A polygenic model for integration of linkage and pathway information.

We introduce an approximate model for linkage curves which accommodates the polygenic structure of complex diseases and accounts for the simultaneous action of closely located genes. The model is extended so that information on biological pathways can be integrated. Using data on rheumatoid arthritis, we describe some of the many applications which the model allows: it can be used to test for residual linkage in the presence of already established loci, to derive a global test for linkage, to test for the relevance of a gene list in terms of linkage and to help in candidate gene prioritization by integration of gene-pathway annotation data.

Score test for age at onset genetic linkage analysis in selected sibling pairs.

A new score statistic is derived, which uses information from registries (age-specific incidences) and family studies (sib-sib marginal correlation) to weight affected sibling pairs according to their age at onset. Age at onset of sibling pairs is modelled by a gamma frailty model. From this model we derive a bivariate survival function, which depends on the marginal survival and on the marginal correlation. The score statistic for linkage is a classical nonparametric linkage (NPL) statistic where the identical by descent sharing is weighted by a particular function of the age at onset data. Since the statistic is based on survival models, it can also be applied to discordant and healthy sibling pairs. Simulation studies show that the proposed method is robust and more powerful than standard NPL methods. As illustration we apply the new score statistic to data from a breast cancer study.

[Early surgery or a wait-and-see policy in lumbosacral radicular syndrome: a randomized study]. / Vroeg opereren of langer afwachten voor het lumbosacraal radiculair syndroom: een gerandomiseerd onderzoek.

OBJECTIVE: To compare early surgery with expectative policy and later surgery if necessary in patients with sciatica that did not resolve within 6 weeks. DESIGN: Randomized multicentre clinical trial (ISRCTN 26872154). METHODS: Patients who had had severe sciatica for 6 to 12 weeks were randomized to early surgery or to prolonged conservative treatment with later surgery if necessary. The primary outcomes were the Roland Disability Questionnaire score, the visual-analogue scale for leg pain score, and the patient's report of their perceived recovery over the first year after randomization. Repeated measures analysis according to the intention-to-treat principle was used to analyse the outcome curves for both groups. RESULTS: A total of 283 patients were included and randomized. Of 141 patients assigned to undergo early surgery, 125 (89%) underwent microdiscectomy after a mean of 2.2 weeks. Of 142 patients assigned to conservative treatment, 55 (39%) still had to undergo surgical treatment after a mean of 18.7 weeks. There was no significant overall difference in disability scores during the first year (p = 0.13). Leg pain lessened more quickly in patients assigned to early surgery (p < 0.001). Patients assigned to early surgery also reported a faster rate of perceived recovery (hazard ratio (HR): 1.97; 95% CI: 1.72-2.22; p < 0.001). In both groups, however, the probability of perceived recovery after 1 year of follow-up was 95%. CONCLUSIONS: The 1-year outcomes were similar for patients assigned to early surgery and those assigned to extended conservative treatment with later surgery if necessary but the rates of reduction of leg pain and of perceived recovery were faster in those assigned to early surgery.

Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment.

BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations of mismatch repair genes, usually in hMLH1 or hMSH2. All earlier studies on penetrance except one population based study were conducted in HNPCC families and did not correct for the way in which these families were ascertained. OBJECTIVE: To obtain estimates of the risk of colorectal cancer (CRC) and endometrial cancer (EC) for carriers of disease causing mutations of the hMSH2 and hMLH1 genes. METHODS: Families with known germline mutations of hMLH1 (n = 39) and hMSH2 (n = 45) were extracted from the Dutch HNPCC cancer registry. Ascertainment-corrected maximum likelihood estimation was carried out on a competing risks model for cancer of the colorectum and endometrium. RESULTS: Both loci were analysed jointly as there was no significant difference in risk (p = 0.08). At age 70, colorectal cancer risk for men was 26.7% (95% confidence interval, 12.6% to 51.0%) and for women, 22.4% (10.6% to 43.8%); the risk for endometrial cancer was 31.5% (11.1% to 70.3%). CONCLUSIONS: Current estimates of the CRC risk of mutations to the hMLH1 and hMSH2 locus should be replaced by considerably lower risks which account for the selection of the families.

Comparison of the predictive power of different prognostic indices for overall survival in patients with advanced ovarian carcinoma.

