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PubMed2006

Class distinction between follicular adenomas and follicular carcinomas of the thyroid gland on the basis of their signature expression.

BACKGROUND: Nodules of the thyroid gland are observed frequently in patients who undergo ultrasound studies. The majority of these nodules are benign, corresponding to goiters or adenomas, and only a small fraction corresponds to carcinomas. Among thyroid tumors, the diagnosis of follicular adenocarcinomas by preoperative fine-needle aspiration biopsy is a major challenge, because it requires inspection of the entire capsule to differentiate it from adenoma. Consequently, large numbers of patients undergo unnecessary thyroidectomy. METHODS: Using data from gene expression analysis, the authors applied Fisher linear discriminant analysis and searched for expression signatures of individual samples of adenomas and follicular carcinomas that could be used as molecular classifiers for the precise classification of malignant and nonmalignant lesions. RESULTS: Fourteen trios of genes were described that fulfilled the criteria for the correct classification of 100% of samples. The robustness of these trios was verified by using leave-1-out cross-validation and bootstrap analyses. The results demonstrated that, by combining trios, better classifiers could be generated that correctly classified >92% of samples. CONCLUSIONS: The strategy of classifiers based on individual signatures was a useful strategy for distinguishing between samples with very similar expression profiles.

Adenocarcinoma, Follicular↗

PubMed2006

Low predictive accuracy of the Kattan postoperative nomogram for renal cell carcinoma recurrence in a population of French patients.

BACKGROUND: The aim of the current study was to establish the predictive accuracy of the Kattan postoperative nomogram for nonmetastatic renal cell carcinoma (RCC) by comparing predictions with actual disease recurrence in patients who underwent surgery in a single center in France. METHODS: Between 1985 and 2000, 844 patients were treated for RCC. The following data were collated: age, symptoms, histology, tumor size, grade, TNM 1997 stage, recurrence, and progression. For each patient a prognostic score (predicted probability) for recurrence-free survival (RFS) at 5 years was calculated using the Kattan nomogram. The discriminating ability of the model was assessed by Harrell's concordance index (c-index). Bootstrapping was used to assess confidence intervals. Furthermore, survival was then estimated by the Kaplan-Meier method and Cox proportional hazards regression analysis. RESULTS: In all, 565 patients (median age, 62 years) were included. At the time of the last follow-up, 81 patients had died and 101 had experienced RCC recurrence. The c-index for RFS (Kattan nomogram) was only 0.607 (95% confidence interval [CI]: 0.576-0.635). The 5-year RFS rate and cancer-specific survival rate were 81.5% and 84.7%, respectively. Of the 4 variables included in the nomogram, only TNM stage was associated with recurrence in a multivariate analysis (Cox analysis) (P = .022). CONCLUSIONS: There was a discrepancy between predicted RFS as estimated by the Kattan nomogram and the likelihood of being recurrence-free at 5 years according to the Cox analysis in the current population of patients. However, until new dynamic models become available clinicians may still improve their predictive ability by using the current nomogram.

Carcinoma, Renal Cell↗

PubMed2007

Cumulative cost pattern comparison of prostate cancer treatments.

BACKGROUND: Studies that compare prostate cancer treatment costs show wide variation. None compare all contemporary treatment costs, and most focus on initial treatment costs. The authors compared healthcare utilization and cost patterns of prostate cancer treatments over a span of 5.5 years in 4553 newly diagnosed patients stratified by age and risk group. METHODS: Contemporary treatment and evaluation patterns for prostate cancer were identified by using CaPSURE, a national disease registry of men with prostate cancer that included ongoing clinical data collection from 31 academic and community urology practices and biennial patient-reported outcome questionnaires that included demography, medical condition, comorbidity, risk measures, and healthcare utilization. Costs of outpatient visits, medications, and hospitalizations were applied from various national sources. Recurrent events analysis (MCF) accounted for left and right censorship. A mixed effects regression model with bootstrapping for skewed cost data quantified the relation between MCF cost, age, and risk. RESULTS: Prostate-related costs in the first 6 months after treatment were 11,495 dollars, (from 2586 dollars for watchful waiting (WW) to 24,204 dollars for external beam radiation. After 6 months, average cost was only 3044 dollars. Annual cost is 7740 dollars, highest for androgen deprivation therapy (12,590 dollars) and lowest for watch waiting (5843 dollars). Risk and age were significantly related to initial treatment choice. Cumulative cost (42,570 dollars) allowed a better estimate of treatment pattern costs. CONCLUSIONS: The cost burden of prostate cancer is high, but it varies by treatment type even when controlling for disease, age, and stage. Cumulative cost analysis allowed inclusion of adverse events and disease recurrence costs, making new cost comparisons evident among treatments.

