Statistical methods in public health and epidemiology: a look at the recent past and projections for the next decade.

This article attempts to prognosticate from past patterns, the type of statistical methods that will be used in published public health and epidemiological studies in the decade that follows the millennium. With this in mind, we conducted a study that would characterize trends in use of statistical methods in two major public health journals: the American Journal of Public Health, and the American Journal of Epidemiology. We took a probability sample of 348 articles published in these journals between 1970 and 1998. For each article sampled, we abstracted information on the design of the study and the types of statistical methods used in the article. Our major findings are that the proportion of articles using statistical methods as well as the mean number of statistical methods used per article has increased dramatically over the three decades surveyed. Also, the proportion of published articles using study designs that we classified as analytic has increased over the years. We also examined patterns of use in these journals of three statistical methodologies: logistic regression, proportional hazards regression, and methods for analysis of data from complex sample surveys. These methods were selected because they had been introduced initially in the late 1960s or early 1970s and had made considerable impact on data analysis in the biomedical sciences in the 1970s-90s. Estimated usage of each of these techniques remained relatively low until user-friendly software became available. Our overall conclusions are that new statistical methods are developed on the basis of need, disseminated to potential users over a course of many years, and often do not reach maximum use until tools for their comfortable use are made readily available to potential users. Based on these conclusions, we identify certain needs that are not now being met and which are likely to generate new statistical methodologies that we will see in the next decade.

Time to nursing home admission for persons with Alzheimer's disease: the effect of health care system characteristics.

OBJECTIVE: To study the influence of state health care system characteristics on time to nursing home admission (NHA) for persons with Alzheimer's disease (AD). METHOD: Up to nine years of Consortium to Establish a Registry for Alzheimer's Disease (CERAD) data on 639 non-Latino White individuals were merged with longitudinal data from the 28 states in which the CERAD participants resided. The state variables reflected characteristics of each state's long-term care (LTC) system, including Medicaid LTC spending practices and the supply of LTC providers. Cox Proportional Hazards Models with time-varying covariates were used to evaluate the risk factors associated with time to NHA. RESULTS: There was differential influence of state variables by marital status. For unmarried non-Latino White persons with AD, a higher percentage of Medicaid LTC spending on home and community-based services (HCBS) was significantly associated with a longer time to NHA. For married persons, a greater number of home health agencies was associated with a longer time to NHA. Other associations also varied by marital status. CONCLUSION: Study findings support the utility of targeted continued expanded provision of HCBS by states and provide a basis for future research regarding the impact of changing state health care systems on LTC utilization for persons with AD.

Hip fracture incidence among elderly Hispanics.

OBJECTIVES: This study estimated hip fracture incidence for elderly Hispanics in the United States. METHODS: A cohort of Spanish-surnamed 1992 Medicare enrollees was followed for 2 years. Hip fractures were identified by inpatient diagnostic code. RESULTS: For Hispanic women, the national age-adjusted hip fracture rate was 7.3 per 1000 person-years; for men, the rate was 3.3. Rates varied markedly, with higher rates for the predominantly Mexican-American southwestern states than for Puerto Ricans. CONCLUSIONS: Nationally, the Hispanic population is at intermediate risk of hip fracture between Blacks and Whites, but geographic variation suggests that Mexican Americans are at higher risk than Puerto Ricans.

Hip fracture incidence among elderly Asian-American populations.

This study estimated national age- and sex-specific nontraumatic hip fracture incidence rates for elderly Chinese Americans, Japanese Americans, and Korean Americans. Based on a 50 percent sample of 1992 Medicare enrollees with the race/ethnicity code "Asian" and "other," cohorts of persons with distinctive Chinese (n = 24,366), Japanese (n = 28,762), and Korean (n = 5,470) names were followed passively for 2 years for a hospitalization with a diagnostic code indicating hip fracture. Cohorts of whites and blacks were followed for comparison. Year of immigration was deduced from the year of issuance of the Social Security number. Age-adjusted hip fracture incidence was lower for all three Asian-American groups than for whites. For females, the standardized fracture ratio relative to whites was 30.1 for Chinese, 73.2 for Japanese, and 52.8 for Koreans; for males, the standardized fracture ratio was 41.9 for Chinese, 58.1 for Japanese, and 90.7 for Koreans. Persons whose Social Security numbers were issued after the immigration Act of 1965 had an adjusted relative risk of 1.37 (95% confidence interval 1.05-1.78) compared with those in the US before that year, after adjustment for age, sex, and ethnic group.

