Dynamic pseudo-observations: a robust approach to dynamic prediction in competing risks.

In this article, we propose a new approach to the problem of dynamic prediction of survival data in the presence of competing risks as an extension of the landmark model for ordinary survival data. The key feature of our method is the introduction of dynamic pseudo-observations constructed from the prediction probabilities at different landmark prediction times. They specifically address the issue of estimating covariate effects directly on the cumulative incidence scale in competing risks. A flexible generalized linear model based on these dynamic pseudo-observations and a generalized estimation equations approach to estimate the baseline and covariate effects will result in the desired dynamic predictions and robust standard errors. Our approach has a number of attractive features. It focuses directly on the prediction probabilities of interest, avoiding in this way complex modeling of cause-specific hazards or subdistribution hazards. As a result, it is robust against departures from these omnibus models. From a computational point of view an advantage of our approach is that it can be fitted with existing statistical software and that a variety of link functions and regression models can be considered, once the dynamic pseudo-observations have been estimated. We illustrate our approach on a real data set of chronic myeloid leukemia patients after bone marrow transplantation.

Dynamic prediction by landmarking in competing risks.

We propose an extension of the landmark model for ordinary survival data as a new approach to the problem of dynamic prediction in competing risks with time-dependent covariates. We fix a set of landmark time points tLM within the follow-up interval. For each of these landmark time points tLM , we create a landmark data set by selecting individuals at risk at tLM ; we fix the value of the time-dependent covariate in each landmark data set at tLM . We assume Cox proportional hazard models for the cause-specific hazards and consider smoothing the (possibly) time-dependent effect of the covariate for the different landmark data sets. Fitting this model is possible within the standard statistical software. We illustrate the features of the landmark modelling on a real data set on bone marrow transplantation.

Robust age at onset linkage analysis in nuclear families.

OBJECTIVE: Standard methods for linkage analysis ignore the phenotype of the parents when they are not genotyped. However, this information can be useful for gene mapping. In this paper we propose methods for age at onset genetic linkage analysis in sibling pairs, taking into account parental age at onset. METHODS: Two new score statistics are derived, one from an additive gamma frailty model and one from a log-normal frailty model. The score statistics are classical non-parametric linkage (NPL) statistics weighted by a function of the age at onset of the four family members. The weight depends on information from registries (age-specific incidences) and family studies (sib-sib and father-mother correlation). RESULTS: In order to investigate how age at onset of sibs and their parents affect the information for linkage analysis the weight functions were studied for rare and common disease models, realistic models for breast cancer and human lifespan. We studied the performance of the weighted NPL methods by simulations. As illustration, the score statistics were applied to the GAW12 data. The results show that it is useful to include parental age at onset information in genetic linkage analysis.

A new serially correlated gamma-frailty process for longitudinal count data.

We describe a new multivariate gamma distribution and discuss its implication in a Poisson-correlated gamma-frailty model. This model is introduced to account for between-subjects correlation occurring in longitudinal count data. For likelihood-based inference involving distributions in which high-dimensional dependencies are present, it may be useful to approximate likelihoods based on the univariate or bivariate marginal distributions. The merit of composite likelihood is to reduce the computational complexity of the full likelihood. A 2-stage composite-likelihood procedure is developed for estimating the model parameters. The suggested method is applied to a meta-analysis study for survival curves.

Meta-analysis of pairs of survival curves under heterogeneity: a Poisson correlated gamma-frailty approach.

We address the problem of meta-analysis of pairs of survival curves under heterogeneity. Starting point for the meta-analysis is a set of studies, each comparing the same two treatments, containing information about multiple survival outcomes. Under heterogeneity, we model the number of events using an extension of the Poisson correlated gamma-frailty model with serial within-arm and positive between-arm correlations. The parameters of the models are estimated following a two-stage estimation procedure. In the first stage the underlying hazards and between-study variance are estimated using the marginals, while a second stage is used to estimate both within-arm and between-arm correlations. The methodology is illustrated with an observational study on breast cancer.

Bivariate random effects meta-analysis of ROC curves.

