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PubMed1999

Sensitivity, functional analysis, and behavior genetics: a response to Freeman et al.

Freeman et al. (1998) asserted that sensitivity theory is circular, unsupported by empirical evidence, and represents an "either/or" decision in regard to applied behavior analysis. We reply by showing that sensitivities are objectively measured and that our theory permits testable predictions. Further, we briefly summarize the results of recent studies that support our theory, including investigations that link sensitivities to genes and challenging behavior. Finally, we reject the idea that sensitivity theory and functional analysis represent an "either/or" viewpoint and call again for research to integrate these approaches.

Behavioral Symptoms↗
PubMedDate not supplied

Industry-sponsored economic studies in critical and intensive care versus studies sponsored by nonprofit organizations.

The purpose of this analysis of health economic studies in the field of intensive and critical care was to investigate whether any relationship could be established between type of sponsorship and (1) type of economic analysis, (2) health technology assessed, (3) sensitivity analysis performed, (4) publication status, and (5) qualitative cost assessment. Using the terms critical care or intensive care, all health economics publications in the field of critical and intensive care were identified in the Health Economic Evaluations Database (HEED, Version 1995-2001) on the basis of sponsorship and comparative studies. This search yielded a total of 42 eligible articles. Their evaluations were prepared independently by 2 investigators on the basis of specific criteria. When evaluators disagreed, a third investigator provided a deciding evaluation. There was no statistically demonstrable relationship between types of sponsorship and sensitivity analysis performed, publication status, types of economic analysis, or qualitative cost assessment.

Cost Control↗
PubMed2003

Industry-sponsored economic studies in oncology vs studies sponsored by nonprofit organisations.

The purpose of this analysis of health economic studies in the field of oncology was to investigate among sponsored studies whether any relationship could be established between the type of sponsorship and (1) type of economic analysis, (2) health technology assessed, (3) sensitivity analysis performed, (4) publication status, and (5) qualitative conclusions about costs. The Health Economic Evaluations Database (HEED, version 1995-2000) was searched on the basis of oncological ICD-9 codes, sponsorship, and comparative studies. This search yielded a total of 150 eligible articles. Their evaluations were prepared independently by two investigators, on the basis of specific criteria. When evaluators disagreed, a third investigator provided a deciding evaluation. There was no statistically significant relationship between the type of sponsorship and sensitivity analysis performed (P=0.29) or publication status (P=0.08). However, we found a significant relationship between the types of sponsorship and of economic analysis (P=0.004), the health technology assessed (P<0.0001), and qualitative cost assessment (P=0.002). Studies with industrial sponsorship were 2.56 (99% lower confidence interval (CI)=1.28) times more likely to involve cost-minimisation analyses, were 0.04 (99% higher CI=0.39) times less likely to investigate diagnostic screening methods, and were 1.86 (99% lower CI=1.21) times more likely to reach positive qualitative conclusions about costs than studies supported by nonprofit organisations. In conclusion, our results suggest that there is a greater probability that industry-sponsored economic studies in the field of oncology tend to be cost-minimisation analyses, to investigate less likely diagnostic screening methods, and to draw positive qualitative conclusions about costs, as compared to studies supported by nonprofit organisations.

Conflict of Interest↗
PubMed1984

Sensitive quantitative analysis of disulfide bonds in polypeptides and proteins.

A sensitive quantitative method has been developed to determine the number of disulfide bonds in peptides and proteins. The disulfide bonds of several peptides and proteins were cleaved quantitatively by excess sodium sulfite at pH 9.5 and room temperature. Guanidine thiocyanate (2 M) was added to the protein solutions in order to denature them and thereby make the disulfide bonds accessible. The reaction with sulfite leads to a thiosulfonate and a free sulfhydryl group; the concentration of the latter was determined by reaction with disodium 2-nitro-5-thiosulfobenzoate (NTSB) in the presence of excess sodium sulfite. The synthesis, purification, and characterization of NTSB are described. The assay is rapid, requiring 3-5 min for oligopeptides and 20 min for proteins, and is as sensitive and quantitative as the sulfhydryl group assay employing 5,5'-dithiobis(2-nitrobenzoic acid) (Ellman's reagent). It can be used for the analysis of as little as 10(8) mol of disulfide bonds, with an error of +/- 3%.

Chemical Phenomena↗
PubMed2000

Issues involved in a metaanalysis of rheumatoid arthritis radiographic progression. Analysis issues.

Missing data in controlled clinical trials may create uncertainty in the results of a study based on non-missing data. We used 4 approaches of sensitivity analysis to address this problem. Radiographic progression data were used from a randomized controlled trial of patients with rheumatoid arthritis treated with leflunomide, methotrexate, or placebo for 12 months as an example. The mean change from baseline of the Sharp total radiographic score was the primary efficacy variable for the evaluation of leflunomide in comparison with placebo in the retardation of radiographic progression. Computer simulations were used in some of these approaches. The proportion of missing radiographic data was 26.4%. Result from the non-missing data showed that leflunomide was highly statistically significantly better than placebo in the retardation of radiographic progression. Results from the sensitivity analysis showed that radiographic data are sufficiently robust that it is unlikely that the missing data would have changed the conclusions from the analysis based on non-missing data. The potential effect of missing data in the results of a clinical trial may be addressed by various methods of sensitivity analysis. Computer simulation can be a useful tool in some of these approaches.