Aged↗

PubMed1991

Mixed model segregation analysis of LDL-C concentration with genotype-covariate interaction.

Mixed model complex segregation analyses have in the past ignored the possibility of genotype-covariate interaction. Only in the nonmixed model with polygenic heritability equal to zero have segregation analyses been performed that allowed for genotype specific regression of the phenotype on covariates. We present an extension of Hasstedt's [1982] mixed model likelihood approximation which does allow for genotype-covariate interaction in the mixed model. Following description of this approximation, we validate the likelihood calculation by a Monte Carlo procedure based on the actual pedigree and missing data structure used in a complex segregation analysis of low density plus very low density lipoprotein cholesterol (LDL-C + VLDL-C) in baboons. The observed averages of the bootstrap parameter estimates adequately recover the generating values, which included parameters specifying genotype-covariate interaction. We then applied both a traditional complex segregation analysis and an analysis with genotype-covariate interaction to test for the presence of a major locus affecting LDL-C levels in baboons. The model including genotype-covariate interaction was significantly different from the model without interactions, and strongly supported the hypothesis that there is a segregating Mendelian locus as opposed to a random environmental factor. This major locus accounts for approximately 46% of the variance in LDL-C levels, as compared to 40% explained by a locus with no genotype-covariate interaction.

Animals↗

PubMed2006

A tree-based model for allele-sharing-based linkage analysis in human complex diseases.

By adapting a well-known affected-relative-pair linkage model that can incorporate covariate or sub-phenotype information [Olson, 1999: Am J Hum Genet 65:1760-1769], we have developed a recursive-partitioning (RP) algorithm (tree-based model) for identifying phenotype and covariate groupings that interact with the evidence for linkage. This strategy is designed to identify subgroups of affected relative pairs demonstrating increased evidence for linkage, where subgroups are defined by pair-level or family-level covariates. After growing a full tree, we identified optimal tree size through a form of tree pruning and chose the best covariate at each split by using bootstrap algorithms. Simulation studies showed that power to detect linkage can increase in the presence of gene-environment interactions, depending on the magnitude of the interaction. As expected, however, power can decrease by examining more covariates, despite the pruning to optimize tree size. The RP model correctly identifies tree structure in a large proportion of simulations. We applied the RP model to a dataset of families with bipolar affective disorder (BPAD) where linkage regions on chromosome 18 have been previously identified. Using the all-pairs score in Genehunter, the NPL tests showed no regions with strong linkage evidence on chromosome 18. However, using the RP model, several suggestive regions were found on chromosome 18. Two covariates appeared to influence the degree of linkage: the type II BPAD subtype and a pattern of displaying mania before or after a depressive episode. The RP model has the potential to identify previously unknown gene-environmental interactions; here we have demonstrated the practical utility and potential this new methodology holds.

Algorithms↗

PubMed2003

Nonlinear synchronization in EEG and whole-head MEG recordings of healthy subjects.

According to Friston, brain dynamics can be modelled as a large ensemble of coupled nonlinear dynamical subsystems with unstable and transient dynamics. In the present study, two predictions from this model (the existence of nonlinear synchronization between macroscopic field potentials and itinerant nonlinear dynamics) were investigated. The dependence of nonlinearity on the method of measuring brain activity (EEG vs. MEG) was also investigated. Dataset I consisted of 10 MEG recordings in 10 healthy subjects. Dataset II consisted of simultaneously recorded MEG (126 channels) and EEG (19 channels) in 5 healthy subjects. Nonlinear coupling was assessed with the synchronization likelihood S and dynamic itinerancy with the synchronization entropy Hs. Significance was assessed with a bootstrap procedure ("surrogate data testing"), comparing S and Hs with their distribution under the null hypothesis of stationary, linear dynamics. Significant nonlinear synchronization was detected in 14 of 15 subjects. The nonlinear dynamics were associated with a high index of itinerant behaviour. Nonlinear interdependence was significantly more apparent in MEG data than EEG. Synchronous oscillations in MEG and EEG recordings contain a significant nonlinear component that exhibits characteristics of unstable and itinerant behaviour. These findings are in line with Friston's proposal that the brain can be conceived as a large ensemble of coupled nonlinear dynamical subsystems with labile and unstable dynamics. The spatial scale and physical properties of MEG acquisition may increase the sensitivity of the data to underlying nonlinear structure.

