of time to death among patients with tuberculosis were estimated using the Kaplan-Meier method, and comparisons were made using the log-rank test. To calculate tuberculosis rates by immunologic status, we divided the time each participant was followed into the number of years during which CD4 lymphocyte counts were 200 cells/mm3 or greater and the number of years after CD4 lymphocyte counts were less than 200 cells/mm3. Time for these CD4 groups was then summed for all participants. Rates were calculated as the number of tuberculosis cases in each group divided by the number of years followed. One participant who did not have CD4 measurements was omitted from these calculations. Twenty-three participants who were never tested for PPD response were excluded from PPD conversion rates and calculations of tuberculosis rates by PPD status. Participants who were tested for PPD response at least once were classified into one of three groups: positive at entry, newly positive (converted), or negative. One hundred seventy-two of 1107 participants were assigned to groups on the basis of only one test. Baseline PPD status was assigned for 66 participants who were not tested at study entry by using the first reported test and time followed calculated from the date of that test. For participants who developed tuberculosis, only the results of PPD tests done before diagnosis were considered. Tuberculin converters were considered to be part of the negative group before becoming PPD positive and to be part of the newly positive group after converting. Persons who reported a history of isoniazid use or tuberculosis before the study or who received isoniazid for at least 6 months during follow-up were considered to have completed prophylactic therapy. All others were considered to have not been given prophylaxis. Time before completion of isoniazid therapy was included with time followed in the untreated group. Restricted tuberculosis rates were calculated by PPD status for those considered to have not received prophylaxis. Results Patient Characteristics at Baseline Overall, 1171 HIV-seropositive persons entered the study. Follow-up was completed for 1130 persons (96%), whose baseline characteristics are shown in Table 1. Approximately 1% of patients reported a history of tuberculosis, 8% reported a previous positive result on a PPD test, and 4% reported previous use of isoniazid. The median CD4 T-lymphocyte count among HIV-seropositive patients was 410 cells/mm3: Thirty-six percent of patients had counts of at least 500 cells/mm3, 44% had counts between 200 and 499 cells/mm3, and 19% had counts of less than 200 cells/mm3. At study entry, 6% of patients were PPD positive, 42% were reactive to mumps antigen, and 54% were anergic. A cross-sectional analysis of skin-test results at baseline in this cohort has been described in detail elsewhere [18]. Table 1. Baseline Characteristics of the Study Chart* Patient Follow-up The median duration of follow-up was 53 months. By the end of the study, 655 persons had survived after a median follow-up of 57 months (range, 31 to 64 months), 354 had died after a median follow-up of 31 months (range, 1 to 63 months), and 121 withdrew or were lost to follow-up after a median of 25 months (range, 1 to 61 months). Participants received PPD skin tests a median of three times, and 1107 (98%) participants were evaluated at least once. Sixty-six (6%) participants were PPD positive when first tested. Among the 1041 patients who were PPD negative at first testing, 29 subsequently became PPD positive (0.8 conversions per 100 person-years). During follow-up, isoniazid prophylaxis was prescribed for 110 persons (10%), but only 53 (5%) received therapy for 6 months or more. Inc

Impact of comorbidity on lung cancer survival

Lung cancer is associated with smoking and age, both of which are associated with comorbidity. We evaluated the impact of comorbidity on lung cancer survival. Data on 56 comorbidities were abstracted from the records of a cohort of 1,155 patients. Survival effects were evaluated with Cox regression (outcome crude death). The adjusted R2 statistic was used to compare the survival variation explained by predictive variables. No comorbidity was observed in 11.7% of patients, while 54.3% had 3 or more (mean 2.97) comorbidities. In multivariate analysis, 19 comorbidities were associated with survival: HIV/AIDS, tuberculosis, previous metastatic cancer, thyroid/glandular diseases, electrolyte imbalance, anemia, other blood diseases, dementia, neurologic disease, congestive heart failure, COPD, asthma, pulmonary fibrosis, liver disease, gastrointestinal bleeding, renal disease, connective tissue disease, osteoporosis and peripheral vascular disease. Only the latter was protective. Some of the hazards of comorbidities were explained by more directly acting comorbidities and/or receipt of treatment. Stage explained 25.4% of the survival variation. In addition to stage, the 19 comorbidities explained 6.1%, treatments 9.2%, age 3.7% and histology 1.3%. Thirteen uncommon comorbidities (prevalence <6%) affected 21.2% of patients and explained 3.5% of the survival variation. Comorbidity count and the Charlson index were significant predictors but explained only 2.5% and 2.0% of the survival variation, respectively. Comorbidity has a major impact on survival in early‐ and late‐stage disease, and even infrequent deleterious comorbidities are important collectively. Comorbidity count and the Charlson index failed to capture much information. Clinical practice and trials need to consider the effect of comorbidity in lung cancer patients.

