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Biomedical subjects

R A Wolfe

Publications and source records attributed to R A Wolfe.

At least 19 recordsLinked to original sources
PubMed1998

Use of community versus individual socioeconomic data in predicting variation in hospital use.

OBJECTIVES: (1) To examine the association of socioeconomic characteristics (SES) with hospitalization by age group, and when using measures of SES at the community as opposed to the individual level. (2) Thus, to support the inference that socioeconomic factors are important in the analysis of small area utilization data and address potential criticisms of this conclusion. DATA SOURCES: The 1989 Michigan Inpatient Database (MIDB), the 1990 U.S. Census, the 1989 Area Resource File (ARF), and the 1990 National Health Interview Survey (NHIS). STUDY DESIGN: A qualitative comparison of socioeconomic predictors of hospitalization in two cross-sectional analyses when using community as opposed to individual socioeconomic characteristics was done. DATA EXTRACTION. Hospitalizations (excluding delivery) were extracted by county from the MIDB and by individual from the NHIS. SES variables were extracted from the U.S. Census for communities and from the NHIS for individuals. Measures of employment for communities were from the ARF and information on health insurance and health status of individuals from the NHIS. PRINCIPAL FINDINGS: Both analyses show similar age-specific patterns for income and education. The effects were greatest in young adults, and diminished with increasing age. Accounting for multiple admissions did not change these conclusions. In the individual-level data the addition of variables representing health and insurance status substantially diminished the size of the coefficients for the socioeconomic variables. CONCLUSIONS: By comparison to parallel individual-level analyses, small area analyses with community-level SES characteristics appear to represent the effect of individual-level characteristics. They are also not substantially affected by the inability to track individuals with multiple readmissions across hospitals. We conclude that the impact of SES characteristics on hospitalization rates is consistent when measured by individual or community-level measures and varies substantially by age. These variables should be included in analyses of small area variation.

Adolescent↗
PubMed1997

Long-term renal allograft survival: prognostic implication of the timing of acute rejection episodes.

BACKGROUND: The timing of an acute rejection may have a variable impact on renal allograft survival. To determine whether the time of first acute transplant rejection (ATR) is an independent predictor of long-term allograft survival, we studied 31,600 first cadaveric renal transplants that were functional on the first transplant anniversary, from 217 U.S. centers. METHODS: Transplant patients were divided into four groups according to the time to the first ATR: no rejection in year 1 (group I); predischarge ATR (group II); first ATR between discharge and month 6 (group III); and first ATR in months 7-12 (group IV). RESULTS: Four-year allograft survival after year 1, estimated by a Cox proportional hazard model adjusting for 19 cofactors, was 78%, 72%, 69%, and 54% for groups I-IV, respectively (P<0.0001 for each comparison to group I). In those patients who had ATR episodes in more than one time period, later episodes were associated with worse long-term allograft survival, an observation that was independent of previous ATR episodes. CONCLUSIONS: We conclude that late occurrence of a first acute rejection portends a worse prognosis for allograft survival after the first year. Later rejections, in combination with previous rejections, also lead to worse long-term allograft survival. Unlike early ATRs occurring in the setting of supervised immunosuppression, late occurring ATR may reflect inadequate immunosuppression from noncompliant behavior or may reflect disruption or lack of immune tolerance to the allograft. Efforts to minimize late transplant loss require a combination of strategies directed at both immunologic and behavioral factors.

Acute Disease↗
PubMed1997

Delayed graft function: risk factors and implications for renal allograft survival.

Delayed graft function (DGF) may be associated with diminished kidney allograft survival. We studied the risk factors that lead to nonimmediate function of a renal allograft and the consequences of DGF on short- and long-term renal transplant survival. Data from the U.S. Renal Data System were used to measure the relationships among cold ischemia time, delayed graft function, acute rejection, and graft survival in 37,216 primary cadaveric renal transplants (1985-1992). These relationships were investigated using the unconditional logistic and Cox multivariate regression methods. Cold ischemia time was strongly associated with DGF, with a 23% increase in the risk of DGF for every 6 hr of cold ischemia (P<0.001). Acute transplant rejection occurred more frequently in grafts with delayed function (37% vs. 20%; odds ratio=2.25, P=0.001). DGF was independently predictive of 5-year graft loss (relative risk=1.53, P<0.001). The presence of both early acute rejection and DGF portended a dismal 5-year graft survival rate of 35%. Zero-HLA mismatch conferred a 10-15% improvement in 1- and 5-year graft survival regardless of early functional status of the allograft. However, the 5-year graft survival rate in HLA-mismatched kidneys without DGF was significantly higher than that of zero-mismatched kidneys with DGF (63% vs. 51%; P<0.001). DGF independently portends a significant reduction in short- and long-term graft survival. Delayed function and early rejection episodes exerted an additive adverse effect on allograft survival. The deleterious impact of delayed function is comparatively more severe than that of poor HLA matching.