Meta-analysis of receiver operating characteristic (ROC)-curve data is often done with fixed-effects models, which suffer many shortcomings. Some random-effects models have been proposed to execute a meta-analysis of ROC-curve data, but these models are not often used in practice. Straightforward modeling techniques for multivariate random-effects meta-analysis of ROC-curve data are needed. The 1st aim of this article is to present a practical method that addresses the drawbacks of the fixed-effects summary ROC (SROC) method of Littenberg and Moses. Sensitivities and specificities are analyzed simultaneously using a bivariate random-effects model. The 2nd aim is to show that other SROC curves can also be derived from the bivariate model through different characterizations of the estimated bivariate normal distribution. Thereby the authors show that the bivariate random-effects approach not only extends the SROC approach but also provides a unifying framework for other approaches. The authors bring the statistical meta-analysis of ROC-curve data back into a framework of relatively standard multivariate meta-analysis with random effects. The analyses were carried out using the software package SAS (Proc NLMIXED).

Anxious-retarded depression: relation to two-year outcome of major depressive disorder.

BACKGROUND: Anxious-retarded depression is a two-dimensionally defined subcategory of depression derived from DSM-IV melancholia. It is related to increased plasma vasopressin, correlative plasma vasopressin and cortisol levels, and a positive family history. We now explored its relation with outcome. METHODS: Seventy depressed patients were included to follow-up for two years. Outcome was defined by time until full-remission. Cox regression analyses were used to compare anxious-retarded and non-anxious-retarded patients, as well as melancholic and non-melancholic patients. RESULTS: Anxious-retarded depression had poor outcome. LIMITATIONS: The number of patients was relatively small. CONCLUSION: The poor outcome of anxious-retarded depression further supports its validity.

Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.

BACKGROUND: In BRCA2 mutation carriers, increased risks have been reported for several cancer sites besides breast and ovary. As most of the families included in earlier reports were selected on the basis of multiple breast/ovarian cancer cases, it is possible that risk estimates may differ in mutation carriers with a less striking family history. METHODS: In the Netherlands, 139 BRCA2 families with 66 different pathogenic mutations were included in a nationwide study. To avoid testing bias, we chose not to estimate risk in typed carriers, but rather in male and female family members with a 50% prior probability of being a carrier (n = 1811). The relative risk (RR) for each cancer site with the exception of breast and ovarian cancer was determined by comparing observed numbers with those expected, based on Dutch cancer incidence rates. RESULTS: We observed an excess risk for four cancer sites: pancreas (RR 5.9; 95% confidence interval (CI) 3.2 to 10.0), prostate (2.5; 1.6 to 3.8), bone (14.4; 2.9 to 42.1) and pharynx (7.3; 2.0 to 18.6). A small increase was observed for cancer of the digestive tract (1.5; 1.1 to 1.9). Histological verification was available for 46% of the tumours. Nearly all increased risks reached statistical significance for men only. Cancer risks tended to be higher for people before the age of 65 years. Moreover, families with mutations outside the previously defined ovarian cancer cluster region tended to have a higher cancer risk. CONCLUSIONS: We found that BRCA2 carriers are at increased risk for cancers of the prostate and pancreas, and possibly bone and pharynx. Larger databases with extended follow up are needed to provide insight into mutation specific risks of selected carriers in BRCA2 families.

Predictability of the survival of patients with advanced ovarian cancer.

Based on material from two clinical trials performed by The Netherlands Joint Study Group for Ovarian Cancer, we constructed a prognostic index (PI) with considerable predictive power for long-term survival of patients treated with cytotoxic combination chemotherapy including cisplatin. The pretreatment characteristics needed for the calculation of the PI are the Karnofsky index, the site of metastases expressed as the International Federation of Gynecology and Obstetrics (FIGO) stage, the size of residual tumor, the Broders' grade, and the presence of ascites. In the subgroup comprising the 10% of the patients with the best prognosis, 4-year survival was 75%, whereas all of the patients in the subgroup comprising the 10% with the poorest prognosis died within 4 years, which illustrates the large variability of the prognosis among patients. The PI was found to retain its value after response was achieved. The information provided by the PI can be expected to be useful in treatment planning and for proper stratification of patients in clinical trials.