Tuberculin and Anergy Testing in HIV-Seropositive and HIV-Seronegative Persons

Human immunodeficiency virus (HIV) is playing a substantial role in the resurgence of tuberculosis in the United States. Particularly affected are people in urban areas, where there are large populations of HIV-infected persons [1-8]. Urban subpopulations with a high prevalence of HIV infection, such as intravenous drug users (a group already at increased risk for tuberculosis before the appearance of the acquired immunodeficiency syndrome [AIDS]), have the highest tuberculosis attack rates [3]. Unlike other AIDS-associated opportunistic pathogens, Mycobacterium tuberculosis is readily communicable among persons with all levels of immunity. Recently, tuberculosis outbreaks, some with multidrug-resistant strains, have occurred among HIV-positive patients with transmission to HIV-negative patients and health care workers [9-13]. Prevention strategies rely heavily on the use of tuberculin purified protein derivative (PPD) to identify persons harboring M. tuberculosis [14]. Anergy, a consequence of HIV infection, undermines these strategies in persons at the highest risk for tuberculosis infection and subsequent active disease [15-18]. A negative PPD test result in this setting could be attributable to a true lack of exposure to tuberculosis or simply to the incapacity of the patient to manifest an appropriate cell-mediated immune response. To reduce the measured prevalence of anergy and thereby increase the proportion of tuberculin nonreactors who can be considered truly PPD negative, the Centers for Disease Control and Prevention (CDC) has recommended the additional use of at least two delayed-type hypersensitivity control antigens (mumps antigen plus Candida antigen or tetanus toxoid) when screening HIV-infected patients. Thus, persons from populations with a prevalence of tuberculous infection of 10% or more and who are tuberculin negative but not anergic may be spared preventive therapy with isoniazid [19]. However, the ability of control antigens to predict the likelihood that a negative PPD test result is truly negative in this highly anergic population is unknown. To improve approaches to tuberculosis prophylaxis, more data are needed about the relations among delayed-type hypersensitivity responsiveness, the prevalence of tuberculosis, and the waning immunity associated with progressive HIV infection. In an ongoing multicenter study of the natural history of the pulmonary complications associated with HIV infection, we have been examining these factors prospectively in a cohort of 1353 persons in 6 U.S. geographic areas. Recently, we evaluated baseline delayed-type hypersensitivity responses in this cohort of HIV-seropositive and HIV-seronegative persons and identified variables associated with tuberculin reactivity and anergy. Methods Patients and Study Design The Pulmonary Complications of HIV Infection Study is a multicenter study designed to prospectively describe the frequency, types, and effect of pulmonary complications in HIV-infected persons, both before and after the development of AIDS. All diagnoses, treatments, and outcomes are recorded and monitored in a common database. Because our purpose was to evaluate longitudinally both the early and late pulmonary manifestations of HIV infection, each center attempted to recruit about 170 HIV-seropositive participants, half with CD4 lymphocyte counts of 400 cells/mm3 or more and no HIV-related symptoms and half with fewer than 400 CD4 cells/mm3 or symptomatic HIV-infection (defined by a temperature of 38 C or more for at least 2 weeks, involuntary weight loss of 10% or more from baseline, diarrhea of at least a 1-month duration, oral candidiasis, or oral hairy leukoplakia). Within each group, participants were drawn from one of three HIV transmission categories (homosexual men, male and female intravenous drug users, and women with heterosexually acquired HIV infection) to reflect their approximate distribution at each clinical site. About 30 HIV-seronegative homosexual men and intravenous drug users were also recruited at each site to serve as controls. Participants had to be willing and able to comply with the protocol and were required to give informed consent. The study was reviewed and approved by the institutional review board at each site. Exclusion criteria included Centers for Disease Control and Prevention (CDC)-defined AIDS [20], severe non-HIV-related disease likely to affect survival, lung disorders likely to interfere with the required evaluations, acute pulmonary processes, immunosuppressive therapies within the previous 6 months, and treatment for active tuberculosis within the past 12 months. From November 1988 through February 1990, we enrolled 1353 persons in the study, of whom 1171 were HIV seropositive and 182 were HIV seronegative. Human immunodeficiency virus serologic status was confirmed at study entry using a licensed enzyme-linked immunosorbent assay and a Western blot assay. Further baseline evaluation included a complete medical history, a physical examination, hematologic and biochemical studies, T-lymphocyte subset analysis, delayed-type hypersensitivity testing, a chest roentgenogram, and pulmonary function measurements. Measurement of Delayed-Type Hypersensitivity Response We tested delayed-type hypersensitivity with the following antigens: mumps antigen (Connaught Laboratories, Inc., Swiftwater, Pennsylvania); Dermatophytin 0 (Candida) at 1:100 dilution (Hollister-Stier, Spokane, Washington); Dermatophytin (trichophytin) at 1:100 dilution (Hollister-Stier); and tuberculin PPD at a strength of 5 tuberculin units per 0.1-mL dose (Connaught Laboratories, Ltd., Willowdale, Ontario, Canada). Tests were administered by intradermal injection of 0.1 mL of antigen (Mantoux method) and read by a trained observer 48 to 72 hours after application in most participants (the interval exceeded 4 days in 18 persons). Response was recorded as the greatest diameter of induration. We used the current standard operational criteria for a positive response: induration of at least 5 mm for all antigens except PPD, for which an induration of 10 mm was required among HIV-uninfected persons [19]. Anergy was defined as 0 mm of induration for all delayed-type hypersensitivity antigens administered in a given panel. Unless otherwise specified, a test battery of tuberculin PPD, mumps antigen, and Candida antigen was used to define anergy. At one site, however, the investigators did not distinguish between induration and erythema for the mumps, Candida, and trichophytin tests, documenting reactions to these antigens in terms of millimeters of erythema. When examined by zone diameter, their measurements were generally consistent with those from the other centers. Furthermore, the results of multivariate analyses with and without the data from this site were similar. Other investigators have shown a high degree of correlation between induration and erythema with these antigens [21]. Thus, for the purposes of our analysis, responses were recorded in millimeters of induration. Because trichophytin elicited a positive reaction in only 14.0% of those tested, it was dropped from the delayed-type hypersensitivity battery midway through the enrollment period. Although lot numbers varied, the skin tests used at the centers were supplied by the same manufacturers, with a single exception: At one site, investigators used a different Candida preparation. The Candida test results for this center (247 participants) were excluded from all analyses involving this antigen. Determination of Lymphocyte Subsets Lymphocyte subsets were determined for CD3, CD4, and CD8 receptor-bearing cells by the same laboratory at each site. All laboratories participated in the flow cytometry quality control program sponsored by the National Institute of Allergy and Infectious Diseases [22]. Statistical Analysis All analyses are based on data collected during the baseline evaluation. Statistical significance for comparisons of proportions was determined by chi-square or Fisher exact test [23]. For comparisons among nonindependent groups, repeated-measures analysis for categorical outcomes was used to determine statistical significance [24, 25]. Logistic regression models were used to study the relation between PPD positivity or anergy and potential risk factors [26]. Risk factors considered were HIV status; CD4 count among HIV-seropositive persons; intravenous drug use; race or ethnicity; a history of a positive PPD test result, tuberculosis, or BCG vaccination; age; gender; and socioeconomic status. Seventy-seven participants, including women with heterosexually acquired infection and persons who were not white, black, or Hispanic, were excluded from all multivariate analyses because of small sample sizes. Initial models included HIV status (positive or negative), intravenous drug use (presence or absence), race or ethnicity (white, black, or Hispanic), a history of a positive PPD test result, and age, as well as interaction terms, to determine whether the effect of HIV positivity varied among these groups or whether the effect of drug use varied by race. No statistically significant interactions were observed. All odds ratios presented were derived from subsequent models containing main effects only. A dichotomous variable indicating the 12% of the cohort who did not have a high school diploma was used as an index of socioeconomic status and was included in all final models. All tests were two sided. A P value of 0.05 was considered statistically significant. Ninety-five percent CIs are given when appropriate. Results Patient Characteristics During the 16-month enrollment period, 1171 HIV-seropositive and 182 HIV-seronegative persons entered the study. The two groups were similar with regard to age, sex, race, transmission category, and tuberculosis-associated history (Table 1). Of the 1165 men, 966 (82.9%) were homosexual; of the 188 women, 132 (70.2%) were intravenous drug users.