Adult↗
PubMed1997

Low density lipoprotein receptor-related protein modulates the expression of tissue-type plasminogen activator in human colon fibroblasts.

Human colon fibroblasts (HCF) produce tissue-type plasminogen activator (t-PA) in culture, but after 24-48 h, t-PA ceases to accumulate in the medium. Here, we report negative feedback regulation of t-PA expression, exerted by t-PA or complexes of t-PA with its physiological inhibitor, plasminogen activator inhibitor type 1 (PAI-1). Inhibition of t-PA expression could be induced by addition of exogenous t-PA or t-PA.PAI-1 complexes and reversed by monoclonal antibody directed against the active site of t-PA. Analysis of metabolically radiolabeled protein and cellular mRNA showed that both t-PA protein and mRNA levels declined considerably after 24 h. When 125I-labeled t-PA or t-PA.PAI-1 complexes were incubated with HCF, monensin-inhibitable endocytosis and catabolism were observed. The low density lipoprotein receptor-related protein (LRP) was found to be expressed by HCF and to mediate these events. Addition of the 39-kDa receptor-associated protein (RAP), an antagonist for ligand interactions with LRP, removed the block to t-PA expression and restored its accumulation in the medium. Moreover, RAP completely prevented the degradation of exogenous 125I-labeled t-PA by HCF, suggesting that LRP is the endocytic receptor for t-PA in these cells. These results demonstrate that cellular modulation of t-PA expression in HCF involves LRP receptor-mediated clearance of t-PA. This LRP receptor-mediated event results in down-regulation of t-PA expression at the mRNA level.

Cells, Cultured↗
PubMed1997

Association of gender and access to cadaveric renal transplantation.

Previous studies have revealed that females are less likely than males to receive a renal transplant, the most successful form of treatment of end-stage renal disease (ESRD). The purpose of this study was to determine whether the barrier is to inclusion on the transplant waiting list or to transplantation after being placed on the transplant waiting list. An existing data set was used that included data from the Michigan Kidney Registry, supplemented with data received from the Organ Procurement Agency of Michigan. White and black patients less than 65 years of age and starting ESRD treatment between January 1, 1984, and December 31, 1989, were included. Cox proportional hazards models were used to determine the effect of gender on (1) time to transplantation among all ESRD patients, (2) time from diagnosis of ESRD to inclusion on the transplant waiting list among all ESRD patients, and (3) time from inclusion on the waiting list to transplantation among those patients on the waiting list. Patients were censored at the time of living-related transplantation or death, and were monitored until December 31, 1989. In all, 5,026 incident ESRD patients were included in the study (44.3% female). Of these, 1,626 patients were included on the waiting list (40.1% female); 823 of these received a transplant (37.7% female). Adjusting for age, race, and diagnosis, females were 25% less likely to receive a cadaveric transplant than males (female to male relative rate ratio [RR], 0.75; P < 0.001). Females with ESRD aged 46 to 55 years and 56 to 65 years were 33% (RR, 0.67; P < 0.001) and 29% (RR, 0.71; P < 0.05) less likely to be included on the transplant waiting list, respectively, than their male counterparts. There was no difference in the rate of wait list inclusion among ESRD patients younger than 46 years. Females with ESRD who were included on the transplant waiting list were 26% (RR, 0.74; P < 0.001) less likely to receive a transplant than males on the waiting list. These results indicate that females are both less likely to be on the transplant waiting list (ages over 45 years) and, once on the list, less likely to receive a transplant (all ages) than males. Further study is necessary to determine the factors contributing to these important barriers to transplantation among females with ESRD.

