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PubMed1992

Sensitivity analysis of a new model of carcinogenesis.

A new simulation model of carcinogenesis is described which, in addition to the features of a standard clonal two-stage model (loss of both copies of a tumor suppressor gene by point mutations, cell division and cell death), includes a quantitative description of mitotic recombination, DNA repair, and cell to cell interactions in all stages. The model is implemented as a discrete event process. The results of a sensitivity analysis of the model are presented. The most sensitive parameters were found to be: the number of normal cells at risk, and the division rate, death rate and DNA repair efficiency for the intermediate stage cells. Accurate information about these parameters is important for a quantitative understanding of carcinogenesis. The sensitivity of the model to the number of normal cells indicates the importance of understanding the nature of the cells at risk, for example, stem cells vs. differentiated cells. The model can be used to assess the importance of chromosomal damage such as mitotic recombination and epigenetic mechanisms such as hyperplasia and cytotoxicity in the onset of malignant tumors.

Cell Death↗
PubMed2002

Prediction of skin burn injury. Part 2: Parametric and sensitivity analysis.

Part 2 of this paper presents an analysis of variance (ANOVA) for investigating the precedence of the various parameters, and the effects of varying these parameters, in assessment of burn injury resulting from the exposure of skin surface to heat sources. A one-dimensional model based on the finite difference method (FDM), as implemented in a spreadsheet software application, is applied to the assessment of burn injury. Henriques' theory of skin burns is used for determining the spatial and temporal extent of tissue damage. The ranks of the effects of various factors were obtained. It was found that the highest ranked factor is the initial tissue temperature followed by the thermal conductivity of the epidermal layer. The effect of blood perfusion rate is ranked much below the combinations of other factors. The results from the present numerical experiment agree well with the results obtained by Palla. Sensitivity analysis of the critical exposure levels was also carried out and results are discussed. In this study, the effects of the various parameters on injury threshold were investigated. Again, the results indicate that the four parameters: thermal conductivity of the epidermis and dermis, convective heat transfer coefficient and initial tissue temperature, have a pronounced influence on assessing the burn injury threshold. It was also found that fat thermal conductivity and blood perfusion rate have no obvious effect on injury threshold. A two-dimensional analysis was further conducted to determine the sensitivity of the predicted injury to the values of frequency factor, P, and apparent activation energy, deltaE, used in the models. Part 1 of this study details the development of the computer models based on the one- and two-dimensional bioheat equations.

Analysis of Variance↗
PubMed1997

Sensitivity analysis of one-dimensional heat transfer in tissue with temperature-dependent perfusion.

Design criteria for implantable heat-generating devices such as the total artificial heart require the determination of safe thresholds for chronic heating. This involves in-vivo experiments in which tissue temperature distributions are obtained in response to known heat sources. Prior to experimental studies, simulation using a mathematical model can help optimize the design of experiments. In this paper, a theoretical analysis of heat transfer is presented that describes the dynamic, one-dimensional distribution of temperature from a heated surface. Loss of heat by perfusion is represented by temperature-independent and temperature-dependent terms that can reflect changes in local control of blood flow. Model simulations using physiologically appropriate parameter values indicate that the temperature elevation profile caused by a heated surface adjacent to tissue may extend several centimeters into the tissue. Furthermore, sensitivity analysis indicates the conditions under which temperature profiles are sensitive to changes in thermal diffusivity and perfusion parameters. This information provides the basis for estimation of model parameters in different tissues and for prediction of the thermal responses of these tissues.

Body Temperature Regulation↗
PubMed2005

Reducing whole body physiologically based pharmacokinetic models using global sensitivity analysis: diazepam case study.

There are situations in drug development where one may wish to reduce the dimensionality and complexity of whole body physiologically based pharmacokinetic models. A technique for formal reduction of such models, based on global sensitivity analysis, is suggested. Using this approach mean and variance of tissue(s) and/or blood concentrations are preserved in the reduced models. Extended Fourier amplitude sensitivity test (FAST), a global sensitivity technique, takes a sampling approach, acknowledging parameter variability and uncertainty, to calculate the impact of parameters on concentration variance. We used existing literature rules for formal model reduction to identify all possible smaller dimensionally models. To discriminate among those competing mechanistic models extended FAST was used, whereby we treated model structural uncertainty as another factor contributing to the overall uncertainty. A previously developed 14 compartment whole body physiologically based model for diazepam disposition in rat was reduced to three alternative reduced models, with preserved arterial mean and variance concentration profiles.

