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Results for “Surrogate variables analysis”

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PubMed2004

Comparative evaluation of simple indices of insulin resistance.

Various surrogate methods for the quantification of insulin sensitivity have been proposed. A comparative evaluation is lacking and is relevant for the standardization of investigative methods and comparability of results. The aims of the study were to perform a comparative validation of fasting insulin, homeostasis model assessment (HOMA), Quantitative Insulin Sensitivity Check Index (QUICKI), and revised-QUICKI (R-QUICKI) against minimal model derived estimates of insulin sensitivity (SI(MM)) in nondiabetic people and to carry out a comparative evaluation of the ability of these indices as means for the identification of individuals with the metabolic syndrome (MS) on a population basis. We used 2 data sets defined as "validation sample" and "prevalence sample". Validation sample: a total of 162 healthy men and women aged 30 to 65 years were studied by frequently sampled intravenous glucose tolerance test (FSIVGTT). SI(MM) was calculated with the Minmod program. Prevalence sample: a total of 2,731 nondiabetic men and women aged 35 to 65 years were studied. In both samples, anthropometry, blood pressure, fasting glucose, insulin, triglycerides, high-density lipoprotein (HDL) cholesterol, and free fatty acid (FFA) were measured. HOMA, QUICKI, and R-QUICKI were calculated. The MS was defined according to the Adult Treatment Panel III. Validation sample: insulin, HOMA, QUICKI, and R-QUICKI significantly correlated with SI(MM) (r = -0,53, -0.52, 0.41, 0.33; all P < .001). The finding was confirmed in obese (body mass index [BMI] > or =25 kg/m(2)), but in the normal weight, the correlation coefficient for QUICKI was significantly smaller than for the other indices. Receiver operator characteristic (ROC) curve analysis performed with SI(MM) below or above the lowest 25th percentile (ie, insulin resistance yes, no) as the outcome variable and each of the 4 indices as the test variable showed no significant differences in the areas under the curve. Prevalence sample: prevalence of the MS progressively increased across quartiles of insulin resistance as evaluated by any of the 4 indices, with no significant differences between them. The novel indices QUICKI and R-QUICKI do not perform better than HOMA and fasting insulin as surrogate measures of insulin resistance or means for the identification of people with MS in the general population.

Adult↗

PubMed1991

Adjustment for non-differential misclassification error in the generalized linear model.

It is well known that estimates of association between an outcome variable and a set of categorical covariates, some of which are measured with misclassification, tend to be biased upon application of the usual methods of estimation that ignore the classification error. We propose a method to adjust for misclassification in covariates when one applies the generalized linear model. In the case where one can observe some true covariates only through surrogates, we combine a latent class analysis with the approach to incorporate multiple surrogates into the model. We include discussion on the efficacy of repeated measurements which one can view as a special case of multiple surrogates with identical distribution. We provide two examples to demonstrate the applicability of the method and the efficacy of multiple replicates for a covariate subject to misclassification in a regression framework.

Adolescent↗

PubMed2005

Dynamic contrast enhanced MRI in the differential diagnosis of soft tissue tumors.

PURPOSE: The value of the dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) in differentiating benign and malignant soft tissue tumors was investigated. MATERIALS AND METHODS: Turbo FLASH DCE-MRI was performed on 22 subjects (2-74 years) with soft tissue tumors. Enhancement in the first min (E(max/1)), second min (E(max/2)) and maximum peak enhancement (E(max)), and steepest slope were calculated. Discriminant analyses were performed to reveal parametric differences of benign and malignant lesions. RESULTS: Diagnosis of benign (N = 10) tumors were hemangioma (n = 3), neurogenic tumor (n = 3) lipoma (n = 2), giant cell tumor (n = 1) and desmoid (n = 1), whereas malignant lesions (N = 12) were classified as liposarcoma (n = 5), malignant fibrous histiocytoma (n = 5) and synovial sarcoma (n = 2). For malignant lesions E(max/1) was 65-198%, E(max/2) was 65-145%, E(max) was 78-198%, and steepest slope was 1.45-4.06. For benign lesions these values were 4-98%, 5-105%, 7-125% and 0.67-2.57, respectively. To determine the relation between the variables analysed, Pearson correlation coefficients were calculated. E(max) was found to be highly correlated with other variables (rxy > 0.86, P < 0.0001). Consequently, this variable was excluded from the discriminant analysis. In order to determine discrimination of malignant and benign tumors using E(max/1), E(max/2,) and steepest slope of the enhancement curve logistic regression was applied to the above mentioned data. When combined these parameters had a 95.5% of overall accuracy in classifying benign and malignant lesions (P = 0.004). CONCLUSION: DCE-MRI parameters that thought to be the surrogate markers of tumoral microcirculation and tissue perfusion provides a specific preoperative diagnosis. Dynamic imaging parameters are therefore advocated for monitoring the effect of chemotherapy in soft tissue tumors.

