Treatment of death in the analysis of longitudinal studies of gerontological outcomes.

BACKGROUND: Longitudinal studies in gerontology are characterized by termination of measurement from death. Death is related to many important gerontological outcomes, such as functional disability, and may, over time, change the composition of an older study population. For these reasons, treating death as noninformative censoring of a longitudinal outcome may result in biased estimates of regression coefficients related to that outcome. METHODS: In a longitudinal study of community-living older persons, we analytically and graphically illustrate the dependence between death and functional disability. Relative to survivors, decedents display a rapid decline of functional ability in the months preceding death. Death's strong relationship with functional disability demonstrates that death is not independent of this outcome and, hence, leads to informative censoring. We also demonstrate the "healthy survivor effect" that results from death's selection effect, with respect to functional disability, on the longitudinal makeup of an older study population. RESULTS: We briefly survey commonly used approaches for longitudinal modeling of gerontological outcomes, with special emphasis on their treatment of death. Most common methods treat death as noninformative censoring. However, joint modeling methods are described that take into account any dependency between death and a longitudinal outcome. CONCLUSIONS: In longitudinal studies of older persons, death is often related to gerontological outcomes and, therefore, cannot be safely assumed to represent noninformative censoring. Such analyzes must account for the dependence between outcomes and death as well as the changing nature of the cohort.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Presenting manifestations, cigarette smoking, and detection bias in age at diagnosis of lung cancer.

PURPOSE: To examine the possible role of detection bias in the association between amount of cigarette smoking and age at diagnosis of lung cancer. The bias can occur because primary lung cancer can often escape detection during life and will be found (if at all) as a "necropsy surprise" unless a diagnostic workup is provoked by such presenting manifestations as hemoptysis and a localized chest lesion. The necropsy surprises will be reduced and the reported rates of pre-mortem incidence will be raised if a cigarette smoking history also acts as a diagnostic incentive. METHODS: This possibility was examined in a case series of 1266 patients whose primary lung cancer had been carefully classified according to diverse features at the time of presentation. For the total case group and for pertinent clinical, anatomic, and demographic subgroups, we then examined the trends for age at diagnosis in relation to amount of cigarette smoking. RESULTS: The overall age at diagnosis (median = 63 years; mean = 61.2) remained essentially similar in five ordinal groups of Tumor, Nodes, Metastases (TNM) and four of five Clinical Severity stages, but had an inverse monotonic gradient in six ordinal groups of customary cigarette smoking [from none to >2 packs per day (ppd)]. Because an earlier age of discovery can be explained by either etiologic or detection-bias roles for heavier smoking, its impact was checked in subgroups with and without diagnostically provocative manifestations. In localized lesions, the smoking-age gradient vanished if suspicious "indicator" symptoms were present, but persisted if they were absent. Regardless of symptoms, the age gradient was strengthened in non-localized cancer lesions where smoking might particularly point to a primary diagnostic source in the lung. CONCLUSIONS: Detection bias may play a distinctive, although often overlooked, role in the work-up decisions that precede and lead to a diagnosis of lung cancer.

Prior healthcare utilization as a predictor of survival for medical intensive care unit patients.

OBJECTIVE: To determine whether measures of inpatient care utilization from the year preceding admission to a medical intensive care unit (MICU) improve physiology-based predictions of hospital and 1-yr survival. DESIGN: Inception cohort study with a validation cohort. SETTING: The MICU in university-affiliated Department of Veterans Affairs Medical Center. PATIENTS: A total of 1,200 consecutive patients admitted to the MICU. MEASUREMENTS AND MAIN RESULTS: Increased use of inpatient health care before MICU admission was associated with increased mortality. However, inpatient utilization data failed to improve physiology-based logistic models for hospital and 1-yr survival (p > .15 for improvement in the area under the receiver operating characteristic curve for both end points in the validation cohort), whereas physiologic data improved models derived from measures of inpatient care (p < .001 for both end points). Empirically derived inpatient care models used only information from the few days preceding MICU admission, despite the availability of a full year of data. CONCLUSIONS: Chronic illness, as gauged by a need for frequent inpatient care in the year before MICU admission, is not independently predictive of poor short- or long-term survival. Clinicians should not attempt to predict survival of prospective MICU patients by the extent of previous inpatient care.

Immunotherapy of sepsis: flawed concept or faulty implementation?