Validation of a 5-covariate prognostic index (PI5) (performance status, stage, residual tumor size, histological grade, and ascites) derived from a group of 268 Dutch patients with advanced ovarian carcinoma was performed in a similar study of 301 Danish patients. Analysis of survival suggested an alternative 4-covariate PI (performance status, residual tumor size, age, weight/body surface) for the latter group. As residual tumor size and performance status were common to both indices, the predictive power of this 2-covariate PI (PI2) was also assessed in the Danish study and, subsequently, validated in the Dutch patients. The PI5 defined 10 and 9% of the Dutch patients as low and high risk patients with 3-year survival rates of 80 and 8%, respectively. In the Danish study the PI5 classified 14% to be high risk patients with a 3-year survival rate of 18%. Only a few patients (3%) were classified as low risk, making comparisons irrelevant. The PI2 classified 33 and 26% of the Danish patients as having 3-year survival rates of 67 and 13%, respectively. The corresponding Dutch PI2 values were 41 and 15% of the patients with 3-year survival rates of 60 and 8%, respectively. Although the PI5 possessed a better validity in the Danish study than the PI2 in the Dutch study, the PI2 may be the best prognostic index available for general use.

Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer.

PURPOSE: To determine the side effects and feasibility of cisplatin and carboplatin each in combination with paclitaxel as front-line therapy in advanced epithelial ovarian cancer. PATIENTS AND METHODS: Patients were randomly allocated to receive paclitaxel 175 mg/m(2) intravenously as a 3-hour infusion followed by either cisplatin 75 mg/m(2) or carboplatin (area under the plasma concentration-time curve of 5), both on day 1. The schedule was repeated every 3 weeks for at least six cycles. Women allocated to paclitaxel-cisplatin were admitted to the hospital, whereas the carboplatin regimen was administered to outpatients. RESULTS: A total of 208 eligible patients were randomized. Both regimens could be delivered in an optimal dose and without significant delay. Paclitaxel-carboplatin produced significantly less nausea and vomiting (P: <.01) and less peripheral neurotoxicity (P: =.04) but more granulocytopenia and thrombocytopenia (P: <.01). The overall response rate in 132 patients with measurable disease was 64% (84 of 132 patients), and in patients with elevated CA 125 levels at start, it was 74% (132 of 178 patients). With a median follow-up time of 37 months, the median progression-free survival time of all patients was 16 months and the median overall survival time was 31 months. The small number of patients entered onto the study caused wide confidence intervals (CIs) around the hazards ratio for progression-free survival of paclitaxel-carboplatin compared with paclitaxel-cisplatin (hazards ratio, 1.07; 95% CI, 0.78 to 1.48) and did not allow conclusions about efficacy. CONCLUSION: Paclitaxel-carboplatin is a feasible regimen for outpatients with ovarian cancer and has a better toxicity profile than paclitaxel-cisplatin.

Surgery groups differed in adverse outcome probabilities and can be used to adjust hospital comparisons.

BACKGROUND AND OBJECTIVE: In the Netherlands, all procedures in general surgery are categorized into 12 surgery groups by the Association of Surgeons of the Netherlands. The purpose of this study was to assess whether surgery groups differ in adverse outcome probabilities, to decide whether hospital comparisons on adverse outcomes should be adjusted for differences in surgery groups. METHODS: All surgical patients in one hospital discharged in 1997-1999 were included. Only the first operation during admission was included, with the assumption that successive operations were treatment of adverse outcomes. To avoid bias, only operations with procedures from the same surgery group were included. A total of 6,025 admissions were included and analyzed by a two-step multilevel analysis. RESULTS: Four surgery groups had fewer admissions with adverse outcomes than expected, and two groups had more. After adjustment for patient and operation characteristics, the remaining variance between surgery groups is still large. Similar results were found when differences in mortality were analyzed. CONCLUSION: Surgery group can therefore be used to adjust hospital comparisons for differences in surgical procedure mix.

Vertical modelling: Analysis of competing risks data with missing causes of failure.

We propose vertical modelling as a natural approach to the problem of analysis of competing risks data when failure types are missing for some individuals. Under a natural missing-at-random assumption for these missing failure types, we use the observed data likelihood to estimate its parameters and show that the all-cause hazard and the relative hazards appearing in vertical modelling are indeed key quantities of this likelihood. This fact has practical implications in that it suggests vertical modelling as a simple and attractive method of analysis in competing risks with missing causes of failure; all individuals are used in estimating the all-cause hazard and only those with non-missing cause of failure for relative hazards. The relative hazards also appear in a multiple imputation approach to the same problem proposed by Lu and Tsiatis and in the EM algorithm. We compare the vertical modelling approach with the method of Goetghebeur and Ryan for a breast cancer data set, highlighting the different aspects they contribute to the data analysis.