Animals↗
PubMed2005

Sensitivity analysis for informative censoring in parametric survival models.

Most statistical methods for censored survival data assume there is no dependence between the lifetime and censoring mechanisms, an assumption which is often doubtful in practice. In this paper we study a parametric model which allows for dependence in terms of a parameter delta and a bias function B(t, theta). We propose a sensitivity analysis on the estimate of the parameter of interest for small values of delta. This parameter measures the dependence between the lifetime and the censoring mechanisms. Its size can be interpreted in terms of a correlation coefficient between the two mechanisms. A medical example suggests that even a small degree of dependence between the failure and censoring processes can have a noticeable effect on the analysis.

Data Interpretation, Statistical↗
PubMed2006

MALDI-TOF mass spectrometry for quantitative, specific, and sensitive analysis of DNA and RNA.

Cell-free fetal DNA and RNA released into the maternal circulation offer new opportunities to study fetal and pregnancy-associated abnormalities. Similarly, tumor cells can release cell-free DNA and RNA into the peripheral circulation, and these cell-free DNA and RNA can be used for cancer diagnosis, monitoring, and prognosis. However, these DNA and RNA often exist at very low concentrations (for fetal DNA, approximately 20 genome-equivalents (G.E.)/mL of plasma in the first trimester). The analysis is further complicated by the predominant amount of blood cell-derived DNA and RNA. MALDI-TOF mass spectrometry can provide quantitative, specific, and sensitive analysis of DNA and RNA, and thus may be a useful technology for the field.

DNA↗
PubMed2006

Application of robust statistical methods for sensitivity analysis of health-related quality of life outcomes.

BACKGROUND: Researchers often use conventional parametric procedures to test hypotheses of health-related quality of life (HRQL) mean equality across patient groups. However, these techniques are sensitive to the presence of skewed distributions and unequal group variances, which may characterize many HRQL measures. PURPOSE: To conduct a sensitivity analysis of conventional and robust approaches to test hypotheses of mean equality on HRQL measures for hematopoietic stem cell transplantation survivors and a healthy comparison group. METHODS: The methods applied were the conventional parametric procedure of least-squares analysis of variance applied to the raw scores, the conventional parametric procedure applied to transformed data, and a robust approximate degrees of freedom parametric procedure utilizing trimmed means and Winsorized variances. RESULTS: The choice of analysis method affected the conclusions about the null hypothesis of mean equality. More commonly observed, however, was a substantial difference in the value of the F-statistic and standard errors which was particularly evident in the measures with greater degrees of skewness and heterogeneity of variances. CONCLUSIONS: Robust statistical tests should be incorporated into sensitivity analyses when analyzing HRQL data.

Adult↗
PubMed2006

Including multiple imputation in a sensitivity analysis for clinical trials with treatment failures.

When treatment failures occur during the course of a clinical trial, the treatment regimen following failure may be changed. This change in therapy complicates comparisons among the original treatment arms. As in some clinical trials with dropouts, intent-to-treat analysis can yield a large bias. We examine the use of multiple imputation to replace observations after treatment failure has occurred. As a sensitivity analysis, this approach is compared to existing methods for handling treatment failures - removing treatment failure subjects, removing data after the onset of treatment failure, and imputation the last observation prior to treatment failure for all subsequent observations - in addition to an analysis of all collected data based on randomized treatment assignment. A data set from the Asthma Clinical Research Network is used to demonstrate the methods.