Gram-negative bacillary sepsis is a leading cause of death among patients hospitalized in intensive care units. While initial clinical studies with the passive administration of anti-endotoxin core-glycolipid (CGL) antibodies for the treatment and prophylaxis of sepsis showed promising results, subsequent studies failed to show a consistent benefit. There appears to be a good correlation between anti-CGL antibody levels at the onset of sepsis and maintenance of antibody levels during sepsis with outcome. Previous clinical studies may have failed because insufficient amounts of antibody were administered early in the course of sepsis. Unlike the case with anti-CGL antibodies, polyvalent, hyperimmune type-specific antibody preparations may prevent the development of infections; however, these antibodies also must be provided in adequate amounts and in close proximity to infection in order to provide a beneficial effect. These pharmacokinetic requirements may limit the utility of passive immunotherapy for the prophylaxis of sepsis. Active immunization of acutely traumatized patients or of rats subsequently rendered neutropenic with cyclophosphamide induced high antibody levels for extended periods of time. Since trauma and other conditions are associated with a Th(2) response, these conditions may favor antibody formation following active immunization. Active immunization with both anti-CGL and/or polyvalent-specific vaccines for the prophylaxis of sepsis with passive supplementation at the onset of sepsis is an approach that merits further investigation.

Importance of functional measures in predicting mortality among older hospitalized patients.

CONTEXT: Measures of physical and cognitive function are strong prognostic predictors of hospital outcomes for older persons, but current risk adjustment and burden of illness assessment indices do not include these measures. OBJECTIVE: To evaluate and validate the contribution of functional measures to the ability of 5 standard burden of illness indices (Charlson, Acute Physiology and Chronic Health Evaluation [APACHE] II, Disease Staging, All Patient Refined Diagnosis Related Groups, and a clinician's subjective rating) in predicting 90-day and 2-year mortality among older hospitalized patients. DESIGN: Two prospective cohort studies. SETTING: General medicine service, university teaching hospital. PATIENTS: For the development cohort, 207 consecutive patients aged 70 years or older, and for the validation cohort, 318 comparable patients. MAIN OUTCOME MEASURE: Death within 90 days and 2 years from the index admission. RESULTS: In the development cohort, 29 patients (14%) and 81 patients (39%) died within 90 days and 2 years, respectively. A functional axis was developed using 3 independent risk factors: impairment in instrumental activities of daily living, Mini-Mental State Examination score of less than 20, and shortened Geriatric Depression Scale score of 7 or higher, creating low-, intermediate-, and high-risk groups with associated mortality rates of 20%, 32%, and 60%, respectively (P<.001); the C statistic for the final model was 0.69. The corresponding mortality rates in the validation cohort, in which 59 (19%) and 138 (43%) died within 90 days and 2 years, respectively, were 24%, 45%, and 60% (P<.001); the C statistic for the final model was 0.66. For each burden of illness index, the functional axis contributed significantly to the predictive ability of the model for both 90 days and 2 years. When the functional axis and each burden of illness measure were analyzed in cross-stratified format, mortality rates increased progressively from low-risk to high-risk functional groups within strata of burden of illness indices (double-gradient phenomenon). The contributions of functional and burden of illness measures were substantive and interrelated. CONCLUSIONS: Functional measures are strong predictors of 90-day and 2-year mortality after hospitalization. Furthermore, these measures contribute substantially to the prognostic ability of 5 burden of illness indices. Optimal risk adjustment for older hospitalized patients should incorporate functional status variables.

Magnitude and duration of the effect of sepsis on survival. Department of Veterans Affairs Systemic Sepsis Cooperative Studies Group.

OBJECTIVE: To determine the magnitude and duration of the effects of sepsis on survival. DESIGN: Cohort study. SETTING: The 10 Department of Veterans Affairs Medical Centers of the Systemic Sepsis Cooperative Studies Group, which from 1983 to 1986 conducted the Department of Veterans Affairs Cooperative Study of Corticosteroids in Systemic Sepsis. PATIENTS: The septic population consisted of 1505 patients with evaluable data from the screening log of the Cooperative Study of Corticosteroids in Systemic Sepsis. All 91830 nonpsychiatric, noninfected patients discharged from the participating medical centers between October 1, 1984, and September 30, 1985, were included in the control population. MAIN OUTCOME MEASURE: Death through 8 years after the index hospitalization. RESULTS: On the basis of a proportional hazards model constructed from the demographic and illness characteristics of the control population, the septic population was at significant risk of dying of nonseptic causes (26% predicted 1-year mortality). In the septic population, the daily risk of dying exceeded predictions from this model for 5 years, and the hazard rate rose with increasing severity of the septic episode throughout the first year (P<.05). Among 30-day survivors, sepsis reduced the remaining mean life span from a predicted 8.03 years to 4.08 years. CONCLUSIONS: Sepsis not only causes deaths acutely, but also increases the risk of death for up to 5 years after the septic episode even after comorbidities are accounted for. The risk of late death during the first year is associated with the severity of the septic episode.

Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study Group.