Adolescent↗

PubMed2004

Tracking repolarization dynamics in real-life data.

Ambulatory (Holter) electrocardiographic recordings provide the tools for tracking temporal instabilities of repolarization during various daily activities. However, analysis of low-amplitude repolarization changes in this setting is challenging due to the presence of multiple artifacts, variable activity levels, and other uncontrolled factors. Here we compare performance of different methods for continuous analysis of repolarization dynamics using simulated signals and real-life Holter recordings. Selection of relatively stable segments with a low baseline drift and accurate correction of baseline wander constitute the first step in repolarization analysis. We describe application of adaptive filtering, which yields more accurate results than non-adaptive techniques. Because small (microvolt-level) residual baseline drifts can be a source of error in tracking repolarization changes, stability of isoelectrical segment has to be controlled. To compare robustness of spectral and time-domain techniques for tracking temporal repolarization instabilities (T-wave alternans, TWA), we used simulated signals with changing heart rate, variable levels of TWA, noise, phase shifts, spurious artifacts, and period-four oscillations. In addition, we compared performances of the inter-beat and intra-beat averaging techniques for tracking dynamics of T-wave alternans. Using the simulated signals and real-life Holter data, we showed that analysis of information both in time and frequency domains combined with control of baseline drifts (surrogate analysis) gives a more reliable estimate of the low-amplitude repolarization dynamics than each of these techniques alone. To summarize, dynamic tracking of low-amplitude repolarization changes in ambulatory recordings is possible during most of the recording time but requires accurate control of baseline wander and stability of isoelectrical segments. Analysis of time-frequency distributions embedded in repolarization dynamics facilitates detection of abrupt and transient repolarization instabilities, including changes in the level of T-wave alternans and slower periodicities.

Artifacts↗

PubMed2004

Role of MRI in multiple sclerosis I: inflammation and lesions.

Conventional magnetic resonance imaging (MRI) can improve accuracy in the diagnosis of multiple sclerosis (MS). Metrics derived from conventional MRI are now routinely used to detect therapeutic effects and extend clinical observations. Hyperintense lesions on T2-weighted MRI scans are related primarily to increased water content and thus cannot distinguish between inflammation, edema, demyelination, Wallerian degeneration, and axonal loss. In addition, T2-weighted and post-contrast images are not sufficiently sensitive to detect occult disease affecting normal appearing gray and white matter. They do not show a reliable correlation with clinical measures of disability and do not provide a complete assessment of therapeutic outcomes. In the past few years a host of advanced MRI techniques and analysis methods have been introduced for the assessment of MS. These MRI techniques appear to have better reliability as surrogate markers for monitoring the pathologic processes that most likely are related to disease activity and clinical progression. They are able to reveal a range of tissue changes that include edema, inflammation, demyelination, axonal loss, and neurodegeneration. Therefore, in a disease with a high degree of longitudinal variability of clinical signs and symptoms within and between patients, and with no current adequate biological markers of disease progression, non-conventional MRI techniques provide a powerful tool to non-invasively study pathological substrates of overt lesions and normal appearing brain tissue. In particular, the use of these techniques is promising in elucidating mechanisms underlying the accumulation of tissue damage, repair and functional reorganization of neural pathways in patients with MS.

Humans↗

PubMed1998

Relationship between didanosine exposure and surrogate marker response in human immunodeficiency virus-infected outpatients.