Algorithms↗
PubMed2000

Coupling relations between molecular electronic and geometrical degrees of freedom in density functional theory and charge sensitivity analysis

The mapping concepts, reflecting the equilibrium, ground-state coupling between the electronic and geometrical degrees of freedom of both closed and open molecular systems are explored within density functional theory (DFT) and charge sensitivity analysis (CSA). After a brief overview of the principal derivatives and relations, including alternative Legendre transformed representations of molecular states, the explicit transformations are derived for the mapping between the nuclear coordinates Q, specifying the molecular geometry, and the 'electronic' coordinates represented by the electron density rho(r), in the local resolution, or the vector N = [N(alpha)] of the atomic electron populations, in the atoms-in-molecule (AIM) resolution. They fall into two categories: the electron following, transforming a given shift of the nuclear coordinates into the conjugate relaxation of the electronic 'coordinates' rho or N, and the electron preceding, 'translating' a specified displacement of these electronic degrees of freedom into the conjugate geometry relaxation. Algorithms for determining such transformations are discussed with a special emphasis placed upon the semiempirical CSA modeling in atomic resolution. Several additional mapping quantities are identified, which reflect the coupling between molecular electronic descriptors, e.g. the number of electrons or the chemical potential, and the relevant geometry-related quantities, e.g. Q or the forces acting on nuclei. Implications of the mapping concepts for chemistry are briefly examined and possible areas for their application are identified.

Journal Article↗
PubMed1996

A sagittal plane model of the knee and cruciate ligaments with application of a sensitivity analysis.

In this investigation the complex multi-bundle structure of the cruciate ligaments and their interaction with the tibiofemoral joint was modeled analytically by representing the different regions of the cruciates with ligament elements. A sensitivity analysis was then performed to describe the effect that variations of the model input parameters had on the model variables (outputs). The effect that the cruciate ligament bundles had in controlling joint kinematics was dependent on knee flexion angle, and the load applied to the tibiofemoral joint. For passive range of knee motion with the thigh in the horizontal plane (a common rehabilitation activity), all cruciate ligament bundles were strained with the joint positioned between 0 and 10 deg of knee flexion, between 10 and 50 deg only the anterior bundle of the posterior cruciate ligament A-PCL was strained, and from 50 to 90 deg both the anteromedial portion of the anterior cruciate ligament A-ACL and the A-PCL were strained. This finding indicates that a strain distribution about a transverse cross section of the cruciates exists, and demonstrates the importance of differentiating between the strained and unstrained (unloaded) states of these ligaments. The strain value of a cruciate ligament bundle was an indication of how the bundle controls joint kinematics, while the unstrained values describe how much the ligament bundle must deform before it becomes strained and a restraint to tibiofemoral joint motion. In response to anterior and posterior directed loads, applied parallel to the tibial plateau, the respective, ACL and PCL load values were larger in magnitude. The sensitivity of the model outputs to the input parameters was highly dependent on knee flexion angle. The geometrical input parameters of the model (including the ligament insertion site locations and articular surface geometry) had the most pronounced effect on the model output quantities, while the stiffness and initial strain conditions of the ligament bundles had less of an effect on the model outputs. When loaded, the strain values of the ligament bundles were sensitive to the ligament insertion site position. The greatest sensitivity of the model outputs was the femoral insertion of the ACL; supporting clinical impressions and previous experimental findings. Changes in the anterior-posterior dimension of the femoral articular surface did not produce a substantial effect on the model outputs, while changes in the proximal-distal dimension created a large effect; similar results were found for the tibial surface dimensions. These findings indicate that rigid body contact between the articular surfaces may not be a realistic assumption particularly with application to the prediction of tibiofemoral compressive loading and the force/strain values of the cruciate ligament elements. This also has important implications for the design and clinical application of total knee replacements (that function as rigid bodies), particularly those that spare the PCL.

Anterior Cruciate Ligament↗
PubMed1997

Uncertainty and sensitivity analysis of the basic reproductive rate. Tuberculosis as an example.

The basic reproductive rate (R0) is a measure of the severity of an epidemic. On the basis of replicated Latin hypercube sampling, the authors performed an uncertainty and sensitivity analysis of the basic reproductive rate of tuberculosis (TB). The uncertainty analysis allowed for the derivation of a frequency distribution for R0 and the assessment of the relative contribution each of the three components of R0 made when TB epidemics first arose centuries ago. (The three components of R0 are associated with fast, slow, and relapse TB.) R0 estimates indicated the existence of fairly severe epidemics when TB epidemics first arose. The R0 for the susceptible persons who developed TB slowly (R0(slow)) contributed the most to the R0 estimates; however, the relative R0(slow) contribution decreased as the severity of TB epidemics increased. The sensitivity of the magnitude of R0 to the uncertainty in estimating values of each of the input parameters was assessed. These results indicated that five of the nine input parameters, because of their estimation uncertainty, were influential in determining the magnitude of R0. This uncertainty and sensitivity methodology provides results that can aid investigators in understanding the historical epidemiology of TB by quantifying the effect of the transmission processes involved. Additionally, this method can be applied to the R0 of any other infectious disease to estimate the probability of an epidemic outbreak.