Adult↗
PubMed1997

Clinical outcome relative to the dose of dialysis is not what you think: the fallacy of the mean.

Several recent retrospective studies of mortality relative to the dose of dialysis have been widely interpreted to indicate that adequate thrice-weekly hemodialysis requires a single pool Kt/V (spKt/V) of at least 1.4 to 1.6 and higher. In these studies, mortality rate has been correlated to the mean delivered spKt/V, (spKt/Vd)m, with coefficient of variation (CV) on the means ranging up to 45%. To evaluate these reported relationships, two large databases were analyzed using population constants to transform urea reduction ratio and spKt/Vd to equilibrated Kt/Vd (eKt/Vd), which expresses dose corrected for treatment time. The eKt/V dose (D) values were correlated to the reported relative risks (RR) of mortality to derive a RR/D function. The RR/D function, derived from these data with stepwise linear regression analysis, is nonlinear, with a steep linear increase in RR for eKt/Vd less than 1.05 and constant RR for eKt/Vd > or = 1.05. This RR/D function is mathematically expressed as RR = 1.96 - 1.03(eKt/Vd) (equation 1) when 0.50 < or = eKt/Vd < or = 1.05, and RR = 0.88 (equation 2) when eKt/V > or = 1.05. We show that regression of RR on (eKt/Vd)m with large CV results in overestimation of RR relative to eKt/Vd for individual patients because of extrapolation of the linear relationship beyond the threshold where the slope becomes zero (see equation 2 above). It is concluded that (1) current clinical data indicate that adequate dialysis is provided with eKt/Vd of 1.0 to 1.1 on a thrice-weekly schedule, (2) it is essential to assure that all patients achieve this level of therapy, which is best accomplished using urea kinetic modeling for both prescription and measurement of delivered eKt/Vd, and (3) the current HEMO study is well designed to determine whether higher levels of eKt/Vd will further improve clinical outcome.

Female↗
PubMed1996

Logical and statistical fallacies in the use of Cox regression models.

Time-dependent covariates are an essential data analysis tool for modeling the effect of a study factor whose value changes during follow-up. However, survival analysis models can yield conclusions that are contrary to the truth if such time-dependent factors are not defined and used carefully. We outline some of the biases that can occur when time-dependent covariates are used improperly in a Cox regression model. For example, we discuss why one should almost never use a covariate that has been averaged over a patient's entire follow-up time as a baseline covariate. Instead, the baseline value should be used as a covariate, or the cumulative average up to each point in time should be used as a time-dependent covariate. We also document why one should use time-dependent covariates with great caution in analyses when the evaluation of a baseline factor is the primary objective. Several simulated examples are given to illustrate the direction and magnitude of the biases that can result from not adhering to some basic assumptions that underlie all survival analysis methodologies.

Bias↗
PubMed1996

The dose of hemodialysis and patient mortality.

The relationship between the delivered dose of hemodialysis and patient mortality remains somewhat controversial. Several observational studies have shown improved patient survival with higher levels of delivered dialysis dose. However, several other unmeasured variables, changes in patient mix or medical management may have impacted on this reported difference in mortality. The current study of a U.S. national sample of 2,311 patients from 347 dialysis units estimates the relationship of delivered hemodialysis dose to mortality, with a statistical adjustment for an extensive list of comorbidity/risk factors. Additionally this study investigated the existence of a dose beyond which more dialysis does not appear to lower mortality. We estimated patient survival using proportional hazards regression techniques, adjusting for 21 patient comorbidity/risk factors with stratification for nine Census regions. The patient sample was 2,311 Medicare hemodialysis patients treated with bicarbonate dialysate as of 12/31/90 who had end-stage renal disease for at least one year. Patient follow-up ranged between 1.5 and 2.4 years. The measurement of delivered therapy was based on two alternative measures of intradialytic urea reduction, the urea reduction ratio (URR) and Kt/V (with adjustment for urea generation and ultrafiltration). Hemodialysis patient mortality showed a strong and robust inverse correlation with delivered hemodialysis dose whether measured by Kt/V or by URR. Mortality risk was lower by 7% (P = 0.001) with each 0.1 higher level of delivered Kt/V. (Expressed in terms of URR, mortality was lower by 11% with each 5 percentage point higher URR; P = 0.001). Above a URR of 70% or a Kt/V of 1.3 these data did not provide statistical evidence of further reductions in mortality. In conclusion, the delivered dose of hemodialysis therapy is an important predictor of patient mortality. In a population of dialysis patients with a very high mortality rate, it appears that increasing the level of delivered therapy offers a practical and efficient means of lowering the mortality rate. The level of hemodialysis dose measured by URR or Kt/V beyond which the mortality rate does not continue to decrease, though not well defined with this study, appears to be above current levels of typical treatment of hemodialysis patients in the U.S.