Risk estimation for healthy women from breast cancer families: new insights and new strategies.

Risk estimation in breast cancer families is often estimated by use of the Claus tables. We analyzed the family histories of 196 counselees; compared the Claus tables with the Claus, the BRCA1/2, the BRCA1/2/ models; and performed linear regression analysis to extend the Claus tables with characteristics of hereditary breast cancer. Finally, we compared the Claus extended method with the Claus, the BRCA1/2, and the BRCA1/2/u models. We found 47% agreement for Claus table versus Claus model; 39% agreement for Claus table versus BRCA1/2 model; 48% agreement for Claus table versus BRCA1/2/u model; 37% agreement for Claus extended method versus Claus model; 44% agreement for Claus extended model versus BRCA1/2 model; and 66% agreement for Claus extended method versus BRCA1/2/u model. The regression formula (Claus extended method) for the lifetime risk for breast cancer was 0.08 + 0.40 (*) Claus Table + 0.07 (*) ovarian cancer + 0.08 (*) bilateral breast cancer + 0.07 (*) multiple cases. This new method for risk estimation, which is an extension of the Claus tables, incorporates information on the presence of ovarian cancer, bilateral breast cancer, and whether there are more than two affected relatives with breast cancer. This extension might offer a good alternative for breast cancer risk estimation in clinical practice.

Time trend in annual kidney graft survival.

First cadaver, unrelated kidney graft survival at one year from 50 Eurotransplant centers was analyzed and found to show marked changes in survival rates over the 20-year period from 1967 to 1986 inclusive. Full information on HLA-A, -B, and -DR matching and use of cyclosporine therapy was only available for the period 1981 to 1986. When these factors were allowed for, the number (and type) of HLA mismatches was shown to have a significant and independent effect on differences in survival rates whereas the effect of cyclosporine differed over the different years.

The impact of center variation on the HLA-DR matching effect in kidney graft survival.

Data from 7436 cases of first-cadaver transplants between 1981 and 1986 from 50 transplant follow-up centers within Eurotransplant, were analyzed with respect to the effect of HLA-DR matching on graft prognosis within the first year posttransplant. The use of cyclosporine was allowed for as well as the variation in graft survival rate between transplant follow-up centers. After adjustment for these variables, HLA-DR matching was still very significant. The effect of CsA on graft survival varied between centers--i.e., interaction was observed--but the effect of HLA-DR mismatching did not vary significantly between centers. Over all the centers there was a 1.4-fold increase in relative risk for each increase in HLA-DR mismatch, corresponding to predicted one-year graft survivals of 86.5%, 81.9%, and 75.4% for 0, 1, and 2 HLA-DR mismatches respectively, in patients receiving CsA, and 72.5%, 64.2%, and 53.6% in patients not receiving CsA.

Factors contributing to long-term kidney graft survival in Eurotransplant.

We examined the graft survival of 12,883 first unrelated kidney grafts from nonliving donors, transplanted between 1 January 1971 and 31 December 1987 within 52 renal transplantation centers participating in the Eurotransplant organization. The 5-year graft survival increased from 38.8% for the period 1971-1975 to 66.0% for the period 1981-1987 for patients treated with cyclosporine, whereas the half-life increased by only 2 years, from 9.7 years to 11.6 years over the same period, based on grafts functioning at 1 year posttransplantation. Results per HLA locus showed considerable improvements within mismatch groups over the entire period. Large differences between mismatch groups for the early years were observed, but within the cyclosporine era only HLA-B showed a statistically significant difference in half-lives (13.2 versus 9.0 years, for 0 and 2 mismatches respectively, P = 0.013). When other prognostic factors were taken into account, it was revealed by means of an exponential model that number of HLA-B mismatches, donor and recipient age and sex, and recipient diagnosis of diabetes had significant effects on the long-term outcome of the grafts. Depending on the combination of these parameters, estimates of half-life varied from 4.9 to 14.5 years. These results show that matching for HLA-B is still of benefit in the longer term and that other prognostic factors play an important role in predicting the late outcome of renal allografts.