Adult↗
PubMed1995

Parametric sensitivity analysis of avian pancreatic polypeptide (APP).

Computer simulations utilizing a classical force field have been widely used to study biomolecular properties. It is important to identify the key force field parameters or structural groups controlling the molecular properties. In the present paper the sensitivity analysis method is applied to study how various partial charges and solvation parameters affect the equilibrium structure and free energy of avian pancreatic polypeptide (APP). The general shape of APP is characterized by its three principal moments of inertia. A molecular dynamics simulation of APP was carried out with the OPLS/Amber force field and a continuum model of solvation energy. The analysis pinpoints the parameters which have the largest (or smallest) impact on the protein equilibrium structure (i.e., the moments of inertia) or free energy. A display of the protein with its atoms colored according to their sensitivities illustrates the patterns of the interactions responsible for the protein stability. The results suggest that the electrostatic interactions play a more dominant role in protein stability than the part of the solvation effect modeled by the atomic solvation parameters.

Animals↗
PubMed2001

Sensitivity analysis for nonrandom dropout: a local influence approach.

Diggle and Kenward (1994, Applied Statistics 43, 49-93) proposed a selection model for continuous longitudinal data subject to nonrandom dropout. It has provoked a large debate about the role for such models. The original enthusiasm was followed by skepticism about the strong but untestable assumptions on which this type of model invariably rests. Since then, the view has emerged that these models should ideally be made part of a sensitivity analysis. This paper presents a formal and flexible approach to such a sensitivity assessment based on local influence (Cook, 1986, Journal of the Royal Statistical Society, Series B 48, 133-169). The influence of perturbing a missing-at-random dropout model in the direction of nonrandom dropout is explored. The method is applied to data from a randomized experiment on the inhibition of testosterone production in rats.

Animals↗
PubMed2002

Decision-tree sensitivity analysis for cost-effectiveness of whole-body FDG PET in the management of patients with non-small-cell lung carcinoma in Japan.

BACKGROUND: Whole-body 2-fluoro-2-D-[18F]deoxyglucose [FDG] positron emission tomography (WB-PET) may be more cost-effective than chest PET because WB-PET does not require conventional imaging (CI) for extrathoracic staging. METHODS: The cost-effectiveness of WB-PET for the management of Japanese patients with non-small-cell lung carcinoma (NSCLC) was assessed. Decision-tree sensitivity analysis was designed, based on the two competing strategies of WB-PET vs. CI. WB-PET was assumed to have a sensitivity and specificity for detecting metastases, of 90% to 100% and CI of 80% to 90%. The prevalences of M1 disease were 34% and 20%. One thousand patients suspected of having NSCLC were simulated in each strategy. We surveyed the relevant literature for the choice of variables. Expected cost saving (CS) and expected life expectancy (LE) for NSCLC patients were calculated. RESULTS: The WB-PET strategy yielded an expected CS of $951 US to $1,493US per patient and an expected LE of minus 0.0246 years to minus 0.0136 years per patient for the 71.4% NSCLC and 34% M1 disease prevalence at our hospital. PET avoided unnecessary bronchoscopies and thoracotomies for incurable and benign diseases. Overall, the CS for each patient was $833US to $2,010US at NSCLC prevalences ranging from 10% to 90%. The LE of the WB-PET strategy was similar to that of the CI strategy. The CS and LE minimally varied in the two situations of 34% and 20% M1 disease prevalence. CONCLUSIONS: The introduction of a WB-PET strategy in place of CI for managing NSCLC patients is potentially cost-effective in Japan.

Algorithms↗
PubMed1999

Microwave imaging using the finite-element method and a sensitivity analysis approach.