Adult↗

PubMed2004

Spatiotemporal wavelet resampling for functional neuroimaging data.

The study of dynamic interdependences between brain regions is currently a very active research field. For any connectivity study, it is important to determine whether correlations between two selected brain regions are statistically significant or only chance effects due to non-specific correlations present throughout the data. In this report, we present a wavelet-based non-parametric technique for testing the null hypothesis that the correlations are typical of the data set and not unique to the regions of interest. This is achieved through spatiotemporal resampling of the data in the wavelet domain. Two functional MRI data sets were analysed: (1) Data from 8 healthy human subjects viewing a checkerboard image, and (2) "Null" data obtained from 3 healthy human subjects, resting with eyes closed. It was demonstrated that constrained resampling of the data in the wavelet domain allows construction of bootstrapped data with four essential properties: (1) Spatial and temporal correlations within and between slices are preserved, (2) The irregular geometry of the intracranial images is maintained, (3) There is adequate type I error control, and (4) Expected experiment-induced correlations are identified. The limitations and possible extensions of the proposed technique are discussed.

Adult↗

PubMed2006

A systematic review and quantitative appraisal of fMRI studies of verbal fluency: role of the left inferior frontal gyrus.

The left inferior frontal gyrus (LIFG) has consistently been associated with both phonologic and semantic operations in functional neuroimaging studies. Two main theories have proposed a different functional organization in the LIFG for these processes. One theory suggests an anatomic parcellation of phonologic and semantic operations within the LIFG. An alternative theory proposes that both processes are encompassed within a supramodal executive function in a single region in the LIFG. To test these theories, we carried out a systematic review of functional magnetic resonance imaging studies employing phonologic and semantic verbal fluency tasks. Seventeen articles meeting our pre-established criteria were found, consisting of 22 relevant experiments with 197 healthy subjects and a total of 41 peak activations in the LIFG. We determined 95% confidence intervals of the mean location (x, y, and z coordinates) of peaks of blood oxygenation level-dependent (BOLD) responses from published phonologic and semantic verbal fluency studies using the nonparametric technique of bootstrap analysis. Significant differences were revealed in dorsal-ventral (z-coordinate) localizations of the peak BOLD response: phonologic verbal fluency peak BOLD response was significantly more dorsal to the peak associated with semantic verbal fluency (confidence interval of difference: 1.9-17.4 mm). No significant differences were evident in antero-posterior (x-coordinate) or medial-lateral (y-coordinate) positions. The results support distinct dorsal-ventral locations for phonologic and semantic processes within the LIFG. Current limitations to meta-analytic integration of published functional neuroimaging studies are discussed.

Brain Mapping↗

PubMed2025

S-GMAS: Genome-Wide Mediation Analysis With Brain Subcortical Shape Mediators.

Mediation analysis is widely utilized in neuroscience to investigate the role of brain image phenotypes in the neurological pathways from genetic exposures to clinical outcomes. However, it is still difficult to conduct mediation analyses with whole genome-wide exposures and brain subcortical shape mediators due to several challenges including (i) large-scale genetic exposures, that is, millions of single-nucleotide polymorphisms (SNPs); (ii) nonlinear Hilbert space for shape mediators; and (iii) statistical inference on the direct and indirect effects. To tackle these challenges, this paper proposes a genome-wide mediation analysis framework with brain subcortical shape mediators. First, to address the issue caused by the high dimensionality in genetic exposures, a fast genome-wide association analysis is conducted to discover potential genetic variants with significant genetic effects on the clinical outcome. Second, the square-root velocity function representations are extracted from the brain subcortical shapes, which fall in an unconstrained linear Hilbert subspace. Third, to identify the underlying causal pathways from the detected SNPs to the clinical outcome implicitly through the shape mediators, we utilize a shape mediation analysis framework consisting of a shape-on-scalar model and a scalar-on-shape model. Furthermore, the bootstrap resampling approach is adopted to investigate both global and spatial significant mediation effects. Finally, our framework is applied to the corpus callosum shape data from the Alzheimer's Disease Neuroimaging Initiative.