The effect of HLA matching on kidney graft survival in separate posttransplantation intervals.

The effect of matching for the HLA antigens has been well established as important in the prognosis of kidney grafts. By analyzing the effect of matching on first transplants from unrelated donors in specific intervals up to 3 years posttransplantation, we show that the effect of HLA-DR matching is strongest in the first 5 months following transplantation (relative risks of graft failure 1.31 and 1.77 for 1 and 2 HLA-DR mismatches, respectively, compared with no mismatches). For patients whose grafts remained functioning after 5 months, there was no significant further improvement in graft survival to 3 years (relative risks 1.16 and 0.98 for 1 and 2 HLA-DR mismatches, respectively, compared with no mismatches)--i.e., the gain in graft survival by matching for HLA-DR appears to be due to its influence in the first 5 months following transplantation. For HLA-B, the matching effect was evident both before and after 5 months (relative risks 1.11 and 1.27 for 1 and 2 HLA-B mismatches, respectively, compared with no mismatches and modelled as constant over the 3-year period), whereas no effect of HLA-A matching was evident in the period up to 3 years.

Cytokine and IL-12 receptor mRNA discriminate between different clinical subtypes in multiple sclerosis.

Little is known about the involvement of cytokines in the pathogenesis of primary progressive (PP) multiple sclerosis (MS). We evaluated in this cross-sectional study whether IL-18, IL-12p35, IL-12p40, TNF-alpha, IFN-gamma, IL-10, IL-4, TGF-beta, IL-12Rbeta1, and IL-12Rbeta2 mRNA expression in unstimulated white blood cells showed significant differences between relapsing-remitting (RR), secondary progressive (SP) and PP MS patients, and healthy controls. All clinical subtypes showed unique mRNA expression patterns as compared to the controls. Both RR and SP patients displayed increased levels of IL-12p40, IL-18, and TGF-beta mRNA compared to controls, whereas PP patients showed only increased IL-18 mRNA levels. Both in PP and SP patients, IFN-gamma and IL-10 mRNA were decreased compared to RR patients and controls. PP patients were unique in that they showed decreased IL-12Rbeta1 mRNA. In conclusion, our data show that the assessment of cytokine (receptor) mRNA profiles is useful to discriminate between the different clinical subtypes and suggest that different cytokines are involved in the pathogenesis of PP MS as compared to RR and SP MS.

Bleeding symptoms in carriers of hemophilia A and B.

In order to investigate the bleeding tendency in clinically identified carriers of hemophilia, a self-administered questionnaire was held among 135 carriers of hemophilia A and B, 25 females with relatives with hemophilia and a matched group consisting of 60 females without relatives with hemophilia. Carriers of hemophilia appeared to suffer more often from bleeding than their relatives or the matched unrelated control group. A relation was seen between factor VIII:C or IX:C activity and the tendency to bleed. Obligatory carriers with normal factor VIII:C levels showed no bleeding tendency and were in this respect similar to a group of 25 females with relatives with hemophilia. This study shows that it is important to assay factor VIII:C or IX:C also in those women in whom the carrier status has already been established otherwise.

Prognostic assessment from studies with non-randomized treatment assignment.

In clinical practice, prognostic factors are primarily used to identify and select patients with a relatively poor prognosis who may need more aggressive treatment in order to improve their prognosis. Preferably, assessment of the ability of prognostic factors to distinguish these high risk patients from low risk patients should take place in the absence of such prognosis-modifying adjuvant therapy. Adjuvant therapy may dilute the effect of prognosticators (covariate-treatment interactions) and such a situation may go unnoticed in tests for interaction because of their low statistical power. These undetected covariate-treatment interactions will bias the estimated effects of prognostic factors in both studies with randomized and non-randomized treatment assignment but the bias will usually be greater in studies when treatment was not randomized. For the evaluation of prognostic factors, it is therefore argued that the study population should be restricted to patients who do not received adjuvant therapy. This restriction might result in a less powerful analysis, but it carries the advantage that undetectable biases are avoided. Non-random treatment assignment will not invalidate this restriction analysis provided that all the prognostic factors on which treatment choice was based, are known and incorporated into the analysis.

