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PubMed2006

Population pharmacokinetics of cyclosporine in chinese cardiac transplant recipients.

STUDY OBJECTIVE: To characterize the population pharmacokinetics of cyclosporine in Chinese patients undergoing cardiac transplantation and to identify the demographic and clinical covariates affecting cyclosporine clearance. DESIGN: Population pharmacokinetic analysis using data from a retrospective chart review. SETTING: Specialty hospital in Hong Kong for treatment of cardiac and pulmonary diseases. PATIENTS: Thirty-eight Chinese adult patients (mean age 46 yrs) who had undergone routine cyclosporine therapeutic drug monitoring after cardiac transplantation between January 1, 1991, and December 31, 2003. MEASUREMENTS AND MAIN RESULTS: Data regarding dosing, demographics, clinical laboratory values, and concurrent drugs were collected retrospectively. Data were included if patients had blood cyclosporine concentrations determined for at least 12 weeks after transplantation; an average of 18 blood samples/patient were collected. Population modeling was performed using a one-compartment linear model with first-order absorption and elimination. Various demographic and clinical covariates were tested for their significant effects on the apparent oral clearance (Cl/F) of cyclosporine. The stability of the final population model was evaluated by using the bootstrap resampling method. Statistically significant associations were observed between Cl/F and each of the following covariates: body weight (BW), use of diltiazem (DIL), and hematocrit value (HCT). The final model was Cl/F=5.00*(1-DIL)+365/HCT+(0.144*BW). The interindividual variabilities of Cl/F and apparent volume of distribution were 14.5% and 40.2%, respectively. The mean parameter estimates obtained from bootstrap analyses were highly consistent with those obtained with the original data set. CONCLUSION: The estimated Cl/F values of cyclosporine in our Chinese cardiac transplant recipients appeared to be similar to those reported for Caucasian cardiac transplant recipients. Thus, our data provide support that a cyclosporine dosage regimen similar to that in Caucasian patients may be needed in Chinese cardiac transplant recipients. However, further studies are required to determine the optimum cyclosporine dosage regimen in the Chinese population.

Adult↗

PubMed2001

Analysis of uncertainties in estimates of components of variance in multivariate ROC analysis.

RATIONALE AND OBJECTIVES: Solutions have previously been presented to the problem of estimating the components of variance in the general linear model used for multivariate receiver operating characteristic (ROC) analysis. The case where the variance components do not change across the modalities under comparison was first treated, followed by the case where they are permitted to change. No analysis of uncertainties in these estimates has been presented previously. MATERIALS AND METHODS: For the case where the variance components do not change across modalities, the "jackknife-after-bootstrap" resampling procedure can be used together with conventional linear propagation of variance to solve for the uncertainties in estimates of the components. For the case where the components are permitted to change across modalities, a slight elaboration of this procedure is presented. RESULTS: The approach was validated by Monte Carlo simulations, where uncertainties in estimates of the variance components calculated by the jackknife-after-bootstrap procedure were found to converge in the mean to the Monte Carlo results over many independent trials. The method is exemplified with data from a study of readers-with and without the aid of a computer-assist modality-given the task of discriminating benign from malignant masses in mammography. CONCLUSION: The present approach is relevant to a broad class of problems where estimates of multiple contributions to the variance observed in ROC assessment of diagnostic modalities are desired, in particular, for the assessment of multiple-reader studies of computer-aided diagnosis in radiology where the variance components may change across reading modalities (eg, unaided vs computer-aided reading).

Analysis of Variance↗

PubMed2002

Application of non-parametric bootstrap methods to estimate confidence intervals for QTL location in a beef cattle QTL experimental population.