Humans↗

PubMed2002

Estimation of the transition matrix of a discrete-time Markov chain.

Discrete-time Markov chains have been successfully used to investigate treatment programs and health care protocols for chronic diseases. In these situations, the transition matrix, which describes the natural progression of the disease, is often estimated from a cohort observed at common intervals. Estimation of the matrix, however, is often complicated by the complex relationship among transition probabilities. This paper summarizes methods to obtain the maximum likelihood estimate of the transition matrix when the cycle length of the model coincides with the observation interval, the cycle length does not coincide with the observation interval, and when the observation intervals are unequal in length. In addition, the bootstrap is discussed as a method to assess the uncertainty of the maximum likelihood estimate and to construct confidence intervals for functions of the transition matrix such as expected survival.

Algorithms↗

PubMed2002

Estimating survival gain for economic evaluations with survival time as principal endpoint: a cost-effectiveness analysis of adding early hormonal therapy to radiotherapy in patients with locally advanced prostate cancer.

The problem of estimating expected outcomes for the economic evaluation of treatments for which the outcome of principal interest is (quality adjusted) survival time has so far not received sufficient attention in the literature. The best estimate of expected survival is mean survival time, but with censored survival data, the true survival time for all the subjects is not known, so the mean is not defined.A possible solution to this estimation problem is illustrated by a retrospective cost-effectiveness analysis of the addition of hormonal therapy to standard radiotherapy for patients with locally advanced prostate cancer. A recently proposed method is used to approach the problem caused by censored cost data, and the impact of uncertainty is assessed by bootstrap resampling techniques. Mean survival time is estimated by a restricted means analysis with the time point of restriction determined by statistical criteria. When average total costs and mean survival time is evaluated at this time point of restriction, the result is that the combined therapy (radiotherapy plus hormonal therapy) increases mean survival time by about 1 year, while reducing the costs per patient for the French health insurance system by 12 700 FF. The time point of restriction may also be determined by other criteria and mean survival time may be estimated by extrapolating the survival curves by means of various parametric survival distributions. We show that the exact results of the economic evaluation are decisively determined by the restriction time point chosen and the approach taken to estimate mean survival time.

Antineoplastic Agents, Hormonal↗

PubMed2003

The determinants of health care expenditure: testing pooling restrictions in small samples.

Health care expenditure has increased substantially in all Western industrialized countries in the last decades. The necessity to contain the increase in health care expenditure has motivated the analysis of its determinants to explain differences across countries and health systems. However, recent studies have questioned the use of cross section data arguing that health systems are too different to allow for such comparisons. In this paper we investigate whether this criticism is really justified. We analyze the variations of health care expenditure in OECD countries relative to income, population aging and technological change. Our analysis is based on pooled cross section data and time series. Firstly, formulating error correction models for individual countries we demonstrate that in almost all cases the investigated variables are cointegrated. Secondly, we use a bootstrap framework for inference and examine whether the influence of explanatory variables is unique across countries. Applying recursive estimation procedures we find evidence for cross country homogeneity during the period 1961-1979. In the last two decades health care dynamics become more and more country specific thus indicating divergence of health systems and the growing importance of country-specific effects in the explanation of differences in health care expenditure.

Analysis of Variance↗

PubMed2004

Ageing and health-care expenditure: the red herring argument revisited.

Zweifel and colleagues have previously proposed that proximity to death is a more important influence on health-care costs than age, suggesting that demographic change per se will not have a large impact on future aggregate health expenditure. However, issues of econometric methodology have led to challenges of the robustness of these findings. This paper revisits the analysis. Using a longitudinal hospital data set from Oxfordshire, England, the two-step Heckman model from the Zweifel study is first replicated, to find that neither age nor proximity to death have a significant effect on hospital costs. Econometric problems with the model are demonstrated, and instead a two-part model shows both age and proximity to death to have significant effects on quarterly hospital costs. Cost predictions, calculated with bootstrapped 95% confidence intervals, further demonstrate that while age may significantly affect quarterly costs, these cost changes are small compared to the tripling of quarterly costs that occurs with approaching death in the last year of life. The analyses show the importance of model selection to properly assess the determinants of health-care expenditures.