Female↗
PubMed1996

Relationship of dose of hemodialysis and cause-specific mortality.

A number of studies have found a relationship of lower all-cause mortality risk for ESRD patients treated with increasing dose of dialysis. The objective of this study was to determine the relationship of delivered dose of dialysis with cause-specific mortality. Data from the USRDS Case Mix Adequacy Study, which includes a national random sample of hemodialysis patients, were utilized. To minimize the contribution of unmeasured residual renal function, the sample used in this analysis (N = 2479) included only patients on dialysis for one year or more. Cox proportional hazards models, stratified for diabetes, were used to analyze the effect of delivered dose of dialysis (measured and reported by both Kt/V and URR) on major causes of death and withdrawal from dialysis, adjusting for other covariates including demographics, comorbid diseases present at start of study, functional status, laboratory values and other dialysis parameters. Patient follow-up for mortality was censored at the earliest of time of transplantation, 60 days after a switch to peritoneal dialysis or at the time of data abstraction. For each 0.1 higher Kt/V, the adjusted relative risk of death due to coronary artery disease was 9% lower (RR = 0.91, P < 0.05), due to other cardiac causes was 12% lower (RR = 0.88, P < 0.01), due to cerebrovascular disease (CVD) was 14% lower (RR = 0.86, P < 0.05), due to infection was 9% lower (RR = 0.91, P = 0.05), and due to other known causes was 6% lower (RR = 0.94, P < 0.05). There was no statistically significant relationship of Kt/V and risk of death among patients who died of malignancy (RR = 0.84, P = 0.10) or among patients whose death cause was missing (RR = 0.95, P = 0.41). The risk of withdrawal from dialysis prior to death due to any cause was 9% lower (RR = 0.91, P < 0.05) for each 0.1 higher Kt/V. The relationships of delivered dose of dialysis, as measured by URR, and cause-specific mortality were essentially similar in relative magnitude and statistical significance as the relationships observed using Kt/V as the measurement of dialysis dose, with the exception that the relationship was less significant for cerebrovascular disease and withdrawal from dialysis. The relationship of dialysis dose with risk of death due to each cause of death category except other cardiac causes and "other" causes appeared to be of greater magnitude and of greater statistical significance among diabetics than non-diabetics. These results indicate that low dose of dialysis is not associated with mortality due to just one isolated cause of death, but rather is due to a number of the major causes of death in this population. This study is consistent with hypotheses that low doses of dialysis may promote atherogenesis, infection, malnutrition and failure to thrive through a variety of pathophysiologic mechanisms. Further study is necessary to confirm these results and to test hypotheses that are developed.

Adult↗
PubMed1996

Effect of the dialysis membrane on mortality of chronic hemodialysis patients.

Mortality of prevalent chronic hemodialysis patients remains high. The potential effect of the dialysis membrane on this mortality has not been previously investigated in a large population of chronic hemodialysis patients. Using data from the United States Renal Data System (USRDS), we analyzed a random sample of 6,536 patients receiving hemodialysis on December 31, 1990. The study design was a historical prospective study. By limiting the study to patients dialyzed for at least one year with bicarbonate dialysate, in whom the dose of dialysis could be calculated, and in whom dialysis membrane and co-existing morbidities were defined, the sample size was reduced to 2,410 patients. A Cox proportional hazards model was used to estimate relative mortality risk. The types of dialysis membranes used were broadly classified into three categories: unsubstituted cellulose, modified cellulose (generally cellulose membranes that have been modified by substitutions of some or most of their hydroxyl moieties) and synthetic membranes that are not cellulose-based. The results of the study suggest that after adjusting for the dose of dialysis and the presence of co-morbid factors, the relative risk of mortality of patients dialyzed with modified cellulose or synthetic membranes was at least 25% less than that of patients treated with unsubstituted cellulose membranes (P < 0.001). To account for the possibility that these differences were due to regional practice patterns, we further stratified the data for nine different regions. There was still a 20% difference in relative risk of mortality between membrane groups with the mortality statistically significantly less in patients treated with synthetic membranes (P < 0.045) compared to patients dialyzed with unsubstituted cellulose membranes. The results of this study suggest that the dialysis membrane plays an important role in the outcome of chronic hemodialysis patients. However, more definitive studies are needed before a cause and effect relationship can be proven.