Identification of a cohort of male and female twins aged 65 years or more in the United States.

In this paper, a method with which to identify a national cohort of elderly twins is proposed. Record linkage algorithms were developed and applied to the > 30 million records contained in the Medicare beneficiary file. The matching algorithm for male/male pairs used race (black or white), last name, date of birth, and state of issuance of the Social Security number. Female/female and male/female pairs were selected with matching on race, date of birth, and the first seven digits of the Social Security number to compensate for the absence of maiden names. A stratified random sample of same-sex and opposite-sex white and black pairs (six groups) were selected and surveyed for determination of the actual prevalence of twins. On the basis of these results, the authors conclude that this method could identify an estimated 18,308 male/male, 7,544 female/female, and 204 male/female pairs of twins aged 65 years or more. This would be the largest sample of older twins ever assembled in the United States and represents a significant new resource for epidemiologic studies of the aging population.

Focal segmental glomerulosclerosis in adult African Americans.

We have previously shown that idiopathic focal segmental glomerulosclerosis (FSGS) is the most common non-proliferative primary glomerulopathy in adult African Americans. In this report we present our experience with treated FSGS in 15 such patients followed over five years. They were all treated with prednisone 60 mg daily for three months, followed by a slow tapering. In addition, two patients later had cyclophosphamide, and five had enalapril. At entry hypertension was present in 73% of the patients, nephrotic syndrome in 87%, and elevated serum creatinine (> or = 1.4 mg/dl) in 40%. Five of the 15 patients (33%) developed end-stage renal failure (ESRF), one of them having a "malignant" course after the advent of pregnancy. Two patients (13%) have chronic renal insufficiency (CRI; serum creatinine > 2.5 mg/dl); three (20%) have mild renal insufficiency (serum creatinine 1.4-2.5 mg/dl), and five patients (33%) have normal renal function. The cumulative renal survival was 93% at five years, but only 26% at eight years. At last follow-up all the ten patients who did not develop ESRF were in partial remission (urinary protein of 1.3 g/day +/- 1.21), but 4 of the 5 patients who did not develop ESRF had no prolonged partial remission of nephrotic syndrome. Neither the initial clinical parameters not the use of enalapril correlated with the renal outcome (univariate analysis). However, 4 of the 5 patients who developed ESRF had elevated serum creatinine at entry, versus only 2 of the 10 not developing ESRF (p = 0.09 by two-sided, and 0.045 by one-sided Fisher's exact test). We conclude that the short-term renal outcome in nephrotic adult African Americans with treated FSGS is comparable to that of the non-African Americans, but their long-term prognosis may be poorer. Patients developing ESRF were more likely to present with elevated serum creatinine. Enalapril did not seem to modify the course of renal disease, but its utility and that of other ACE inhibitors in the treatment of FSGS must await prospective randomized studies.

Acute dilutional anemia and critical left anterior descending coronary artery stenosis impairs end organ oxygen delivery.

OBJECTIVE: Limited cardiac reserve, secondary to coronary disease, may be associated with end organ morbidity. In this study, we investigate the significance of anemia in the pathogenesis of this phenomenon. DESIGN: Nonrandomized controlled animal trial. SETTINGS: Animal laboratory in a university hospital. SUBJECT: Anesthetized dogs. INTERVENTIONS/MEASUREMENTS: Fourteen anesthetized dogs underwent isovolemic hemodilution with 6% hetastarch from a baseline hematocrit of 40 to 20%. Radioactive microspheres were used to evaluate regional blood flow and cardiac index. Systemic oxygen delivery, consumption, serum lactate, and systemic vascular resistance were recorded during each experiment. Arterial venous oxygen difference was determined from arterial and mixed venous blood. Seven dogs had an iatrogenic critical stenosis of their left anterior descending coronary artery (experimental group); seven dogs did not (control). MAIN RESULTS: Only in the control animals, the cardiac index increased by 35% with hemodilution to 20%. Systemic oxygen delivery decreased in both the control and the experimental animals. Systemic oxygen consumption and lactate levels were unchanged in both groups. In the renal cortex, spleen, distal colon, ileum, gallbladder, and stomach body, regional O2 delivery was significantly decreased with hemodilution to 20% in both groups. This finding was also observed in the left ventricle and cervical spinal cord in the experimental group. In addition, regional O2 delivery was reduced in the spleen, distal colon, and gallbladder with hemodilution to only 30%. Regional blood flow in the stomach body, gallbladder, ileum, renal cortex, and distal colon, in both groups, and the spleen in the control group was unchanged from baseline with hemodilution to 20%. However, regional blood flow under all other circumstances (control or experimental) was significantly increased with hemodilution to 20% with the exception of the spleen, which showed significant regional blood flow decrease in the experimental group only. CONCLUSIONS: These data suggest that with limited cardiac reserve, anemia may compromise aerobic splanchnic circulation. These observations may further our understanding of the pathogenesis of cholecystitis, gastric stress ulcers, ileal endotoxin translocation, and ischemic colitis in critically ill patients with coronary artery disease.