Sepsis, an important cause of hospital mortality, continues to be a diagnostic and therapeutic challenge. To define more clearly the impact of encephalopathy on the course of sepsis, the various clinical signs of sepsis, blood culture results, and mortality rates were examined in relation to mental status in septic patients. Patients were classified as having an acutely altered mental status due to sepsis (AAMS), preexisting altered mental status (PAMS), or normal mental status (NMS). Twenty-three (307/1333) percent of the study patients had an acutely altered sensorium secondary to sepsis. Patients with AAMS had a higher mortality (49%) than patients with PAMS (41%) or patients with NMS (26%) (p less than .000001). Multivariate analysis disclosed that altered mental status, hypothermia, hypotension, thrombocytopenia, and the absence of shaking chills were independent predictors of increased mortality in the sepsis syndrome. Patients with Gram-negative bacteremia (28%) were as likely to have AAMS as patients with Gram-positive bacteremia (25%) or patients with negative blood cultures (23%). In summary, alterations in mental status are common in septic patients, and are associated with significantly higher mortality.

Five-year changes in coronary arteries of medical and surgical patients of the Veterans Administration Randomized Study of Bypass Surgery.

Progression of coronary artery disease was evaluated after 5 years of follow-up in 119 medically and 109 surgically treated randomized patients who adhered to their assigned therapy. Progression was defined as the appearance of a new lesion (greater than or equal to 50% stenosis) or worsening of a preexisting lesion in a coronary artery. Progression occurred in 36% (97 of 268) of the arteries in medical patients, in 38% (35 of 93) of the ungrafted arteries in surgical patients, in 74% (72 of 97) of the arteries with patent grafts at 5 years, and in 63% (29 of 46) of the arteries with closed grafts. After adjustment for the vessel system and the severity of disease at baseline, the risk of progression was three to six times higher in grafted arteries than in ungrafted arteries (p less than 0.01). For grafted arteries, the risk of progression was twice as high in arteries with patent grafts compared with those with closed grafts (p = 0.14). The majority (78%) of the progression in grafted arteries was to 100% occlusion. Proximal and distal progression rates in arteries with patent grafts were 74% and 11%, respectively. In the majority of arteries with closed grafts that progressed, the site of progression could not be determined. Regardless of treatment, the risk of progression was two times higher in the right coronary artery than in the left anterior descending or circumflex arteries. Progression risk was also twice as high in arteries with moderate disease at baseline compared with those with minimal or severe disease.

Quality control for cardiac surgery in the Veterans Administration.

The volume of cardiac surgical procedures and the 30-day mortality associated with them were reviewed for the total experience of 72 Veterans Administration medical centers over a 10-year period (1975 to 1984). The total number of cardiopulmonary bypass operations increased from 3,074 in 1975 to 6,455 in 1984, whereas operative mortality declined from 8.3 to 4.7%. Operative mortality associated with isolated valve replacement operations declined from 10.9 to 5.9%. Aortocoronary vein bypass operations, which increased in number from 1,679 to 4,988 over the 10-year period, were associated with an operative mortality of 4.7% in 1975 and 3.6% in 1984. The extent of the patient's disease accounted for most of the operative mortality, but problems related to the adequacy of myocardial protection and the surgical technique were also important factors. These data were compared with similar comprehensive statistics compiled by the New York State Department of Health over a five-year period (1979-1983). Operative mortality rates were quite similar for aortocoronary bypass procedures, mitral valve replacements, and total cardiac operations. However, operative mortality for aortic valve procedures was higher among the Veterans Administration hospitals. In the future, if operative risk factors are clearly defined, a more meaningful comparison of operative mortality among ongoing reviews, such as those being carried out by the Veterans Administration and by New York State, could be used to establish standards of performance for cardiac surgery.

Anatomical relationships between type II pneumonocytes and alveolar septal gaps in the human lung.

This report describes a relationship between type II pneumonocytes and breaks in continuity in the alveolar septum of the human lung. Breaks in continuity of the septum are defined as gaps in the connective tissue matrix of the alveolar septum, with or without discontinuity of the accompanying alveolar epithelium. Septal connective tissue gaps accompanied by epithelial discontinuity are recognized as interalveolar pores of Kohn. When the discontinuity is confined to the connective tissue matrix, epithelial continuity may be maintained by either a single or a double layer of type I epithelium, by a type II cell, or by both type I and type II epithelial cells. Alveolar septal gaps were studied by electron microscopy on random sections in 26 adult human lung specimens and by serially sectioning and montaging the entire circumference of one alveolus to a depth of 103 microns (approximately one-half a normal alveolus) from one of the specimens. Fixation was by way of the airways in most specimens, but by vascular perfusion in the serially sectioned specimen and in seven others. In lungs studied by random sections, we found that the incidence of septal connective tissue gaps with epithelial continuity per specimen correlated with the incidence of pores (r = .468, P less than .016), and also with the incidence of type II cells (r = .422, P less than .025) in the specimen. Five percent of all type II cells observed in the random sections in the 26 specimens (103/1,955) occupied septal gaps, and 2.5% (49/1,955) were located at the rim of a pore. In contrast, in the single serially sectioned montaged alveolus, 69% of all type II cells occupied some type of septal gap, with 24% of all type II cells forming part of the rim of a pore. Over half of all pores in this alveolus were associated with a type II cell. We concluded that a relationship between the incidence of type II cells and gaps in the alveolar septum could be demonstrated on random sections in normal human lungs, which was much more obvious in a single serially sectioned hemialveolus. Serial section techniques of whole alveoli may be necessary to establish relationships that may not be apparent on random sections and that require the study of whole cells in continuity with their environment in order to be identified. The findings may be significant in suggesting a possible role of the type II cell in alveolar septal repair.