Cellulose↗
PubMed1996

Comparing speeds of effectiveness of two treatments.

A variety of methods have been proposed for analyzing and summarizing data from clinical trials of pharmaceutical agents. Methods directed at evaluating the speed of activity of an agent are an important component of such analyses. We review several parameters that are useful for comparing speed of effectiveness and demonstrate their utility, both with didactic examples and with real data. The "survival function" is well suited to evaluating speed of cure, particularly when there is a fraction of the population that does not respond to a particular treatment. Some conditional parameters, such as the survival function among those who are curable, are shown to be inappropriate for the comparison of speeds of cure because they summarize speed of activity in different, and therefore noncomparable, populations. Comparisons based on these conditional survival curves are inappropriate and can lead to the wrong interpretation even when one treatment completely dominates another with respect to speed and efficacy. Methods appropriate for determining an optimal sequence of treatments are briefly reviewed. Examples from the published literature, as well as data from a recent study of venlafaxine, are used to demonstrate both appropriate and flawed interpretations of clinical trial data.

Antidepressive Agents, Second-Generation↗
PubMed1995

Transient effects in the Cox proportional hazards regression model.

We consider a model for mortality rates that includes both the long and short term effects of switching from an initial to a second state, for example, when patients receive an initial treatment and then switch to a second treatment. We include transient effects associated with the switch in the model through the use of time-dependent covariates. One can choose the form of the time-dependent covariate to correspond with a variety of possible transition patterns. We use an exponential decay model to compare the survival experience of transplant versus dialysis treatment of end stage renal disease (ESRD) patients from the Michigan Kidney Registry (MKR). This model involves a hazard function that has an initial effect in mortality at the time of transplant, expected to be higher, followed by a smooth exponential decay to a long term effect, expected to be lower than the risk for those remaining on dialysis. Cox and Oakes used this model to analyse the Stanford Heart Transplant data. The model implicitly suggests there is a time at which the hazard curves (and survival curves) for the treatment groups cross. Those crossing times are useful in advising patients who have the option of receiving a transplant. We describe methods for obtaining estimates of the crossing times and their associated variances, and then apply them in analysing the MKR data.

Cadaver↗
PubMed1995

Relative impact of donor type on renal allograft survival in black and white recipients.

Renal allograft survival of organs from living-related donors (LRDs) is superior to that of organs from cadaveric donors (CAD). Allograft survival rates are lower in black recipients of both CAD and LRD transplants compared with recipients of other races. It is not known whether the superior donor effect of LRD varies between races. We investigated the graft survival outcome of first renal transplants performed in the United States in 1986 and 1989 to determine whether the donor effect differs between black and white recipients. A measurement of "donor type effect" is introduced. There were 7,002 and 7,307 first renal transplants in 1986 and 1989, respectively, for which allograft survival data were available from the United States Renal Data Systems. Both black and white recipients showed a greater than 50% reduction in the risk of allograft loss at all the points studied up to 5 years posttransplant when LRD was chosen over CAD transplantation. A measurement of donor type effect indicates that graft loss is reduced by 7 to 21 percentage points at 1 and 5 years posttransplant. The donor type effect is proportionally equal in both races. Therefore, kidney donation from living relatives as a first transplant should be encouraged for all medically suitable end-stage renal disease patients as a means of improving outcome and reducing CAD transplantation waiting time for patients in whom LRD transplants cannot be performed.

Black People↗
PubMed1995

Endogenous and exogenous pituitary-specific promoters are differentially controlled.