Sensitivity and specificity of diagnostic tests in acute maxillary sinusitis determined by maximum likelihood in the absence of an external standard.

This study shows how to obtain maximum likelihood estimates of test sensitivities and specificities in case of lack of an external standard, using the Expectation Maximisation (EM) algorithm. This method is used to compare four diagnostic tests in patients suspected of acute maxillary sinusitis. Data were analyzed from published studies. Antral aspiration is the test with the highest diagnostic value. The diagnostic value of a positive clinical examination (according to explicit criteria) and of a positive radiograph or ultrasound are comparable. A negative radiograph is of more diagnostic value than a negative clinical examination or ultrasound. The width of the confidence intervals may be too small, due to model deviations which may give incorrect standard errors. However, the estimated likelihood ratios adequately reflect the relative value of the diagnostic tests considered, even when the assumption of independence is dropped.

Antimicrobial treatment in acute maxillary sinusitis: a meta-analysis.

OBJECTIVE: The aims of this study were to assess which antibiotic is most effective in the treatment of acute maxillary sinusitis in otherwise healthy adults and adolescents, and which has the fewest side effects. DESIGN: To assess the short-term effects of antimicrobial treatments, a meta-analysis was performed using Mantel-Haenszel procedures on 16 comparative, randomized studies with a total number of 3358 patients. No placebo-controlled studies were available. Antimicrobial treatments were categorized according to type, spectrum, beta-lactamase inhibition, and bactericidal effect. Outcomes were clinical cure, clinical success, and adverse events. RESULTS: When studies were analyzed separately, we found significant differences between cefpodoxim and cefaclor in relation to clinical cure, and between loracarbef and doxycycline in relation to clinical success. When data was pooled, sulphonamides were significantly more effective than penicillins in relation to clinical cure, and macrolids were more effective than penicillins in relation to clinical success, whereas cephalosporins caused significantly less adverse events than penicillins. When studies were stratified (standard classic meta-analysis), antibiotics with beta-lactamase inhibition offered significantly more clinical cures than antibiotics without beta-lactamase inhibition. However, this significant effect was only due to one study from Southern Europe, published before 1991. CONCLUSION: Differences in outcome between antimicrobial treatments of acute sinusitis in otherwise healthy adults and adolescents appear to be small. Therefore, the cheapest antimicrobial treatment can be selected.

Elevated serum HLA class I levels coincide with acute and chronic graft-versus-host disease.

The ability to predict the likely occurrence of graft-versus-host-disease (GVHD) after BMT would be extremely valuable. We performed a retrospective study on the correlation between soluble HLA class I (sHLA-I) levels and GVHD in the sera of 34 patients receiving an allogeneic BMT and in the sera of 12 patients receiving an autologous BMT. sHLA-I levels measured pre- and at different times post-BMT were correlated with the occurrence of post-BMT complications, ie acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), infections and relapse. No changes in sHLA-I levels (delta sHLA-I) occurred in autologous and allogeneic BMT patients without GVHD. In contrast, sHLA-I reached high levels in patients suffering from GVHD. Increased sHLA-I levels correlated strongly with episodes of both acute and chronic GVHD (P = 0.004 and P = 0.005, respectively). Also during relapse increased sHLA-I levels were found (P = 0.032). During infections sHLA-I levels increased, although not significantly. Kinetic studies gave no evidence that the increase in sHLA-I levels preceded the clinical occurrence of aGVHD or of cGVHD. A slight, but significant correlation was found between total blood bilirubin levels and sHLA-I levels in patients suffering from GVHD (P = 0.037), indicating the contribution of the liver as a source of sHLA-I. We conclude that measurements of sHLA-I levels do not function as a predictive parameter for GVHD, but can be valuable for the monitoring of GVHD after BMT.