We used information available from routine clinic visits to characterize the pharmacokinetics of didanosine in 82 human immunodeficiency virus-infected patients. A total of 271 blood samples were collected for the measurement of didanosine concentrations in plasma (mean +/- standard deviation [SD], 3.30 +/- 2.21 samples/patient). Bayesian estimates of didanosine oral clearance (CL[oral]) were obtained for these patients by the POSTHOC option within the NONMEM software package. Population priors from a previous NONMEM analysis of didanosine pharmacokinetics were used. The mean +/- SD CL(oral) was 132 +/- 27.7 liters/h, which agrees reasonably well with estimates obtained from previous pharmacokinetic studies of didanosine. Estimates of individual didanosine exposure were then used to consider potential relationships between drug exposure and surrogate marker response over a 6-month period. No correlations were found between the didanosine area under the concentration-time curve from 0 to 6 months and the absolute CD4 cell count (r = 0.305; 0.1 < P < 0.2), weight response (r = 0.0857; P > 0.4), or percentage of CD4 lymphocytes (r = 0.0559; P > 0.4). Future efforts to characterize didanosine exposure in outpatients by random sampling methods should involve more directed efforts to limit residual variability in the data.

Adult↗

PubMed2006

Screening of toxicity biomarkers for methionine excess in rats.

Although many animal studies have reported that dietary excess of methionine causes toxic changes including growth suppression and hemolytic anemia, the biochemical mechanism and biomarkers for methionine toxicity have not been well elucidated. The present study aimed to identify toxicity biomarkers from plasma metabolites in rats fed excessive methionine. Young growing rats were fed graded doses of additional methionine for 2 wk. Cluster analysis of multivariate correlations was performed on the physiological and toxicity variables with plasma metabolites detected by GC/MS, amino acid analyzer, and thiol-specific analysis. Indicative variables for hemolysis such as splenic nonheme iron content and plasma bilirubin were grouped in the same cluster as many methionine metabolites. Homocysteine and some undefined metabolites in this cluster were found to be strong discriminators between nontoxic and toxic levels of methionine intake. Product-to-precursor ratios of each methionine metabolite demonstrated that excessive methionine intake caused a marked decrease only in the ratio of cystathionine to homocysteine, suggesting that metabolism from homocysteine to cystathionine would be rate limiting in the disposal of excessive methionine. Collectively from these results, homocysteine appeared to be the most plausible biomarker to assess methionine excess as a surrogate marker both for toxicity and for setting a metabolic upper limit.

Amino Acids↗

PubMed2002

Short and long term non-linear analysis of RR variability series.

The complexity of RR variability is approached in the short and in the long term by means of black-box data analysis. Short term series of a few hundred beats are explored by means of informational entropy and predictability indexes. A correction to biases toward false determinism is performed assuming maximum uncertainty, whenever data do not furnish sufficient recurrences. Non-randomness and non-linearity are tested by means of surrogate data provided by random shuffling and phase randomization respectively. In the long term of the 24-h or of several hours, similar tests based on mutual information are applied and validated by means of surrogate series. In addition the state space reconstruction is carried out by means of state space non-linear filtering addressing directly the reconstructed trajectories. In this condition, parameters characterizing the hypothetical attractor, mainly the maximum Lyapunov exponent, can be reliably identified.

Biophysical Phenomena↗

PubMedDate not supplied

A prognostic index (bladder prognostic index) for bilharzial-related invasive bladder cancer.