Cerebral microbleeds in CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy leading to recurrent cerebral infarcts and dementia. Intracerebral hemorrhage (ICH) has been described sporadically in patients with CADASIL, suggesting that the affected arteries in CADASIL are not bleed-prone. However, the presence of cerebral microbleeds, which often remain undetected on conventional MRI, has not been determined in CADASIL. OBJECTIVE: To determine whether cerebral vessels in patients with CADASIL are prone to microbleeding. METHODS: T2*-weighted gradient echo MRI, which is highly sensitive for visualizing microbleeds, was performed in patients with CADASIL and their family members (n = 63). Known risk factors for ICH were determined for all individuals. On an exploratory basis, the presence of cerebral microbleeds was correlated with demographic variables, vascular risk factors, disease progression, ischemic MR lesions, and genotype. RESULTS: Cerebral microbleeds were present in 31% of symptomatic CADASIL mutation carriers, predominantly in the thalamus. Vascular risk factors such as hypertension did not account for the microbleeds in these patients. Factors associated with microbleeds were age (p = 0.008), Rankin disability score (p = 0.017), antiplatelet use (p = 0.025), number of lacunae on MRI (p = 0.009), and the Arg153Cys Notch3 mutation (p = 0.017). After correction for age, only the Arg153Cys mutation remained significantly associated with the presence of microbleeds. CONCLUSION: Patients with CADASIL have an age-related increased risk of intracerebral microbleeds. This implies that they may have an increased risk for ICH, which should be taken into account in CADASIL diagnosis and patient management.

Paclitaxel (175 mg/m2 over 3 hours) with cisplatin or carboplatin in previously untreated ovarian cancer: an interim analysis.

The side effects of cisplatin (75 mg/m2) in combination with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (175 mg/m2 over 3 hours) are expected to be more severe and frequent than those of carboplatin (area under the concentration-time curve of 5) in combination with the same dose of paclitaxel, but the combinations are expected to be equally effective. A disadvantage of the cisplatin-based regimen is that patients need to be admitted to the hospital. The carboplatin regimen can be administered to outpatients. We tested both combinations administered every 3 weeks in a randomized phase III study in patients with previously untreated epithelial ovarian cancer. An interim analysis for toxicity was performed in 145 patients shortly after study closure. We observed a difference in the incidence of nausea, vomiting, and neurotoxicity favoring the women treated with the carboplatin regimen, but this regimen caused more myelotoxicity. Maturation of the study is awaited before survival data can be analyzed and final conclusions can be drawn.

Risk factors for local recurrence after breast-conserving therapy for invasive carcinomas: a case-control study of histological factors and alterations in oncogene expression.

PURPOSE: Many studies have focused on histological risk factors for local recurrence (LR) after breast-conserving therapy (BCT). In addition to histological factors, we studied alterations in the expression of various proteins in relation to LR using a case-control approach. METHODS AND MATERIALS: Ninety-nine LR occurred in a patient cohort of 1,481 tumors treated with BCT. These patients were randomly matched, each with two controls. Matching was performed for age group (< or = 50 and > 50 years), pN stage, and follow-up time. Histology slides were reviewed. Immunohistochemical staining was performed for the following proteins: bcl-2, CD31, cyclin D1, E-cadherin, EGF receptor, ER, PR, Ki-67, c-erbB2/neu, and p53. Statistical analyses were performed using conditional logistic regression. RESULTS: Sixty-six cases and 139 controls with invasive carcinoma remained for analysis. The following variables were significant risk factors for LR: young age (p = 0.006), high nuclear grade (p = 0.04), high mitotic count (p = 0.03), extensive DCIS around the tumor (p = 0.02) but not within the tumor, poorly differentiated type of DCIS (p = 0.03), > 20% ki-67 positive cells (p = 0.006), and PR negativity (p = 0.03). When the analysis was performed for patients < or = and > 50 years, these risk factors were found in the older patients, but not in the younger patients. CONCLUSION: High mitotic count and Ki-67 positivity are risk factors for LR. EDCIS surrounding the invasive tumor is a risk factor for LR, especially when of poorly differentiated type. Age is an important risk factor for LR independent of other risk factors, including alterations in oncogene expression.

Serum cytokine levels after HLA-identical bone marrow transplantation.