Upper and lower bounds for correlations in 2 X 2 tables--revisited.

The correlation coefficient (r) between two dichotomous variables requires a different interpretation from that of the customary correlation between normally distributed continuous variables, since perfect correlation is usually not +1 or -1. The maximum and minimum possible correlations between two dichotomous variables depend on the marginal distributions. An example using data on smoking and lung cancer illustrates that what appears to be a small correlation in the usual sense may in fact be quite large in relation to the maximum possible. Similarly, the interpretation of R2 as the proportion of variance of the dependent variable that is explained by the independent variable(s) is subject to the same consideration. This paper describes the calculation of the upper and lower limits of r for two dichotomous variables. The problem of interpreting R2 in linear regression and the use of R2 for variable selection in stepwise regression applied to dichotomous data are also discussed and illustrated.

Validation of a risk function to predict mortality in a VA population with coronary artery disease.

A multivariate risk function based on the Cox model was developed in the VA Study of Coronary Artery Bypass Surgery to predict the survival of patients with stable angina pectoris. The methods used in developing and evaluating the performance of the risk function (validation) are described. Performance was evaluated internally by the methods of resubstitution, half-sample replication, and jackknifing, and externally by use of an independent patient population.

Predictors of operative mortality for coronary bypass grafting in patients with ischemic heart disease.

Predictors for operative mortality (OM) were studied in 172 consecutive patients (pts) undergoing coronary artery grafts (CAG) for angina pectoris.Seventy eight pts had Class IV angina; of the 147 patients given propranolol, 41 were gradually withdrawn from propranolol and finally discontinued 24 hours before surgery, and 106 were abruptly withdrawn from propranolol 24 hours before CAG; 20 pts had left main coronary disease; 156 pts had cardiopulmonary bypass (CPB) time shorter than 20 minutes, and 16 pts had a CPB longer than 120 minutes.The operative mortality was 5.2% (9/172) for the entire group. Class IV angina (OM 7%), abrupt propranolol withdrawal (OM 6.6%), left main coronary artery disease (OM 25%), and CPB longer than 120 minutes (OM 50%), all significantly increased OM. These variables were interdependent, however, as many pts belonged to several predictor categories, combinations of predictors were examined, in order to more accurately predict the risk of individual pts. The combination of left main coronary artery disease and CPB longer than 120 minutes; and Class IV angina and CPB longer than 120 minutes were significantly associated with higher operative mortality.We conclude that Class IV angina, abrupt propranolol withdrawal, left main coronary artery disease and prolonged CPB are potent, interdependent predictors of OM in pts undergoing CAG. Consideration of these predictors, alone and in combination, allows effective prediction of OM for CAG in patients with stable angina pectoris.

Incidence and mortality of perioperative myocardial infarction in patients undergoing coronary artery bypass grafting.

The incidence of perioperative myocardial infarction (MI) determined by electrocardiogram was examined in 168 consecutive patients having only coronary artery bypass grafting at Yale-New Haven Hospital from July 1974 to June 1975. The incidence of MI and its mortality were correlated with clinical, hemodynamic, anatomic, and operative factors. Perioperative MI occurred in 23% of all patients (39/168); 26 in the inferior, 11 in the anterior, and two in the anterolateral wall. Three factors appeared related to the occurrence of MI: 1) abrupt propranolol withdrawal 24 hours prior to surgery (Prop) (32%, 33/103); 2) left main coronary artery disease (LMCD) (37%, 7/19); and 3) cardiopulmonary bypass longer than 60 minutes (CPB) (23%, 30/128). To more precisely predict MI, combinations of factors were examined. The combination of LMCD and CPB was 39%, (7/18) while the absence of either yielded an incidence of only 5.1% (2/39) (P less than 0.001). The mortality of patients with MI was 15.4% (6/39) while in patients without MI the mortality was 1.6% (2/129). We conclude that the risk of perioperative MI is significantly increased by abrupt propranolol withdrawal 24 hours before surgery, left main coronary artery disease, and cardiopulmonary bypass longer than 60 minutes in patients undergoing coronary artery bypass grafting. The mortality of perioperative MI is high, despite previous reports of the benignity of perioperative myocardial infarction.