Empirical confidence intervals (CIs) for the estimated quantitative trait locus (QTL) location from selective and non-selective non-parametric bootstrap resampling methods were compared for a genome scan involving an Angus x Brahman reciprocal fullsib backcross population. Genetic maps, based on 357 microsatellite markers, were constructed for 29 chromosomes using CRI-MAP V2.4. Twelve growth, carcass composition and beef quality traits (n = 527-602) were analysed to detect QTLs utilizing (composite) interval mapping approaches. CIs were investigated for 28 likelihood ratio test statistic (LRT) profiles for the one QTL per chromosome model. The CIs from the non-selective bootstrap method were largest (87 7 cM average or 79-2% coverage of test chromosomes). The Selective II procedure produced the smallest CI size (42.3 cM average). However, CI sizes from the Selective II procedure were more variable than those produced by the two LOD drop method. CI ranges from the Selective II procedure were also asymmetrical (relative to the most likely QTL position) due to the bias caused by the tendency for the estimated QTL position to be at a marker position in the bootstrap samples and due to monotonicity and asymmetry of the LRT curve in the original sample.

Animals↗

PubMed2006

Development and validation of a nomogram for predicting outcome of patients with vulvar cancer.

OBJECTIVE: To construct and validate a nomogram to predict relapse-free survival of patients treated for vulvar cancer. METHODS: Data from 244 patients treated for vulvar cancer at a single institution (Creteil, France) were used as a training set to develop and calibrate a nomogram for predicting relapse-free survival and local relapse-free survival. We used bootstrap resampling for the internal validation and we tested the nomogram on an independent validation set of patients (Torino, Italy) for the external validation. RESULTS: The nomograms were based on a Cox proportional hazards regression model. Covariates for the relapse-free survival model included age, T stage, number of metastatic nodes, bilateral lymph node involvement, omission of the lymphadenectomy, margin status, lymphovascular space invasion, and depth of invasion. The concordance indices were 0.85 and 0.83 in the training set before and after bootstrapping, respectively, and 0.83 in the validation set. The predictions of our nomogram discriminated better than did the International Federation of Gynecology and Obstetrics stage (0.83 compared with 0.78, P = .01). The calibration of our nomogram was good. In the validation set, 2-year and 5-year relapse-free survival were well predicted with less than 5% difference between the predicted and observed survivals for each quartile. A nomogram for predicting local relapse was also developed. CONCLUSION: We have developed nomograms for predicting distant and local relapse of vulvar cancer at 2 and 5 years and validated them both internally and externally. These nomograms will be freely available on the International Society for the Study of Vulvovaginal Disease Web site. LEVEL OF EVIDENCE: III.

Adult↗

PubMed2005

Multivariate prediction of major adverse cardiac events after 9914 percutaneous coronary interventions in the north west of England.

OBJECTIVE: To develop a multivariate prediction model for major adverse cardiac events (MACE) after percutaneous coronary interventions (PCIs) by using the North West Quality Improvement Programme in Cardiac Interventions (NWQIP) PCI Registry. SETTING: All NHS centres undertaking adult PCIs in north west England. METHODS: Retrospective analysis of prospectively collected data on 9914 consecutive patients undergoing adult PCI between 1 August 2001 and 31 December 2003. A multivariate logistic regression analysis was undertaken, with the forward stepwise technique, to identify independent risk factors for MACE. The area under the receiver operating characteristic (ROC) curve and the Hosmer-Lemeshow goodness of fit statistic were calculated to assess the performance and calibration of the model, respectively. The statistical model was internally validated by using the technique of bootstrap resampling. MAIN OUTCOME MEASURES: MACE, which were in-hospital mortality, Q wave myocardial infarction, emergency coronary artery bypass graft surgery, and cerebrovascular accidents. RESULTS: Independent variables identified with an increased risk of developing MACE were advanced age, female sex, cerebrovascular disease, cardiogenic shock, priority, and treatment of the left main stem or graft lesions during PCI. The ROC curve for the predicted probability of MACE was 0.76, indicating a good discrimination power. The prediction equation was well calibrated, predicting well at all levels of risk. Bootstrapping showed that estimates were stable. CONCLUSIONS: A contemporaneous multivariate prediction model for MACE after PCI was developed. The NWQIP tool allows calculation of the risk of MACE permitting meaningful risk adjusted comparisons of performance between hospitals and operators.

Adult↗

PubMed2006

Pre-treatment nomogram for disease-specific survival of patients with chemotherapy-naive androgen independent prostate cancer.