Arthritis, Rheumatoid↗
PubMed2005

An investigation into the inputs controlling predictions from a diffuse phosphorus loss model for the UK; the Phosphorus Indicators Tool (PIT).

A simple catchment scale model simulating diffuse phosphorus (P) loss from agricultural land to water, the Phosphorus Indicators Tool (PIT), has been developed. Previous research has shown that this model worked well in simulating the average annual P lost from two catchments: Windermere and Windrush, but it was not known which drivers in the model had the greatest control on predicted P delivery to water from agricultural land. In order to simulate the P export from each catchment source via each hydrological pathway specified individually, 108 coefficients are used in the model code. A univariate sensitivity analysis was conducted to evaluate which coefficient exerted the greatest control on the model output. Results from the univariate analysis suggest that the model is sensitive to a number of coefficients, but importantly, not all of the coefficients that were varied in the sensitivity analysis, altered the model output. The PIT model has been calibrated by optimizing results from the univariate analysis against observed data in the Windermere catchment. The simulated results from model calibration fit the observed data well, at the 95% level. This paper describes the methodology developed for the univariate analysis and evaluates the model calibration procedure against observed data from the Windermere catchment.

Agriculture↗
PubMed1997

Measuring sensitivity in pharmacoeconomic studies. An integration of point-sensitivity and range-sensitivity.

The level of uncertainty with regard to the outcomes of pharmacoeconomic studies cannot be completely covered by the statistical methods routinely employed to handle uncertainty in clinical research. Sensitivity analysis is the most common methodology to deal with the extra uncertainty associated with pharmacoeconomics, and has also been incorporated in recent guidelines on healthcare evaluation. However, the execution of a sensitivity analysis and the interpretation of its results have not yet been standardised, which may lead to subjectivity and consequently weaken the value of economic evaluations. This article presents a method of dealing more systematically with uncertainty and eliminating potential bias in sensitivity analysis, with regard to the measurement of sensitivity and the comparison of the degree of sensitivity between variables. An assessment of the disadvantages of using slope as a measure of sensitivity leads to 2 types of sensitivity analyses (point-sensitivity and range-sensitivity), which are integrated into one method for the measurement of sensitivity.

Economics, Pharmaceutical↗
PubMed2002

Laparoscopic versus open retroperitoneal lymph node dissection: a cost analysis.

PURPOSE: Laparoscopic retroperitoneal lymph node dissection is significantly less morbid than open retroperitoneal lymph node dissection but it is generally more costly due to longer operative time and disposable equipment. In response to budgetary pressure at our large county hospital we identified the cost components of laparoscopic retroperitoneal lymph node dissection that could be targeted to decrease procedure costs before expanding our laparoscopic retroperitoneal lymph node dissection program. MATERIALS AND METHODS: A comprehensive literature review of open and laparoscopic retroperitoneal lymph node dissection was performed and certain parameters were abstracted, including operative time and equipment, hospital stay, perioperative complications and surgical success rates. Using these data the projected overall cost and individual cost centers at our institution were compared for open and laparoscopic retroperitoneal lymph node dissection. Decision tree analysis models were devised to estimate the cost of each treatment using commercially available software. We performed 1 and 2-way sensitivity analysis to evaluate the effect of individual treatment variables on overall cost. Base case analysis involved a young man with clinical stage I nonseminomatous testicular cancer who was a candidate for retroperitoneal lymph node dissection. RESULTS: Based on a review of the costs at our institution open retroperitoneal lymph node dissection was a less costly procedure at $7,162 versus $7,804 for the laparoscopic approach. The slight cost superiority of the open approach was due to significantly lower costs associated with operating room time and equipment. On the other hand, the laparoscopic procedure showed a cost advantage for hospital stay. On 1-way sensitivity analysis laparoscopic dissection was less costly when operative time was less than 3.6 hours, hospitalization was less than 2.2 days or laparoscopic equipment costs were less than $768. On 2-way sensitivity analysis the laparoscopic approach was cost advantageous when performed in less than 5 hours or when the patient was discharged home within 2 days postoperatively. CONCLUSIONS: The primary cost variables for surgical treatment for testicular cancer include operative time, hospital stay and equipment cost. According to published data and decision tree analysis open retroperitoneal lymph node dissection is slightly less costly (less than $650) than laparoscopic retroperitoneal lymph node dissection for the surgical treatment of clinical stage I nonseminomatous testicular cancer at our institution. Our model identifies several measures that can be applied at any institution to render laparoscopic retroperitoneal lymph node dissection economically superior to the open approach.