Blade balloon atrial septostomy in patients with severe primary pulmonary hypertension.

BACKGROUND: Patients with severe primary pulmonary hypertension have a poor prognosis, but those with a patent foramen ovale may survive longer. A few reports of clinical improvement after blade balloon atrial septostomy in patients with severe pulmonary vascular disease have appeared. The purpose of this study was to systematically evaluate the effects of blade balloon atrial septostomy on clinical signs and symptoms, hemodynamics, and survival in patients with severe primary pulmonary hypertension. METHODS AND RESULTS: Blade balloon atrial septostomy was performed on 15 children and young adults with severe primary pulmonary hypertension. Despite maximal medical therapy, prior to septostomy all patients had recurrent syncope and 8 had severe right heart failure. Thirteen patients survived the procedure. After blade balloon atrial septostomy, no patient experienced further syncope, and signs and symptoms of right heart failure improved in all New York Heart Association Class IV patients. Within 24 hours after the procedure and at follow-up catheterization 7 to 27 months after septostomy, there was a significant increase in cardiac index, resulting in an increase in systemic oxygen transport. There was improved long-term survival in the 13 patients who survived blade balloon atrial septostomy compared with similar groups of primary pulmonary hypertension patients who received standard therapy (P < .05). CONCLUSIONS: Blade balloon atrial septostomy resulted in clinical and hemodynamic improvement and improved survival in selected patients with severe primary pulmonary hypertension.

Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin.

OBJECTIVE: To evaluate the effects of long-term-intravenous infusion of prostacyclin on exercise capacity, hemodynamics, and survival in patients with primary pulmonary hypertension. DESIGN: Open, multicenter, uncontrolled trial. SETTING: Four referral centers. PATIENTS: 18 patients with primary pulmonary hypertension: 1 New York Heart Association (NYHA) class II patient, 13 NYHA class III patients, and 4 NYHA class IV patients. INTERVENTIONS: Continuous intravenous prostacyclin administered by portable infusion pumps. All patients were treated with anticoagulant agents. MEASUREMENTS AND MAIN RESULTS: With the 6-minute walk used to evaluate exercise capacity, patients could walk on average more than 100 meters farther after prostacyclin therapy was initiated (distance at 6 months, 370 +/- 119 meters compared with 264 +/- 160 meters at baseline; P < 0.001; distance at 18 months, 408 +/- 138 meters; P = 0.02 compared with baseline). Hemodynamics were improved at 6 months: The cardiac index increased 18% (95% CI, 0.1% to 36.7%; P = 0.02), and mean pulmonary artery pressure and total pulmonary resistance decreased 9% (CI, 1.4% to 15.7%; P = 0.03) and 26% (CI, 6.1% to 46.3%; P = 0.02), respectively, compared with baseline. The improvements in cardiac index and total pulmonary resistance were maintained at 12 months (27% increase [CI, 1.3% to 51.9%; P = 0.05] and 32% decrease [CI, 9.7% to 53.6%; P = 0.02] compared with baseline, respectively). Survival was improved in NYHA class III and IV patients who received continuous prostacyclin (n = 17; follow-up, 37 to 69 months) when compared with historical controls who received standard therapy (National Institutes of Health Primary Pulmonary Hypertension Registry, n = 31, P = 0.045). Kaplan-Meier estimates of 1-, 2-, and 3-year survival rates for the patients treated with prostacyclin were 86.9%, 72.4%, and 63.3%, respectively, compared with 77.4%, 51.6%, and 40.6% for the historical control group (hazard ratio, 2.9 [CI, 1.0 to 8.0; P = 0.045]). Serious complications attributable to the drug and delivery system included two deaths and seven episodes of nonfatal sepsis in three patients. CONCLUSIONS: Continuous intravenous prostacyclin resulted in sustained clinical and hemodynamic improvement and probably in improved survival in patients with severe primary pulmonary hypertension. Despite potentially serious complications, long-term prostacyclin may be especially helpful in seriously ill patients awaiting transplantation.