OBJECTIVE: Our objective was to develop a nomogram that predicts the probability of cancer-specific survival in men with untreated androgen-independent prostate cancer (AIPC). METHODS: AIPC was diagnosed in 129 consecutive patients between 1989 and 2002. No patient received cytotoxic chemotherapy. Univariate and multivariate Cox regression models were used to test the association between prostate-specific antigen (PSA) level at initiation of androgen deprivation, PSA doubling time (PSADT), PSA nadir on androgen deprivation therapy (ADT), time from ADT to AIPC, and AIPC-specific mortality. Multivariate regression coefficients were then used to develop a nomogram predicting AIPC-specific survival at 12-60 mo after AIPC diagnosis. Two-hundred bootstrap resamples were used to internally validate the nomogram. RESULTS: AIPC-specific mortality was recorded in 74 of 129 patients (57.4%). Other-cause mortality was recorded in 7 men (5.4%). Median overall survival was 52.0 mo (mean, 36.0 mo) and median AIPC-specific survival was 54.0 mo (mean, 35.0 mo). In univariate regression models, all variables were significant predictors of AIPC-specific survival (p < or = 0.02). In multivariate models, PSADT and time from androgen deprivation to AIPC remained statistically significant (p < or = 0.004). Bootstrap-corrected predictive accuracy of the nomogram was 80.9% versus 74.9% for our previous model. CONCLUSIONS: A nomogram predicting AIPC-specific survival is between 13% and 14% more accurate than previous nomograms and 6% more accurate than tree regression-based predictions obtained from the same data. Moreover, a nomogram approach combines several advantages, such as user-friendly interface and precise estimation of individual recurrence probability at several time points after AIPC diagnosis, which all patients deserve to know and all treating physicians need to know.

Aged↗

PubMed2006

Nomogram for predicting disease recurrence after radical cystectomy for transitional cell carcinoma of the bladder.

PURPOSE: American Joint Committee on Cancer staging represents the gold standard for prediction of recurrence after radical cystectomy in patients with invasive bladder cancer. We tested the hypothesis that American Joint Committee on Cancer stage based predictions may be improved when pathological tumor and node stage information is combined with additional clinical and pathological variables within a prognostic nomogram. MATERIALS AND METHODS: We used Cox proportional hazards regression analysis to model variables of 728 patients with transitional cell carcinoma of the bladder treated with radical cystectomy and bilateral pelvic lymphadenectomy at 1 of 3 participating institutions. Standard predictors, pT and pN, were complemented by age, gender, tumor grade at cystectomy, presence of lymphovascular invasion, presence of carcinoma in situ in the cystectomy specimen, neoadjuvant chemotherapy, adjuvant chemotherapy and adjuvant radiotherapy. The concordance index was used to quantify the accuracy of regression coefficient based nomograms. A total of 200 bootstrap resamples were used to reduce overfit bias and for internal validation. Calibration plots were used to graphically explore the performance characteristics of the multivariate nomogram. RESULTS: Followup ranged from 0.1 to 183.4 months (median 24.9, mean 36.4). Recurrence was recorded in 249 (34.2%) patients with a median time to recurrence of 108 months (range 0.8 to 131.9). Actuarial recurrence-free probabilities were 69.6% (95% CI 65.8%-73.0%), 60.2% (55.8%-64.3%) and 52.9% (47.3%-58.1%) at 2, 5 and 8 years after cystectomy, respectively. Two-hundred bootstrap corrected predictive accuracy of American Joint Committee on Cancer stage based predictions was 0.748. Accuracy increased by 3.2% (0.780) when age, lymphovascular invasion, carcinoma in situ, neoadjuvant chemotherapy, adjuvant chemotherapy and adjuvant radiotherapy were added to pathological stage information and used within a nomogram. CONCLUSIONS: A nomogram predicting bladder cancer recurrence after cystectomy is 3.2% more accurate than American Joint Committee on Cancer stage based predictions. Moreover, a nomogram approach combines several advantages such as easy and precise estimation of individual recurrence probability at key points after cystectomy, which all patients deserve to know and all treating physicians need to know.