PURPOSE: Bladder cancer is still the most common solid tumor among adult males in Egypt because of the prevalence of bilharzial infestation, especially in the countryside. In this prospective study, we have recorded the prognostic factors for 180 patients with invasive bladder cancer for whom standard radical cystectomy had been performed to develop a prognostic index (bladder prognostic index) that defines high risk patients who are more vulnerable to disease relapse after surgery and who may benefit from additional therapy. PATIENTS AND METHODS: The study was performed between January 1997 and December 1999, in which 180 patients with histopathologically proved invasive bladder cancer associated with bilharziasis underwent radical cystectomy or anterior pelvic exenteration. After surgery, patients were regularly followed for a minimum of 2 years. RESULTS: Our patients included 141 males and 39 females. Squamous cell carcinoma was the most common type (53.3%), and most of the tumors were grade II (61.1%). A total of 173 patients had their tumors operable, while 7 were inoperable. We had 5 (2.8%) operative related mortalities. At 5 years postoperatively, free and overall survival rates for the whole group of patients were 31.44%+/-5.9% and 32.5%+/-6.8%, respectively. Tumor pathologic stage, grade, and nodal affection were the only significant factors with impact on survival (P=0.008, 0.051, and 0.004, respectively). These 3 prognostic indexes were used to design a model to predict an individual patient's risk factor for recurrence. Patients were then assigned to one of the 4 risk groups according to the score achieved in this prognostic index (0=low risk, 1=intermediate risk, and 2 or 3=higher risk). These 4 risk groups had distinctly different rates of disease-free survival, i.e., 91.7%, 53%, 13%, and 7% for low, intermediate, and higher risk groups, respectively. CONCLUSION: Although this prognostic index appears to be of a significant clinical relevance, it needs to be more validated on a larger number of patients, and it could be a surrogate variable for biologic factors responsible for the heterogeneity of bladder cancer.

Adult↗

PubMed1999

[Research on stochastic factors of heart rhythm variability in nonlinear dynamic analysis].

In this study, the influence of external noise on heart rhythm variability (HRV) in nonlinear dynamic analysis and the internal stochastic factor of HRV were discussed in connection with their physiological significance. The sampling rate, stationary and non-uniformity time interval were analyzed. An interpolation algorithm for heart period was introduced. The experiment demonstrated that the influence was highly reduced by the mentioned procedure. The internal stochastic factors of HRV were investigated by several nonlinear dynamic methods such as surrogate data, mutual information and nonlinear forecasting. The results suggested the colligation of deterministic chaos and stochastic process should be a favorite to interpret HRV.

Electrocardiography↗

PubMed1996

Marker processes in survival analysis.

In the development of many diseases there are often associated variables which continuously measure the progress of an individual towards the final expression of the disease (failure). Such variables are stochastic processes, here called marker processes, and, at a given point in time, they may provide information about the current hazard and subsequently on the remaining time to failure. Here we consider a simple additive model for the relationship between the hazard function at time t and the history of the marker process up until time t. We develop some basic calculations based on this model. Interest is focused on statistical applications for markers related to estimation of the survival distribution of time to failure, including (i) the use of markers as surrogate responses for failure with censored data, and (ii) the use of markers as predictors of the time elapsed since onset of a survival process in prevalent individuals. Particular attention is directed to potential gains in efficiency incurred by using marker process information.

Biomarkers↗

PubMed2003

Quantitative Poincaré plot analysis of heart rate variability: effect of endurance training.

The aim of the study was to evaluate the effectiveness of the Poincaré plot analysis of heart rate variability (HRV) in observing endurance training-induced changes. Four 10-min manoeuvres were performed (supine lying, standing, steady state exercising and subsequent recovery) by eight control subjects before and after a short-term endurance training and by eight subjects trained for at least 3 years. HRV was assessed by traditional time- and frequency-domain indexes, in parallel with the Poincaré plot analysis. In the latter each R-R interval is plotted as a function of the previous one, and the standard deviations of the instantaneous and long-term R-R interval variability are calculated. In our subjects, the Poincaré scatter grams became gradually narrower from supine to exercising, with progressive parasympathetic withdrawal. Short- and long-term endurance training led to higher aerobic power ( p<0.05) and ventilatory threshold shifted towards higher power output ( p<0.05). All HRV evaluation methods showed that HRV values were higher after training both during supine lying and standing ( p<0.05). The Poincaré scatter grams were wider in the trained state. Standard deviations of the Poincaré plot were significantly correlated with the main parameters of the time- and frequency-domain analyses, especially concerning the parasympathetic indicators. These results suggested that Poincaré plot parameters as well as the "width" of the scatter gram could be considered as surrogates of time- and frequency-domain analysis to assess training-induced changes in HRV.

Adult↗

PubMed2005

Reproductive period and cognitive function in a representative sample of naturally postmenopausal women aged 60-64 years.