The prognosis of lupus nephritis in African-Americans: a retrospective analysis.

To fully describe the clinical course of lupus nephritis in an African-American population, we report our experience with 54 patients seen at a large inner-city hospital over a period of 14 years. The patients were divided into five histopathologic groups. Group MES (n = 3) represented mesangial nephritis (World Health Organization [WHO] class II) and group FOC (n = 11) represented mild and moderate focal segmental proliferative glomerulonephritis (WHO class III). Group DIF (n = 9) included patients with severe segmental proliferative, diffuse proliferative, membranoproliferative, and membranous and severe superimposed proliferative lesions (WHO classes III, IV, and Vd). Group CRES (n = 9) combined all the patients with cellular crescents in more than 40% of the glomeruli and included patients in WHO classes III (severe), IV, and Vc and d. Group MEM (n = 22) represented membranous nephritis occurring alone or with superimposed mesangial or mild segmental proliferative lesions (WHO class Va and b). Groups DIF and CRES received intensive treatment with high-dose prednisone and cytotoxic drugs. Groups FOC and MEM received lower doses of prednisone, but half of the patients later received intensive treatment largely for severe systemic manifestations. The three patients in group MES remained well. End-stage renal failure (ESRF) developed in 11 of 18 patients in groups DIF and CRES combined, and in two of 22 patients in group MEM. Three of 11 patients in group FOC, five in groups DIF and CRES, and one in group MEM died. The actuarial 5- and 10-year survival rates were, respectively, 78% and 78% for FOC, 80% and 0% for DIF and CRES, and 100% and 100% for MEM (P < 0.03 v DIF/CRES). Five- and 10-year survival rates without ESRF were, respectively, 78% and 78% for FOC, 52% and 0% for DIF and CRES (P < 0.05), and 94% and 85% for MEM (P = 0.002 v DIF/CRES). Univariate proportional hazards regression analysis, uncontrolled for histopathologic groups, showed a significant association between ESRF and severe thrombocytopenia (P = 0.003), serum creatinine above 1.4 mg/dL at entry (P = 0.04), and severe systemic manifestations (P = 0.05). After controlling for histopathologic groups, only thrombocytopenia remained strongly associated with ESRF, both by univariate (P = 0.01) and multivariate (hazard ratio = 14.19, P = 0.05) analyses. We conclude that severe proliferative lupus nephritis in African-Americans has a poor prognosis. For mild and moderate focal proliferative nephritis and uncomplicated membranous lupus nephritis the prognosis is as good as in white patients. Severe thrombocytopenia predicts ESRF.

Measles antibody titers in early infancy.

OBJECTIVE: To determine the prevalence of measles seronegativity among infants younger than 6 months and to ascertain their serologic response to measles vaccine. DESIGN: Cross-sectional measles antibody survey during the 1989 measles epidemic in Chicago, Ill. SETTING: Inner-city perinatal center. PARTICIPANTS: Two hundred three infants younger than 6 months who had been admitted to the neonatal intensive care unit at birth; 130 (64%) of these infants were premature. Transplacental antibody transfer was evaluated in a subset of 89 mother-newborn pairs. INTERVENTION: Administration of measles monovalent vaccine to seronegative infants. MEASUREMENTS/RESULTS: Measles IgG antibody was measured using indirect fluorescent assay. At birth, 19 (38%) of 50 neonates born at less than 37 weeks' gestation had antibody titers that were twofold to fourfold lower than those of their mothers compared with three (8%) of 39 neonates born at more than 37 weeks' gestation (P < .01). Of the 203 study infants, fewer than 4% were seronegative at birth, while 74% of these infants aged 4 to 5 months were seronegative. Univariate logistic regression analysis indicated that the independent variables related to seronegativity were as follows: gestational age at birth (P = .007), chronological age (P < .001), history of having received three or more packed red blood cell transfusions (P < .001), and maternal age at delivery (P = .001). Multiple logistic regression analysis confirmed the association of seronegativity with chronological age (P < .001), gestational age (P < .02) and maternal age at delivery (P < .001). Seroconversion following administration of the measles vaccine was documented in 11 (79%) of 14 infants. CONCLUSION: A significant proportion of 4- to 5-month-old infants who had been admitted to the neonatal intensive care unit at birth lack measurable measles antibody; this population should be taken into account when strategies to control measles are considered.