Adult↗

PubMed2000

Numerical methods for the evaluation of individual bioequivalence criteria.

The evaluation of individual bioequivalence (IBE) by bootstrap resampling using common statistical software, for example SAS, is extremely time consuming. In this article, an estimation procedure that can be implemented in a high level language with the same degree of accuracy as SAS is described. The necessary parameter estimating equations under both least square (LSE) and restricted maximum likelihood (REML) methods are given. The algorithms used to numerically compute these values are outlined and tested, in FORTRAN, on several simulated data sets and shown to reproduce SAS results with at least 10(-3) precision. More importantly, the REML bootstrap algorithm reduces the time taken in SAS by a factor of 20. Secondary results indicate that LSE and REML parameter estimates are similar for mild unbalancedness. PROC MIXED, with unstructured (UN) and compound symmetry heterogeneous (CSH) variance structures give the same results except when the subject-by-treatment interaction variance, sigma(2)(D), is 0 in which case CSH significantly overestimates sigma(2)(D) and underestimates the within-treatment variances. It is concluded that bootstrap evaluation of IBE is efficiently done using either the LSE or REML algorithm in FORTRAN.

Algorithms↗

PubMed2000

Predictors of intussusception in young children.

OBJECTIVE: To identify predictors of intussusception in young children. DESIGN: A retrospective cross-sectional study. SETTING AND PATIENTS: A consecutive sample of children younger than 5 years on whom contrast enemas were performed because of suspected intussusception seen at an urban children's hospital from 1990 to 1995. METHODS: We evaluated historical, clinical, and radiographic variables. Variables documented in 75% or more of the medical records and associated with intussusception (P< or =.20) in the univariate analysis were evaluated in a multiple logistic regression analysis. Variables retaining significance (P< or =.05) in the multivariate analysis were considered independent predictors of intussusception. We used bootstrap resampling techniques to validate the multivariate model. RESULTS: Sixty-eight (59%) of the 115 patients had intussusception. Univariate predictors of intussusception included male sex, age younger than 2 years, history of emesis, rectal bleeding, lethargy, abdominal mass, and a highly suggestive abdominal radiograph. In the multivariate analysis, we identified only 4 independent predictors (adjusted odds ratio; 95% confidence interval): a highly suggestive abdominal radiograph (18.3; 4.0-83.1), rectal bleeding (17.3; 2.9-104.0), male sex (6.2; 1.2-32.3), and a history of emesis (13.4; 1.4-126.0). We identified 3 of these 4 variables (all but emesis) as independent predictors in more than 50% of 1000 bootstrap data samples. CONCLUSIONS: Rectal bleeding, a highly suggestive abdominal radiograph, and male sex are variables independently associated with intussusception in a cohort of children suspected of having this diagnosis. Knowledge of these variables may assist in clinical decision making regarding diagnostic and therapeutic interventions.

California↗

PubMed2003

Clinically relevant interpretation of genotype for resistance to abacavir.

OBJECTIVE: To develop a stepwise methodology for the development and validation of clinically relevant genotypic score for resistance to antiretroviral drugs and to apply this approach to the genotypic resistance to abacavir. METHODS: All patients having received abacavir during the Narval trial were included in this study. The impact of each nucleoside analogue resistance mutation on the virologic response to abacavir was studied in a univariate analysis. Mutations with a P value < 0.20 and those selected by abacavir were retained. According to the number of mutations three levels of resistance were defined. A multivariate analysis accounting for confonding variables assessed whether the genotypic score was an independent predictor of the response. The robustness of the score was analysed using the bootstrap resampling method. RESULTS: In the 175 patients exposed to abacavir, the strongest association between the decrease in viral load and the number of mutations was observed with a set of six mutations at codons 41, 67, 210, 215, 74 and 184 of the reverse transcriptase gene. In patients with fewer than four mutations (no evidence of resistance) the median decrease in viral load was -1.64 log(10) copies/ml while it was -0.69 log(10) and -0.19 log(10) in those with four (possible resistance) and five or six (resistance) mutations respectively. In the multivariate analysis this score was an independent predictor of the response. The bootstrap analysis showed the robustness of the score. CONCLUSIONS: We developed a new strategy for the analysis of correlation between genotype profile at baseline and virologic response.