Lung Cancer Risk Prediction: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Models and Validation

INTRODUCTION Identification of individuals at high risk for lung cancer should be of value to individuals, patients, clinicians, and researchers. Existing prediction models have only modest capabilities to classify persons at risk accurately. METHODS Prospective data from 70 962 control subjects in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) were used in models for the general population (model 1) and for a subcohort of ever-smokers (N = 38 254) (model 2). Both models included age, socioeconomic status (education), body mass index, family history of lung cancer, chronic obstructive pulmonary disease, recent chest x-ray, smoking status (never, former, or current), pack-years smoked, and smoking duration. Model 2 also included smoking quit-time (time in years since ever-smokers permanently quit smoking). External validation was performed with 44 223 PLCO intervention arm participants who completed a supplemental questionnaire and were subsequently followed. Known available risk factors were included in logistic regression models. Bootstrap optimism-corrected estimates of predictive performance were calculated (internal validation). Nonlinear relationships for age, pack-years smoked, smoking duration, and quit-time were modeled using restricted cubic splines. All reported P values are two-sided. RESULTS During follow-up (median 9.2 years) of the control arm subjects, 1040 lung cancers occurred. During follow-up of the external validation sample (median 3.0 years), 213 lung cancers occurred. For models 1 and 2, bootstrap optimism-corrected receiver operator characteristic area under the curves were 0.857 and 0.805, and calibration slopes (model-predicted probabilities vs observed probabilities) were 0.987 and 0.979, respectively. In the external validation sample, models 1 and 2 had area under the curves of 0.841 and 0.784, respectively. These models had high discrimination in women, men, whites, and nonwhites. CONCLUSION The PLCO lung cancer risk models demonstrate high discrimination and calibration.