Aged↗

PubMed2002

TP53 mutations in breast cancer tumors of patients from Rio de Janeiro, Brazil: association with risk factors and tumor characteristics.

Somatic mutations in the TP53 gene are the most frequently observed genetic alterations in human malignancies, including breast cancer, which is one of the leading causes of death among women in Brazil. In our study, we determined the frequency and the pattern of TP53 mutations in malignant breast tumors from 120 patients living in Rio de Janeiro, Brazil. TP53 mutations were found in 20% of the tumors, which contained a diversity of mutation types: missense (62.5%), nonsense (8.3%), silent (4.2%), intronic (12.5%), insertion (4.2%) and deletion (8.3%). Of a total of 15 missense mutations, 4 were observed at Arg248 and 2 at Cys242, which are directly involved in DNA binding and in zinc binding, respectively. A subgroup of 51 patients was analyzed with respect to the relation between the presence of TP53 mutations and classical risk factors and with tumor and patient characteristics. For this analysis, we used logistic regression and, in order to obtain more precise confidence intervals, they were recalculated using a bootstrap resampling technique. Our results demonstrate that these mutations are not statistically associated with the risk factors or the patients' characteristics. However, the presence of TP53 mutations is strongly associated with the aggressiveness of the tumors, measured by Elston classification (OR = 11.97 and 95% CI of 2.24-307.05). This finding is in agreement with previous studies, which report the presence of TP53 mutations in tumors with poor prognosis. This correlation between tumor aggressiveness and TP53 mutations could be a crucial variable for the treatment and prognosis of breast cancer.

Adult↗

PubMed2006

Risk assessment for biochemical recurrence prior to radical prostatectomy: significant enhancement contributed by human glandular kallikrein 2 (hK2) and free prostate specific antigen (PSA) in men with moderate PSA-elevation in serum.

Most models to predict biochemical recurrence (BCR) of prostate cancer use pretreatment serum prostate-specific antigen (PSA), clinical stage and prostate biopsy Gleason grade. We investigated whether human glandular kallikrein 2 (hK2) and free prostate-specific antigen (fPSA) measured in pretreatment serum enhance prediction. We retrospectively measured total PSA (tPSA), fPSA and hK2 in preoperative serum samples from 461 men with localized prostate cancer treated with radical prostatectomy between 1999 and 2001. We developed a regression model to predict BCR using preoperative tPSA, clinical stage and biopsy Gleason grade. We then compared the predictive accuracy of this "base" model with a model with fPSA and hK2 as additional predictors. BCR was observed in 90 patients (20%), including 48 patients with a pretreatment tPSA < or = 14 ng/ml (13%), and 28 patients (10%) with a pretreatment tPSA < or = 10 ng/ml. Overall, the predictive accuracy of the base model (bootstrap-corrected concordance index of 0.813) was not improved after the addition of fPSA or hK2 (0.818). However, for men with moderate tPSA-elevation (tPSA < or = 10 ng/ml), addition of fPSA and hK2 data increased predictive accuracy (from a base model concordance index of 0.756-0.815, p = 0.005). The improvement in accuracy was not sensitive to the threshold for "moderately elevated" PSA. For patients with a moderate tPSA-elevation (tPSA < or = 10 ng/ml), which closely corresponds to concurrent disease demographics, BCR-prediction was enhanced when fPSA and hK2 were added to the conventional model. Measurements of fPSA and hK2 improve on our ability to counsel patients prior to treatment as to their risk of BCR.

Aged↗

PubMed2007

Free PSA isoforms and intact and cleaved forms of urokinase plasminogen activator receptor in serum improve selection of patients for prostate cancer biopsy.