Algorithms↗

PubMed2003

Development and validation of a prediction model for strokes after coronary artery bypass grafting.

BACKGROUND: A prospective study of patients undergoing coronary artery bypass graft surgery (CABG) was conducted to identify patient and disease factors related to the development of a perioperative stroke. A preoperative risk prediction model was developed and validated based on regionally collected data. METHODS: We performed a regional observational study of 33,062 consecutive patients undergoing isolated CABG surgery in northern New England between 1992 and 2001. The regional stroke rate was 1.61% (532 strokes). We developed a preoperative stroke risk prediction model using logistic regression analysis, and validated the model using bootstrap resampling techniques. We assessed the model's fit, discrimination, and stability. RESULTS: The final regression model included the following variables: age, gender, presence of diabetes, presence of vascular disease, renal failure or creatinine greater than or equal to 2 mg/dL, ejection fraction less than 40%, and urgent or emergency. The model significantly predicted (chi(2) [14 d.f.] = 258.72, p < 0.0001) the occurrence of stroke. The correlation between the observed and expected strokes was 0.99. The risk prediction model discriminated well, with an area under the relative operating characteristic curve of 0.70 (95% CI, 0.67 to 0.72). In addition, the model had acceptable internal validity and stability as seen by bootstrap techniques. CONCLUSIONS: We developed a robust risk prediction model for stroke using seven readily obtainable preoperative variables. The risk prediction model performs well, and enables a clinician to estimate rapidly and accurately a CABG patient's preoperative risk of stroke.

Adult↗

PubMed2006

Population pharmacokinetics of darbepoetin alfa in haemodialysis and peritoneal dialysis patients after intravenous administration.

AIMS: To characterize the pharmacokinetics of darbepoetin alfa and covariate relationships in haemodialysis (HD) and peritoneal dialysis (PD) patients. METHODS: Data were collected from 131 (63 HD and 68 PD) patients who received darbepoetin alfa intravenously. A total of 917 serum concentrations were available. The data were analysed by nonlinear mixed effect modelling using NONMEM with a model including endogenous erythropoietin production. In addition, the final model was evaluated using bootstrap resampling. RESULTS: The selected basic model was a two-compartment model with a combination of additive and the constant coefficient of variation error models. The significant covariates were weight (WT) for clearance (CL) and the volume of central compartment (V(1)), and the dialysis technique (DIA) for V(1). The typical values of CL and V(1) were 0.0807 l h(-1) and 2.51 l, respectively. V(1) in PD patients was 17% higher than in HD patients. With the introduction of WT in CL and WT and DIA in V(1), interindividual variability decreased from 27.1% to 20.6% in CL and from 29.1% to 21.8% in V(1). The mean parameter estimates from the bootstrap datasets were similar to those from the original dataset. Evaluation by bootstrapping showed that the final model was stable. CONCLUSIONS: The results of the present analysis suggest no dosage regimen change is warranted for darbepoetin alfa in HD and PD patients over the range of distribution of covariates included in this study.

Adult↗

PubMed2005

Population pharmacokinetics of epinastine, a histamine H1 receptor antagonist, in adults and children.