BACKGROUND: Altered profiles of cytokine production are observed after bone marrow transplantation (BMT). The presence of certain cytokines in serum can be indicative for BMT-related complications, such as graft-versus-host disease (GVHD) and infections. The putative correlation between abnormal serum cytokine levels and BMT-related complications was further analyzed in this retrospective study. METHODS: Serum levels of a panel of cytokines and cytokine-associated molecules (i.e., interleukin [IL]-1alpha, IL-1beta, IL-4, IL-6, IL-10, IL-12, IL-1 receptor antagonist, and the soluble a chain of the IL-2 receptor [sIL-2R alpha]) were assessed in 329 sera of 46 patients who had undergone HLA-identical or autologous BMT. Serum cytokine levels of the BMT donor and of the patients before BMT and at different time points during the post-BMT period were measured. The results were correlated with relapse, acute GVHD, chronic GVHD, and infections. RESULTS: Serum levels of IL-1alpha, IL-1beta, IL-4, and IL-12 were undetectable. The transplantation regimen itself causes a significant rise in IL-10 and sIL-2R alpha levels in patients receiving allogeneic bone marrow. In the post-BMT period, increased IL-6 serum levels were significantly correlated with infections. Increased IL-10 levels were significantly correlated with acute graft-versus-host disease, chronic GVHD, and infections. Increased sIL-2R alpha levels were correlated with chronic GVHD, as were IL-1 receptor antagonist levels. CONCLUSIONS: During the post-HLA-identical BMT period, the serum cytokine levels of IL-6 were enhanced during infections, whereas the sIL-2R alpha levels were increased during chronic GVHD. The serum levels of IL-10 and of the cytokine-related molecule IL-1ra were enhanced during both infections and chronic GVHD. These results further substantiate the complex cytokine cascade that is initiated by the conditioning regimen and that evolves further in reaction to BMT-related complications and their treatments.

Analysis of the renal transplant waiting list: application of a parametric competing risk method.

BACKGROUND: The strong competition for scarce renal graft resources jeopardizes an individual patient's chances of a transplantation within a reasonable time scale. This study was undertaken to quantify these chances of receiving a transplant. METHODS: All patients registered for their first renal allograft between January 1980 and December 1993 (n=40,636) in Eurotransplant were selected. The influence of patient characteristics, such as age, HLA phenotype frequency, % panel-reactive antibodies, period of registration, and ABO blood group, on the waiting list outflow was studied. The competing risk method was applied, and Poisson models were built to estimate the risk factor effects. RESULTS: The chance of transplantation within 10 years after registration was overestimated by Kaplan-Meier (84%); using the competing risk method it was only 74%. The predicted chance for death on the waiting list was overestimated by 33% (45% Kaplan-Meier vs. 12% competing risk). A time-varying covariate effect on the chances of waiting list outflow was observed. Favorable factors for quick transplantation, such as blood group AB or a common HLA phenotype, were no longer seen to be driving forces for transplantation once 5 to 6 years of waiting time had been accrued. CONCLUSION: When multiple outcomes exist, Kaplan-Meier estimates should not be interpreted as survival rates, while competing risk estimates yield appropriate chances. A significantly decaying effect of the usual allocation parameters is observed with ongoing waiting time. This phenomenon is the statistical basis for redesigning allocation strategies. Organ exchange algorithms should have the potential to adapt to these time-varying effects.

Serum transforming growth factor-beta1 levels in bone marrow transplant recipients correlate with blood cell counts and chronic graft-versus-host disease.

OBJECTIVE: Profound immunosuppression and extensive fibrotic changes in the skin are characteristic for graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Transforming growth factor (TGF)-beta is a potent immunosuppressive cytokine that plays an important regulatory role in the immune response. In addition, TGF-beta promotes wound repair but has also been implicated in tissue fibrosis. These characteristics prompted us to question whether serum TGF-beta levels would be associated with GVHD after BMT. METHODS: In this study, total TGF-beta1 levels in serum from HLA-identical BMT recipients before and at several time intervals after transplantation were quantified and correlated with platelet and white blood cell (WBC) counts and with the presence of acute and chronic GVHD in a multivariate analysis. RESULTS: TGF-beta1 levels were readily detectable in healthy controls and in BMT recipients before BMT. In all patients, a rapid drop in TGF-beta1 levels was seen during the BMT conditioning regimen. After 20-50 days postBMT, TGF-beta1 levels started to increase to normal levels. Platelet and WBC counts were strongly correlated with TGF-beta1 levels (r=0.810, P<0.001, and r=0.733, P<0.001, respectively). Multivariate analysis also revealed that TGF-beta1 levels were significantly increased during chronic GVHD and that the increase during acute GVHD reached levels of significance (P=0.009 and P=0.053, respectively). CONCLUSIONS: These results show that total TGF-beta1 levels correlate significantly with platelet and WBC counts and that chronic GVHD is associated with an increase in serum TGF-beta1, independent of platelet or WBC counts.