Clinicians currently use simple cut-points, such as serum prostate-specific antigen (PSA) >or=4 ng/ml, to decide whether to recommend further work-up for prostate cancer (PCa). As an alternative strategy, we evaluated multivariable models giving probabilities of a PCa diagnosis based on PSA and several circulating novel biomarkers. We measured total PSA, free PSA (fPSA), fPSA subfractions (single-chain fPSA-I and multichain fPSA-N), total human glandular kallikrein 2 (hK2) and full-length and cleaved forms of soluble urokinase plasminogen activator receptor (suPAR) in pretreatment serum from 355 men referred for prostate biopsy. Age and total PSA were combined in a "base" regression model to predict biopsy outcome. We then compared this base model to models supplemented by various combinations of circulating markers, using concordance index (AUC) to measure diagnostic discrimination. PCa prediction was significantly enhanced by models supplemented by measurements of suPAR fragments and fPSA isoforms. Addition of these markers improved bootstrap-corrected AUC from 0.611 for a cut-point and 0.706 for the base model to 0.754 for the full model (p=0.005). This improved diagnostic accuracy was also seen in subanalysis of patients with PSA 2-9.99 ng/ml and normal findings on DRE (0.652 vs. 0.715, p=0.039). In this setting, hK2 did not add diagnostic information. Measurements of individual forms of suPAR and PSA isoforms contributed significantly to discrimination of men with PCa from those with no evidence of malignancy.

Aged↗

PubMed2026

Pretreatment EBV-DNA/TLG-Based Risk Stratification Is Associated With Survival Outcomes in Nonmetastatic Nasopharyngeal Carcinoma: An Exploratory Study.

Whether combining pretreatment plasma Epstein-Barr virus DNA (EBV-DNA) with 18F-FDG PET/CT-derived total lesion glycolysis (TLG) improves prognostic stratification in nonmetastatic nasopharyngeal carcinoma (NPC) is unclear, particularly in nonendemic populations. We retrospectively analyzed 86 eligible nonmetastatic NPC patients treated with definitive radiotherapy (2010-2024) at a single nonendemic-region institution. EBV-DNA (prespecified cutoff 3500 copies/mL) and TLG (cutoff 200, ROC-derived within this cohort) were dichotomized. Both were available in 59/86 patients (68.6%), who differed from the rest in nodal and overall stage and in RT technique. Baseline PET/CT was in-house in 57 of 86 patients, and a robustness analysis in that subgroup is reported. Given limited events (13 PFS, 9 OS), Cox analyses are exploratory and were supplemented with penalized regression and bootstrap validation. At a median follow-up of 75.5 months, 5-year PFS and OS for the whole cohort (n = 86) were 81.1% and 85.9%. The EBV-DNAhigh/TLGhigh subgroup remained associated with inferior PFS after adjustment in an exploratory model (adjusted HR = 3.97, 95% CI: 1.32-11.93) and, in a single-variable model, with inferior OS (HR = 4.13, 95% CI: 1.10-15.52). Discrimination was comparable to the individual-biomarker model for PFS and lower for OS. Five-year PFS fell monotonically across the four risk groups in the complete-case cohort (n = 59; 89.7%-58.3%). OS differed across groups (log-rank p = 0.044) but was not strictly monotonic, with wide, overlapping confidence intervals. This two-biomarker model is hypothesis-generating and needs prospective, multicenter validation before any consideration of risk-adapted treatment.

Epstein–Barr virus DNA↗

PubMed1991

An analysis of the origin of metazoans, using comparisons of partial sequences of the 28S RNA, reveals an early emergence of triploblasts.

In order to study the origin of metazoans, we have compared sequences from the 5' end of the large subunit ribosomal RNA of a number of protists, fungi, plants and metazoans, including all diploblastic phyla (sequences of 10 new species have been determined, including that of the placozoan, Trichoplax adhaerens). These sequences were analyzed using distance matrix, maximum parsimony and maximum likelihood methods, and the validity of the results was ascertained with bootstrapping and species removal or addition. Triploblasts and diploblasts formed two clearly separated monophyletic units; this divergence, which apparently preceded the diversification of diploblastic animals (i.e. the successive sponge, ctenophore, cnidarian radiations), showed a much more ancient origin of triploblasts with respect to diploblasts than classically assumed. These results do not exclude the possibility that triploblasts and diploblasts arose independently from different protists.

Animals↗