AIMS: Our objective was to develop a population pharmacokinetic (PPK) model for epinastine, a histamine H(1) receptor antagonist, in adults and children and to obtain pharmacokinetic information to support dosing recommendations in children. METHODS: A total of 1510 plasma samples were collected from 62 healthy adult volunteers and 62 paediatric atopic dermatitis patients. The data were analysed using the NONMEM program according to a two-compartment model with first-order absorption. In addition, the final PPK model was evaluated by means of bootstrapping resampling. RESULTS: The oral clearance (CL/F) was found to be associated with body weight, formulation and food status. The volume of distribution of the central compartment (V(1)/F) was related to body weight and food status. An absorption lag time was apparent in fed subjects. On the other hand, other covariates (formulation on V(1)/F, volume of distribution of the peripheral compartment (V(2)/F), first-order absorption rate constant (Ka) and absorption lag time (ALAG); food status on V(2)/F and Ka; body weight on V(2)/F) were not statistically significant. No effect of age on CL/F, V(1)/F or V(2)/F was found. The mean parameter estimates obtained with an additional 200 bootstrap replicates of data were within 90-117% of those obtained with the original data set. These results suggest that the pharmacokinetics of epinastine are similar in adults and in children, except for the effect of the difference of body weight. The result of the application of the PPK model to the clinical trial in paediatric patients, in which dosage was determined based on the body weight (from 14 kg to less than 24 kg; 10 mg dose, 24 kg or more; 20 mg dose), showed that the C(max) and AUC (25.6 +/- 6.9 ng ml(-1) and 246.8 +/- 68.2 ng h ml(-1)) were almost same levels with those of adults after administration of 20 mg (26.9 +/- 9.1 ng ml(-1) and 281.6 +/- 90.5 ng h ml(-1)). CONCLUSIONS: A PPK model for epinastine was established and further evaluation by bootstrapping indicated that this model is stable. The model shows that, if dosage is adjusted based on the body weight, the epinastine exposure in paediatric patients is similar to that in adults.

Adult↗

PubMed2005

Does a patient's self-reported health-related quality of life predict survival beyond key biomedical data in advanced colorectal cancer?

The purpose of this study was to determine whether baseline patients' self reported health-related quality of life (HRQOL) parameters could predict survival beyond key biomedical prognostic factors in patients with metastatic colorectal cancer. The analysis was conducted on 299 patients. HRQOL baseline scores were assessed using the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core30 (EORTC QLQ-C30). The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. In addition, a bootstrap resampling technique was used to assess the stability of the outcomes. The final multivariate Cox regression model retained four variables as independent prognostic factors for survival: white blood cell (WBC) count with a hazard ratio (HR) of 1.961 (95% CI, 1.439-2.672; P<0.001), alkaline phosphatase with HR=1.509 (95% CI, 1.126-2.022; P=0.005), number of sites involved with HR=1.108 (95% CI, 1.024-1.198; P=0.01) and the patient's score on the social functioning scale with HR=0.991 (95% CI, 0.987-0.996; P<0.001) which translates into a 9% decrease in the patient's hazard of death for any 10 point increase. The independent prognostic importance of social functioning and the stability of the final Cox regression model were also confirmed by the additional bootstrap model averaging analysis, based on 1000 bootstrap-generated samples. The results suggest that social functioning, acts as a prognostic measure of survival beyond a number of previously known biomedical parameters.

Adult↗

PubMed2003

Population pharmacokinetics of an angiotensin II receptor antagonist, telmisartan, in healthy volunteers and hypertensive patients.

OBJECTIVE: To describe the factors affecting pharmacokinetics of telmisartan, an angiotensin II receptor antagonist, a population pharmacokinetic (PPK) model has been developed based upon the data collected from healthy volunteers and hypertensive patients. METHODS: A total of 1566 plasma samples were collected from 20 healthy volunteers and 129 hypertensive patients, together with the demographic background. The data were analyzed by the NONMEM program using two-compartment model with first-order absorption. The robustness of the obtained PPK model was validated by the bootstrapping resampling method. RESULTS: The oral clearance (CL/F) was found to be associated with age, dose and alcohol consumption, but neither related to serum creatinine nor smoking history. The volume of distribution for the central compartment was related to age and dose, and the volume of distribution for the peripheral compartment was related to body weight and gender. The absorption rate constant (Ka) and the absorption lag time were described as function of dose. The CL/F decreased with advanced age. The CL/F decreased and Ka increased with higher dose, reflecting the super-proportional increase in the plasma levels of telmisartan. The AUC and C(max) values predicted by the present PPK model were well consistent with the observed values. The means of parameter estimates obtained with 200 bootstrap replicates were within 95-111% of the final parameter estimates from the original data set. CONCLUSION: A PPK model for telmisartan developed here well described the individual variability and exposure, and robustness of the model has been validated by the bootstrapping method.

Journal Article↗

PubMed2004

Genotypic determinants of the virological response to tenofovir disoproxil fumarate in nucleoside reverse transcriptase inhibitor-experienced patients.