The outcome of kidney grafts from multiorgan donors and kidney only donors.

From 1988 to 1994, 15356 renal cadaveric transplantations have been performed within the Eurotransplant area (Austria, Belgium, Germany, Luxembourg and The Netherlands); 8746 kidneys were obtained from multiorgan donors and 6610 from kidney only donors. To evaluate the impact of the procurement policy, multiorgan donor (MOD) versus kidney only donor (KOD), on renal graft survival, an observational study has been performed. Multivariate analysis using Cox's proportional hazards model served to quantify the role of the procurement policy on renal graft survival after adjustment for other prognostic factors. The kidneys obtained from MODs had a significantly better graft survival at 1, 3, and 5 years after transplantation than the kidneys obtained from KODs (85%, 75%, and 58% versus 78%, 68%, and 46% (P=0.0001). In the Cox model, patients transplanted with a KOD kidney had a 1.28 times higher risk of losing their graft than patients transplanted with a MOD kidney. This benefit in graft survival for MOD kidneys could not be explained by the fact that the MODs were younger and male, and that UW was used as preservation solution. A plausible explanation is that MODs, on average, because of the nonrenal transplants, are better supervised. We expect that optimal donor management will contribute to a better outcome of all renal grafts.

Mortality rates after heart transplantation: how to compare center-specific outcome data?

BACKGROUND: Studies of outcome in cardiac transplantation have focused primarily on identifying patient- and donor-related factors associated with patient mortality. Less consideration has been given to the impact of the transplant center. This study was undertaken to assess variability in heart transplantation outcome in Eurotransplant centers to provide a framework for auditing. METHODS AND RESULTS: In a 2-year period, 1,401 adult patients underwent heart transplantation in 45 centers. The 1-year patient survival rate was 76% (95% CI, 74%-78%) with a range of 0% to 100% at the center level. The risk-adjusted center effect on mortality was estimated by calculating a standardized difference between the observed number of deaths 1 year after transplantation and the expected number of deaths based on the case mix. By assessing within- and between-center variations with empirical Bayes (EB) methods, after adjustment for all registered prognostic factors, an improved estimate of the true center effect was obtained. Compared with the standard risk-adjusted center effect method, fewer outlying centers were identified with the EB method. CONCLUSION: EB methods, because they are known to incorporate more information from the data, enable a more precise and realistic portrayal of heart transplant centers' performances, compared with other risk-adjusted center effect methods. In the context of auditing procedures, EB methods should preferably be used for the identification of centers that deviate significantly from quality standards.

Permanent detrimental effect of nonimmunological factors on long-term renal graft survival: a parsimonious model of time-dependency.

PURPOSE: We attempted to model and test the pattern of effects of prognostic factors on renal graft survival during the posttransplantation time course. PATIENTS AND METHODS: Patients who received a cadaveric kidney-only transplant between January 1990 and December 1995 in Eurotransplant, who received cyclosporine as induction therapy, and who had a complete follow-up at the time of analysis were included in the study (n= 10614). An index summarizing all covariate information was calculated and used for modeling the time-dependent effects with relation to graft failure. RESULTS: The immunological factors (HLA mismatch and % panel-reactive antibody) were seen to have a slowly decreasing negative effect on renal graft survival. The cold ischemic trauma (>24 hr) exerted a permanent detrimental effect on the grafts. The use of organs obtained from old donors was associated with a constant higher risk of graft loss. CONCLUSIONS: An analysis of determinants of human allograft dysfunction should also study the interaction between the effects and time. Nonimmunological factors had a constant detrimental effect on graft failure, whereas the impact of the immunological factors--although remaining important for late graft loss--very slowly decreased. In the context of marginal transplants, clustering of unfavorable factors should be avoided to prevent late graft losses.

Long-term effect of inhaled corticosteroids on growth rate in adolescents with asthma.