We have engineered GH3 cells with reporter genes under control of the growth hormone and prolactin promoters and measured protein production. The results indicate very low level production of reporter proteins from the cells regardless of the promoter used to drive expression. This was surprising in light of the observation that the cells still produced high levels of endogenous growth hormone and prolactin. Chinese hamster ovary (CHO) cells were engineered to express the Pit-1 transactivator. Transfection of reporter genes under control of the prolactin promoter demonstrated a clear enhancement of expression levels compared to the same promoter in parental CHO cells. Pit-1 expression is not sufficient, however, for high level, stable expression from the growth hormone promoter. These results indicate that the growth hormone and prolactin promoters are not sufficient for high level, stable expression even in normally permissive cells and suggest that Pit-1 alone is not sufficient for strong promoter activity from the integrated plasmids.

Animals↗
PubMed1995

The United States Renal Data System: a source of national norms for ESRD patient outcome and process of care.

The Annual Data Report of the United States Renal Data System provides a rich resource of published summaries of the United States norms for end-stage renal disease (ESRD) patient outcome and process of care. It includes summaries of patient mortality rates, hospitalization rates, causes of death, and rates of withdrawal from dialysis based on a near-census of ESRD patients in the United States. Norms for some measures of the process of delivering dialysis therapy, including dose of dialysis are also reported, based on a national random sample of ESRD patients. National summaries of measures of patient outcome and process of care provide a useful benchmark against which specific experience can be compared. Such comparisons can be part of a quality improvement program that encourages caregivers to provide high quality care to ESRD patients. While the Annual Data Report provides summaries of several fundamental measures related to high quality care, including patient survival and quality of life, other measures need to be developed and studied, including more direct measures of quality of life.

Cause of Death↗
PubMed1995

Inferior outcome of two-haplotype matched renal transplants in blacks: role of early rejection.

Acute rejection in the early post-transplant period is a major determinant of long-term outcome. A cohort analysis was performed to evaluate the race-specific incidence rates of early acute rejection episodes (AR) and delayed graft function (DGF) in Americans of African (blacks) and European (whites) descent (N = 2565) who received a 2-HM living-related donor (LRD) first kidney transplant between 1984 and 1992. After adjusting for center and recipient characteristics, blacks had a higher incidence of AR during the initial transplant hospitalization (blacks 13.2% vs. whites 7.4%, OR = 1.64, P = 0.02). DGF also occurred more frequently in blacks (unadjusted OR = 1.58, P = 0.07). Blacks with AR had significantly worse Cox-adjusted five year graft survival than similarly affected whites (blacks 50% vs. whites 76%, P < 0.01). We conclude that failure to take immunosuppressive medications cannot be implicated as a cause of the higher incidence of AR during the initial transplant hospitalization in black kidney transplant recipients. The excess risk of AR in blacks may reflect previously reported intrinsic differences in immune responsiveness and/or pharmacokinetics of immunosuppressive agents. The profound deleterious effect of AR appears to be largely responsible for the accelerated rate of late graft loss in African Americans.

Adult↗
PubMed1995

Hospitalization among United States dialysis patients: hemodialysis versus peritoneal dialysis.

Measurements of hospitalization in the dialysis population are important because they provide insight into the morbidity and the cost of treatment among dialysis patients. Prior comparisons of hospitalization for different dialysis modalities have had conflicting results. This study was designed to compare hospitalization for patients treated with peritoneal dialysis (PD) versus hemodialysis (HD) using the data from the U.S. Renal Data System 1993 Annual Data Report. The study population included all Medicare dialysis patients prevalent on January 1, 1988 through 1990. Patients were monitored to transplantation, death, or end of the calendar year for a total of 189,654 patient years. Hospital admission rates were computed from the total number of hospital admissions during the year divided by the total number of patient years at risk. Patients were classified by treatment modality (PD, HD), cause of ESRD (diabetes as a cause of ESRD versus all other causes), age (0 to 19, 20 to 44, 45 to 65, +65), and race (black, white). Rate ratios (RR:PD/HD) for hospital admissions per year at risk were estimated, while adjusting for the other factors with Poison regression. On average, hospital admission rates per patient year at risk for dialysis patients treated with PD were 14% higher than for those treated with HD (RR = 1.14; 95% confidence interval (Cl), 1.13 to 1.15) when adjusting for race, age, gender, and cause of ESRD. The excess in the overall adjusted admission rates in PD patients compared with HD patients was higher for black than for white patients (RR:PD/HD = 1.22 versus RR = 1.11; 95% Cl, 1.10 to 1.13).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