OBJECTIVE: To assess the genotypic determinants of the virological response to tenofovir disoproxil fumarate (TDF) in a multicentre cohort of antiretroviral (ARV)-experienced patients receiving TDF as a part of a salvage therapy. METHODS: HIV-1 genotype was assessed at baseline in a subgroup of 161 patients of the French expanded access program receiving a stable TDF-including regimen for 3 months or more. Reverse transcriptase mutations associated with the viral load decrease at month 3 with a P-value <0.15 were retained for the construction of a mutation score. The score was then validated using a multivariate analysis and bootstrap resampling method. RESULTS: The strongest association with decrease in viral load was observed with a set of seven mutations (TDF mutation score) that consisted of M41L, E44D, D67N, T69D/N/S, L74V, L210W and T215Y/F RT mutations. The RT K65R mutation and the insertions at codon 69 were not included in the analysis due to low prevalences. A TDF mutation score of < or = 2 predicted the absence of resistance to TDF and > or = 6 mutations predicted resistance to TDF with corresponding reductions in viral load of -1.3 +/- 1.1, and +0.1 +/- 0.7 log10 copies/ml, respectively. In patients with a TDF mutation score of 3-5, the decrease in viral load was -0.8 +/- 1.0 log10 copies/ml and was considered possibly resistant. In the multivariate analysis, a TDF mutation score > or = 6, previous use of amprenavir, indinavir and lopinavir, and co-prescription of didanosine were associated with a worse virological response. The bootstrap analysis showed the robustness of the TDF mutation score. CONCLUSION: In ARV-experienced patients receiving TDF-containing regimens, a score derived from seven reverse transcriptase mutations was shown to be independently predictive of the virological response.

Adenine↗

PubMed1996

Confidence intervals in QTL mapping by bootstrapping.

The determination of empirical confidence intervals for the location of quantitative trait loci (QTLs) was investigated using simulation. Empirical confidence intervals were calculated using a bootstrap resampling method for a backcross population derived from inbred lines. Sample sizes were either 200 or 500 individuals, and the QTL explained 1, 5, or 10% of the phenotypic variance. The method worked well in that the proportion of empirical confidence intervals that contained the simulated QTL was close to expectation. In general, the confidence intervals were slightly conservatively biased. Correlations between the test statistic and the width of the confidence interval were strongly negative, so that the stronger the evidence for a QTL segregating, the smaller the empirical confidence interval for its location. The size of the average confidence interval depended heavily on the population size and the effect of the QTL. Marker spacing had only a small effect on the average empirical confidence interval. The LOD drop-off method to calculate empirical support intervals gave confidence intervals that generally were too small, in particular if confidence intervals were calculated only for samples above a certain significance threshold. The bootstrap method is easy to implement and is useful in the analysis of experimental data.

Animals↗

PubMed2000

Nucleolus organizer regions (AgNORs) and total tumor mass are independent prognostic parameters for treatment-free period in chronic lymphocytic leukemia.

The aim of our study was to evaluate whether the nucleolus organizer regions (AgNOR) of circulating lymphocytes in chronic lymphocytic leukemia (CLL) could predict the duration of the stable phase (treatment-free period) of this disease. Age, sex, peripheral lymphoctes, hemoglobin, platelet count, Binet's stage, total tumor mass (TTM) and AgNOR pattern at diagnosis were assessed in 57 patients and compared with the time from diagnosis until patients fulfilled the criteria to start chemotherapy. In univariate Cox regression, Binet's stage, hemoglobin, number of peripheral lymphocytes, TTM and the percentage of lymphocytes containing one AgNOR cluster (circulating proliferative fraction) had predictive value. In the multivariate Cox model, only TTM and the percentage of cells with one AgNOR cluster were independent factors predicting the duration of the stable phase. Repetition of these analyses in 500 data sets created by bootstrap resampling confirmed the results. Summing up the percentage of lymphocytes with an AgNOR cluster and the TTM value, a simple prognostic index could be created to give information about the duration of the stable phase in CLL.

Cell Division↗