The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease.

The acute chest syndrome (ACS), a pneumonia-like illness in sickle cell patients, is one of the most frequent causes of their morbidity and hospitalizations. Repeated ACS events may predict the development of chronic lung disease. ACS is reported as a frequent cause of death in these patients. We examine here the incidence and risk factors of ACS in 3,751 patients with sickle cell disease who were observed prospectively for at least 2 years (19,867 patient-years [pt-yrs]) as part of a multicenter national study group. The ACS, defined by a new pulmonary infiltrate on x-ray, occurred at least once in 1,085 patients (2,100 events). ACS incidence was higher in patients with homozygous sickle cell disease (SS; 12.8/100 pt-yrs) and in patients with sickle cell-beta(0) -thalassemic (9.4/100 pt-yrs), and lower in patients with hemoglobin (Hb) SC disease (5.2/100 pt-yrs) and patients with sickle cell-beta(+) thalassemia (3.9/100 pt-yrs). alpha-Thalassemia did not affect the rate of ACS incidence in SS patients. Within each Hb type the incidence was strongly but inversely related to age, being highest in children 2 to 4 years of age (25.3/100 pt-yrs in SS) and decreasing gradually to its lowest value in adults (8.8/100 pt-yrs in SS). In SS children (< 10 years of age), we documented an age-related within-person reduction in ACS attack rates. Adults with a higher ACS rate had a higher rate of mortality (from all causes) than those with low ACS rates. This increased rate of mortality might also have contributed to the decline in ACS rate with age. In multivariate analysis, other factors affecting incidence in SS patients were degree of anemia (lower ACS rates in patients with lower steady-state Hb levels) and fetal Hb (lower rates in patients with high fetal Hb). There was also a positive association between ACS rate and steady-state leukocyte count. The relationship of ACS rate to higher steady-state Hb levels in SS patients is unexplained but might be caused by increased blood viscosity.

Timing of single lung transplantation for primary pulmonary hypertension.

Single lung transplantation has been advocated as a definitive treatment for primary pulmonary hypertension. Because of reports of improved survival in some patients with vasodilators and anticoagulants, the timing of referral for single lung transplantation needs to be examined. Survival in primary pulmonary hypertension was estimated, with the use of a proportional hazards model, from data obtained from the National Institutes of Health registry on primary pulmonary hypertension. Waiting times for single lung transplantation, obtained from the United Network for Organ Sharing, were found to follow an exponential distribution. Under the assumption that waiting time and survival are independent, a model was developed to estimate the probability of surviving to single lung transplantation, depending on the waiting time for a single lung transplantation, and the delay in transplant referral. Examples were computed with hemodynamic data from the National Institutes of Health registry on primary pulmonary hypertension: waiting times of 6, 12, 18, and 24 months and delays in single lung transplantation referral of 0, 1, 2, and 3 years. For a waiting time of 6 months, the chance of surviving to single lung transplantation with a 3-year delay varies from 19% for a patient with a mean pulmonary artery pressure of 80 mm Hg to 72% for a patient with a mean pulmonary artery pressure of 41 mm Hg. For a waiting time of 24 months and a 3-year delay in single lung transplantation referral, this probability varies from 14% (mean pulmonary artery pressure 80 mm Hg) to 59% (mean pulmonary artery pressure 41 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholic beverages and breast cancer: some observations on published case-control studies.