BACKGROUND: Greater lifetime estrogen exposure has been postulated to result in better cognition in later life, particularly in the area of verbal memory. In women, the highest levels of endogenous estrogen occur during their reproductive period, between menarche and menopause. OBJECTIVE: To investigate the association between reproductive period and cognition. METHODS: The sample consisted of 760 naturally postmenopausal women aged 60-64 years (mean age 62.5 +/- 1.5 years) participating in the PATH Through Life Study who were randomly drawn from the population of Canberra, Australia. Participants were administered a verbal learning test (immediate recall and 1-minute delay), the Mini-Mental State Examination (MMSE), digit span backwards, the Symbol-Digit Modalities Test and simple and choice reaction time tests. RESULTS: There were no significant associations detected between reproductive period and performance on any of the cognitive tests, either before or after controlling for potential confounding variables. CONCLUSIONS: Reproductive period, a surrogate measure of endogenous estrogen exposure, had no detectable effect on cognitive performance in this sample.

Australia↗

PubMed2003

Interactions between dialysis-related volume exposures, nutritional surrogates and mortality among ESRD patients.

BACKGROUND: Interdialytic weight gain is used as a surrogate for volume expansion in haemodialysis patients and as an indicator of non-compliance. Increased weight gain is associated with both a greater mortality risk and better nutrition indices. This analysis characterizes the association between dialysis-related volume expansion and mortality in the context of its interaction with nutritional surrogates. METHODS: All patients receiving haemodialysis through Fresenius Medical Care-North America during 1998 were included. The percentage reduction in weight or intradialytic weight loss (IDWL%) was defined as the difference between the average of pre- and post-dialysis weights from the last 3 months of 1997 expressed as a percentage of post-dialysis weight. Associations between IDWL% and clinical and demographic variables were estimated using linear regression. The association between mortality risk and IDWL% was estimated using Cox proportional hazards regression. RESULTS: Younger age, male gender, the presence of diabetes mellitus, decreasing cholesterol, post-dialysis weight and pre-dialysis blood pressure (systolic and pulse pressure) were associated with increased IDWL%. Increasing IDWL% was associated with increasing phosphorus, creatinine, albumin, potassium and urea reduction ratio. Increasing IDWL% was significantly associated with mortality at 1 year [hazard ratio (HR) = 1.07, P = 0.003]. Among patients with diabetes mellitus, increasing IDWL% was associated with a mortality HR of 1.03 (P = 0.02). Among patients without diabetes mellitus, increasing IDWL% was not associated with an increased mortality risk. Increasing IDWL% is associated with a greater mortality risk among patients with creatinine <7.26, which failed to remain significant for patients whose creatinine was >or=7.26 mg/dl. Increasing IDWL% is associated with a greater mortality risk among patients with greater post-dialysis weight, greater body mass index and lower serum sodium measurements. CONCLUSIONS: This study confirms and extends the findings of the deleterious association between increasing IDWL% and mortality among patients with diabetes mellitus and among subgroups based on serum creatinine and body weight. The putative deleterious effect of dialysis-related volume expansion on mortality must be interpreted in the context of the patient's diabetic and nutritional status.

Adolescent↗

PubMed2005

Surrogate markers and survival in women receiving first-line combination anthracycline chemotherapy for advanced breast cancer.

Surrogate markers may help predict the effects of first-line treatment on survival. This metaregression analysis examines the relationship between several surrogate markers and survival in women with advanced breast cancer after receiving first-line combination anthracycline chemotherapy 5-fluorouracil, adriamycin and cyclophosphamide (FAC) or 5-fluorouracil, epirubicin and cyclophosphamide (FEC). From a systematic literature review, we identified 42 randomised trials. The surrogate markers were complete or partial tumour response, progressive disease and time to progression. The treatment effect on survival was quantified by the hazard ratio. The treatment effect on each surrogate marker was quantified by the odds ratio (or ratio of median time to progression). The relationship between survival and each surrogate marker was assessed by a weighted linear regression of the hazard ratio against the odds ratio. There was a significant linear association between survival and complete or partial tumour response (P<0.001, R(2)=34%), complete tumour response (P=0.02, R(2)=12%), progressive disease (P<0.001, R(2)=38%) and time to progression (P<0.0001, R(2)=56%); R(2) is the proportion of the variability in the treatment effect on survival that is explained by the treatment effect on the surrogate marker. Time to progression may be a useful surrogate marker for predicting survival in women receiving first-line anthracycline chemotherapy and could be used to estimate the survival benefit in future trials of first-line chemotherapy compared to FAC or FEC. The other markers, tumour response and progressive disease, were less good.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Changes in baroreceptor sensitivity for heart rate during normotensive pregnancy and the puerperium.