A method for reconstructing the constitutive parameters of two-dimensional (2-D) penetrable scatterers from scattered field measurements is presented. This method is based on the differential formulation of the forward scattering problem, which is solved by applying the finite-element method (FEM). Given a set of scattered field measurements, the objective is to minimize a cost function which consists of two terms. The first is the standard error term, which is related to the measurements and their estimates, while the second term, which is related to the Tikhonov regularization, is used to heal the ill posedness of the inverse problem. The iterative Polak-Ribière nonlinear conjugate gradient algorithm is applied to the minimization of the cost function. During each iteration of the algorithm, the direction of correction is computed by using a sensitivity analysis approach, which is carried out by an elaborate finite-element scheme. The adoption of the finite-element method results in sparse systems of equations, while the computational burden is further reduced by applying the adjoint state vector methodology. Finally, a microwave medical imaging application, which is related to the detection of proliferated bone marrow, is examined, while the robustness of the proposed technique in the presence of noise and for different regularization levels is investigated.

Bone Marrow↗
PubMed2006

Determination of protection zones for Dutch groundwater wells against virus contamination--uncertainty and sensitivity analysis.

Protection zones of shallow unconfined aquifers in The Netherlands were calculated that allow protection against virus contamination to the level that the infection risk of 10(-4) per person per year is not exceeded with a 95% certainty. An uncertainty and a sensitivity analysis of the calculated protection zones were included. It was concluded that protection zones of 1 to 2 years travel time (206-418 m) are needed (6 to 12 times the currently applied travel time of 60 days). This will lead to enlargement of protection zones, encompassing 110 unconfined groundwater well systems that produce 3 x 10(8) m3 y(-1) of drinking water (38% of total Dutch production from groundwater). A smaller protection zone is possible if it can be shown that an aquifer has properties that lead to greater reduction of virus contamination, like more attachment. Deeper aquifers beneath aquitards of at least 2 years of vertical travel time are adequately protected because vertical flow in the aquitards is only 0.7 m per year. The most sensitive parameters are virus attachment and inactivation. The next most sensitive parameters are grain size of the sand, abstraction rate of groundwater, virus concentrations in raw sewage and consumption of unboiled drinking water. Research is recommended on additional protection by attachment and under unsaturated conditions.

Models, Biological↗
PubMed2005

Are the acute effects of particulate matter on mortality in the National Morbidity, Mortality, and Air Pollution Study the result of inadequate control for weather and season? A sensitivity analysis using flexible distributed lag models.

Time-series studies have linked daily variations in nonaccidental deaths with daily variations in ambient particulate matter air pollution, while controlling for qualitatively larger influences of weather and season. Although time-series analyses typically include nonlinear terms for weather and season, questions remain as to whether models to date have completely controlled for these important predictors. In this paper, the authors use two flexible versions of distributed lag models to control extensively for the confounding effects of weather and season. One version builds on the current approach to controlling for weather, while the other version offers a new approach. The authors conduct a comprehensive sensitivity analysis of the particulate matter-mortality relation by applying these methods to the recently updated National Morbidity, Mortality, and Air Pollution Study database that comprises air pollution, weather, and mortality time series from 1987 to 2000 for 100 US cities. They combine city-specific estimates of the short-term effects of particulate matter on mortality using a Bayesian hierarchical model. They conclude that, within the broad classes of models considered, national average estimates of particulate matter relative risk are consistent with previous estimates from this study and are robust to model specification for weather and seasonal confounding.

Aged↗
PubMed1986

A sensitivity analysis of the Thermal Pulse Decay method for measurement of local tissue conductivity and blood perfusion.

The Thermal Pulse Decay (TPD) method for the determination of local tissue thermal conductivity and blood perfusion rate is based on a comparison of measured with theoretically calculated temperatures. A sensitivity analysis of the theoretical model is performed. This analysis supports the establishment of an experimental protocol which reduces the measurement errors: An "optimal" measurement time interval for typical perfusion rates (up to 6 mL/mL/min) was found to be between 3 and 11 s after the heat pulse is turned off. Within this interval, the maximum error in determination of tissue conductivity and blood perfusion caused by experimental measurement errors is expected not to exceed 5 percent. The presently chosen pulse duration of 3 s is in agreement with the analysis as a good compromise between accuracy and excessive tissue heating.

Humans↗