We identified 38 case-control studies investigating possible associations between alcoholic beverage consumption and cancer of the female breast. Each study was characterized according to design features such as: control type (hospital or community based), risk factors controlled for, matching strategy, and statistical power. We examined the effect of these design variables on several outcome variables including identification of any significant elevation in odds ratio and characterization of any dose-response effect. The major finding of this study is that of a striking difference between hospital and community based controlled studies with respect to (1) the level of any estimated dose-response effect, and (2) the finding of statistically significant elevations in odds ratios at levels of consumption below 4 drinks per week. In summary, the generally weak associations reported in these case-control studies along with the measurement and/or selection biases implied by our findings would lead one to the conclusion that present evidence does not support a causal association. This conclusion seems to be in accord with results from cohort studies and with similar conclusions from several other reviews.

Limit to cardiac compensation during acute isovolemic hemodilution: influence of coronary stenosis.

We assessed limit to cardiac compensation during isovolemic hemodilution (HD) in 14 anesthetized dogs. Radioactive microspheres were used to evaluate myocardial blood flow (MBF) and its transmural distribution (endo/epi). Myocardial O2 consumption (MVO2) and percent lactate extraction were determined. Coronary vasodilator reserve was assessed from reactive hyperemic responses. Dogs were divided into group 1, with intact left anterior descending coronary artery (LAD), and group 2, with critical stenosis of LAD. Measurements were obtained at baseline and during graded HD (Hespan) until cardiac failure (CF). CF occurred at lower hematocrit in group 1 compared with group 2 (9 +/- 1 vs. 17 +/- 1%). In group 1, MBF increased during HD to maintain MVO2 constant; increases in MBF were transmurally uniform until CF, when decreased endo/epi and lactate production suggested subendocardial ischemia. Coronary vasodilator reserve decreased progressively during HD and was absent at CF. In group 2, stenotic LAD demonstrated constant MBF (resulting in decreased MVO2) during HD. At CF, these responses along with reduced endo/epi and lactate production indicated local myocardial ischemia. We conclude that 1) with normal coronary circulation, cardiac function was well maintained over a wide range of hematocrits because increases in MBF were transmurally uniform and sufficient to maintain myocardial oxygenation: CF occurred during extreme HD when MBF became maldistributed, resulting in subendocardial ischemia; 2) critical coronary stenosis impaired coronary vascular adjustment to HD and reduced significantly tolerance of left ventricle to HD; and 3) present findings underscore the importance of recruitment of coronary vasodilator reserve in preserving total and regional myocardial oxygenation during HD.

The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension.

BACKGROUND: Primary pulmonary hypertension is a progressive, fatal disease of unknown cause. Vasodilator drugs have been used as a treatment, but their efficacy is uncertain. METHODS: We treated 64 patients with primary pulmonary hypertension with high doses of calcium-channel blockers. Patients who responded to treatment (defined as those whose pulmonary-artery pressure and pulmonary vascular resistance immediately fell by more than 20 percent after challenge) were treated for up to five years. Their survival was compared with that of the patients who did not respond and with patients enrolled in the National Institutes of Health (NIH) Registry on Primary Pulmonary Hypertension. Warfarin was given to 55 percent of the patients as concurrent therapy, on the basis of a lung scan showing nonuniformity of pulmonary blood flow (47 percent of patients who responded and 57 percent of those who did not respond). RESULTS: Seventeen patients (26 percent) responded to treatment, as indicated by a 39 percent fall in pulmonary-artery pressure and a 53 percent fall in the pulmonary-vascular-resistance index (P less than 0.001). Nifedipine (mean [+/- SD] daily dose, 172 +/- 41 mg) was given to 13 patients, and diltiazem (mean daily dose, 720 +/- 208 mg) was given to 4 patients. After five years, 94 percent of the patients who responded (16 of 17) were alive, as compared with 55 percent of the patients who did not respond (26 of 47, P = 0.003). The survival of the patients who responded was also significantly better than that of the NIH registry cohort (P = 0.002) and patients from the NIH registry who were treated at the University of Illinois (P = 0.001). The use of warfarin was associated with improved survival (P = 0.025), particularly in the patients who did not respond. CONCLUSIONS: This study suggests that high doses of calcium-channel blockers in patients with primary pulmonary hypertension who respond with reductions in pulmonary-artery pressure and pulmonary vascular resistance may improve survival over a five-year period.