Normal pregnancy is associated with marked changes in cardiovascular haemodynamics, which in part may be due to changes in autonomic control mechanisms. Baroreflex sensitivity for heart rate (BRS) was calculated in the supine and standing positions using power spectral analysis of pulse interval (PI) and systolic blood pressure (SBP) in 16 normotensive pregnant women and 10 normotensive non-pregnant controls. The pregnant women were studied on three occasions during their pregnancy (early, mid- and late gestation) and once during the puerperium. Supine total SBP variability increased between early and late pregnancy by 79% [95% confidence intervals (CI) 30%, 145%; P<0. 001], and supine high-frequency PI variability decreased by 75% (CI 51%, 88%; P<0.001). Supine BRS fell by 50% (P<0.001), with values returning to early-pregnancy levels in the puerperium, which were similar to those recorded in the control group. Standing SBP variability and BRS values were unchanged during pregnancy and post partum. The low/high frequency ratio of PI variability, taken as a surrogate measure of sympathovagal balance, increased by 137% (CI 42%, 296%; P<0.01) in the supine but not the standing position from early to late pregnancy. This was due to a decrease in high-frequency variability rather than to an increase in low-frequency variability, suggesting that these changes may have been due to vagal withdrawal rather than increased sympathetic activity. Normotensive pregnancy is associated with a marked decrease in supine BRS, although the exact mechanisms for these changes remain unclear. Further studies are required to define whether changes in BRS and sympathovagal tone in early pregnancy can be used to predict the onset of pregnancy-induced hypertension.

Adolescent↗

PubMed2004

Interdependency between heart rate variability and sleep EEG: linear/non-linear?

OBJECTIVE: To investigate whether the interdependency between heart rate variability (HRV) and sleep electroencephalogram (EEG) power spectra is linear or non-linear. METHODS: Heart rate and sleep EEG signals were recorded in 8 healthy young men. Spectral analysis was applied to electrocardiogram and EEG sleep recordings. Synchronization likelihood was computed over the first 3 non-rapid eye movement-rapid eye movement sleep cycles between normalized high frequency of RR intervals (RRI) and all electroencephalographic frequency bands. Comparison to surrogate data of different types was used to attest statistical significance of the coupling between RRI and EEG power bands and its linear or non-linear character. RESULTS: Synchronization likelihood values were statistically greater than univariate surrogate synchronization for all sleep bands both at the individual and the group levels. With reference to multivariate surrogates, synchronization values were statistically greater at the group level and, in a majority of cases, for individual comparison except for sigma and beta bands. CONCLUSIONS: While all electroencephalographic power bands are linked to normalized high frequency RRI band, this interdependency is non-linear for delta, theta and alpha bands. SIGNIFICANCE: Non-linear description is required to capture the full interdependent dynamics of HRV and sleep EEG power bands.

Adolescent↗

PubMed1990

Do-not-resuscitate orders in an extended-care study group.

We examined the charts of 911 nursing home patients in Hennepin County, Minnesota, to determine the prevalence of written do-not-resuscitate (DNR) orders. Information regarding demographic characteristics, and whether a surrogate decisionmaker was available and participated in the decision, was also collected. Twenty-seven percent of patients had DNR orders. Ninety percent of all patients had potentially available surrogate decisionmakers. However, for 31% of patients with DNR orders, there was no documentation of patient or surrogate participation in the DNR decision. Univariate analysis identified female sex; increased age, level of care (skilled versus intermediate), presence of a potential surrogate decisionmaker, and increasing length of time since nursing home admission as factors associated with presence of DNR orders. When a logistic regression model was used, increased age, increased length of time since nursing home admission, skilled versus intermediate level of care, and presence of a surrogate decisionmaker were independently associated with presence of DNR status. Several variables are independently associated with written DNR orders; their relationship to the factors physicians use in decision making requires further study.

Age Factors↗