BACKGROUND: Growth in stature in asthmatic adolescents may be delayed compared to normals as a result of treatment with inhaled corticosteroids (CS) or because of a delay in puberty. However, growth rates in asthmatic children have never been studied when treatment with CS was randomized and when growth was compared with that of matched healthy control subjects. OBJECTIVE: To assess the long-term effect of CS treatment on growth rates in asthmatic adolescents. METHODS: Participants were 40 asthmatic teenagers (mean age 12.8 years) who received randomized treatment with 0.2 mg of albuterol (salbutamol) with either placebo three times a day (BA + PL) or 0.2 mg of budesonide three times a day (BA + CS) for a median period of 22 months in a double-blind controlled study. Growth rates were compared with those of 80 control subjects who were matched for sex, age, height, and duration of follow-up. RESULTS: Growth rates in male patients, but not in female patients, were significantly less than in control subjects (P < .05), a finding consistent with a delay of puberty due to asthma. The mean difference (95% confidence interval) in growth rates between patients treated with BA+PL and their controls was -0.70 (-1.62, 0.22) cm/y; that between patients treated with BA + CS and their controls was -0.44 (-1.25, 0.37) cm/y. The observed mean (SEM) case-control difference between treatment groups was +0.27 (0.58) cm/y in favor of BA + CS. CONCLUSION: Growth retardation observed in adolescents with asthma may be due to a delay in puberty but not to the prescription of 0.6 mg of budesonide daily.

Prevention of postoperative deep vein thrombosis by a combination of subcutaneous heparin with subcutaneous dihydroergotamine or oral sulphinpyrazone.

In a randomized clinical trial the effect of subcutaneous heparin alone or in combination with dihydroergotamine or sulphinpyrazone in preventing postoperative deep vein thrombosis (DVT) was studied. Sodium heparin (5000 IU) was administered subcutaneously twice daily; dihydroergotamine (1/2 mg) was also administered subcutaneously twice daily, and sulphinpyrazone (400 mg) was administered orally or intravenously twice daily. Administration occurred for at least 7 days. The diagnosis DVT was made with the radiofibrinogen uptake test. 358 patients undergoing major elective abdominal surgery were allocated to three treatment groups: heparin alone (Hep), heparin + dihydroergotamine (DHE-Hep) and heparin + sulphinpyrazone (Sulph-Hep). The frequency of DVT was 14/114 in Hep, 10/115 in DHE-Hep and 20/114 in Sulph-Hep. These differences were not significant. After application of the "logistic regression" procedure of Cox (1) it turned out that the major risk factors for developing DVT were age, sex, weight, type of operation and presence of diabetes mellitus. Also a significant treatment influence was observed (p = 0.001). This treatment effect was most probably due to improvement in the DHE-Hep group. The results in the Sulph-Hep group were not significantly different from those in the Hep group. A risk index was formulated on the basis of the above mentioned risk factors by which the chance of occurrence of DVT during heparin prophylaxis in an individual patient could be predicted. Patients that should receive additional prophylactic treatment can be defined by using this risk index.

Familial clustering of factor VIII and von Willebrand factor levels.

Recently, we found that high levels of clotting factor VIII (>150 IU/dl) are common and make an important contribution to thrombotic risk. The determinants of high factor VIII:C are unclear and might be partly genetic. Therefore, we tested the influence of age, blood group and von Willebrand factor (VWF) levels on factor VIII:C levels, and investigated whether factor VIII:C levels are genetically determined. We performed an analysis of 564 female relatives of hemophilia A patients, who had visited our center for genetic counseling. In univariate analysis, AB0 blood group, age and VWF antigen (VWF:Ag) levels all influenced factor VIII:C levels. After adjustment for the effect of VWF:Ag levels, both blood group and age still had an effect on factor VIII:C levels. In sister pairs, the Pearson correlation coefficient between factor VIII:C levels was 0.17 (p = 0.024) and this correlation remained positive (0.15, p = 0.046) after correction for the influence of VWF:Ag. In mother-daughter pairs, no correlation of factor VIII:C levels was found. The correlation of VWF:Ag levels in sisterpairs was 0.41 (p <0.001) and in mother-daughter pairs 0.44 (p <0.001), in line with the assumption that VWF:Ag levels are under control of autosomal genes. Familial influence on plasma factor VIII:C and VWF:Ag levels was investigated with a recently developed familial aggregation test. This test verifies whether familial aggregation of a particular parameter exists in a set of pedigrees. In 435 women from 168 families, factor VIII:C as well as VWF:Ag levels correlated significantly within families, which suggests a familial influence. The familial aggregation was more prominent for VWF:Ag levels than for factor VIII:C levels, possibly because the genetic effect on VWF:Ag levels is larger than on factor VIII:C levels. Our results support the presence of a familial influence on factor VIII:C as well as on VWF:Ag levels.