Adult↗
PubMedDate not supplied

Impact of model, methodological, and parameter uncertainty in the economic analysis of vaccination programs.

Guidelines for economic evaluations insist that the sensitivity of model results to alternative parameter values should be thoroughly explored. However, differences in model construction and analytical choices (such as the choice of a cost-effectiveness or cost-benefit framework) also introduce uncertainty in results, though these are rarely subjected to a thorough sensitivity analysis. In this article, the authors quantify the effect of model, methodological, and parameter uncertainty, taking varicella vaccination as an example. They used 3 different models (a static model, a dynamic model that only looks at the effect of vaccination on varicella, and a dynamic model that also assesses the implications of vaccination for zoster epidemiology) and 2 forms of analysis (cost-benefit and cost-utility). They also varied the discount rate and time frame of analysis. Probabilistic sensitivity analyses were performed to estimate the impact of parameter uncertainty. In their example, model and methodological choice had a profound effect on estimated cost-effectiveness, but parameter uncertainty played a relatively minor role. Under cost-utility analysis, the probabilistic sensitivity analysis suggested that there was a near certainty that vaccination dominates no vaccination, or the other way around, depending on model choice and perspective. Under cost-benefit analysis, vaccination always appeared to be attractive. Thus, the authors clearly show that model and methodological assumptions can have greater impact on results than parameter estimates, although sensitivity analyses are rarely performed on these sources of uncertainty.

Adolescent↗
PubMed1995

[Evaluation of the costs of mammographic screening program in the city of Florence].

This paper investigated differential direct costs determined by the difference between implementation of mammographic screening program for breast cancer detection in the city of Florence (PFD) and the "absence" of the PFD. The involved resources have been identified, quantified and evaluated. The results of the I round (1991/92) of the PFD involve the following different phases: invitations, mass screening, diagnostic assessment. Differential net costs aumonted to 780 million for total cost, and to 53,000 per screened woman. The PFD invited 27,325 women per year; at the I round, the PFD registered an attendance rate of 53.9% and a recall rate of 4.3%, with a total cost of about one thousand million and a cost per screened woman of about L. 64,000. Instead, economic results of alternative "absence" of screening registered a total cost of 170 million and a cost per screened woman of about L. 100,000. Costs for detected cancer amount about to 8.2 million for PFD and 5.7 million for "absence" of the Program. Sensitivity analysis has been performed texting the fundamental parameters of the PFD: attendance rate, recall rate and life time average of the investiments. The sensitivity analysis, performed on the PFD, registered a variation of total cost from 859 million to 1,216 million and a variation of the total cost per woman screened from L. 43,500 to L. 80,000. Sensitivity analysis results highlighted the fundamental role played by women's attendance and by the percentage of women recalled for diagnostic assessment.

Breast Neoplasms↗
PubMed1996

Cost evaluation of novel therapeutics in rheumatoid arthritis (CENTRA): a decision analysis model.

This study was performed to evaluate the potential costs of a hypothetical novel biological agent (BIO) as a therapy for rheumatoid arthritis (RA), compared with oral methotrexate (MTX) and intramuscular gold (IMG). A decision analysis model was used to compare the total costs of treating a cohort of 10,000 RA patients with each agent for 6 months. Total costs included direct costs and indirect costs. Baseline estimates were subjected to sensitivity analysis. Total costs per person were: MTX, $5,430; IMG, $6,725; BIO, $9,411. In sensitivity analysis, the primary cost drivers for MTX and IMG were the indirect costs of RA and monitoring costs. In contrast, total costs of the BIO were driven predominantly by medication costs. Sensitivity analysis showed, even when efficacy and safety were optimized, costs for the BIO still substantially exceeded those of MTX and IMG. Medication costs will be an important consideration in the development of novel BIOs for RA.

Antirheumatic Agents↗
PubMed2002

Management of ureteral calculi: a cost comparison and decision making analysis.

PURPOSE: We compared the cost of treatment strategies for ureteral calculi using a decision tree model. MATERIALS AND METHODS: A comprehensive literature review was performed to determine the average success rate of each of 3 treatment modalities, namely observation, ureteroscopy and shock wave lithotripsy. Using these success rates decision analysis models were constructed using Data 3.5 software (TreeAge Software, Inc., Williamstown, Massachusetts) to estimate the cost of treatment and followup for each of the 3 treatments. One-way sensitivity analysis was performed to evaluate the effect of varying individual probabilities of success and costs, and 2-way sensitivity analysis was done to evaluate the model for a wide range of potential costs and success rates of ureteroscopy and shock wave lithotripsy. In addition, a table was constructed to enable individual surgeons and institutions to determine the cost impact of ureteroscopy and shock wave lithotripsy in their unique clinical scenarios. RESULTS: Observation was the least costly pathway if no financial cost, such as emergency room visits, was incurred by failed observation. Ureteroscopy was less costly than shock wave lithotripsy for stones at all ureteral locations. A cost difference between the 2 modalities of approximately $1,440, $1,670 and $1,750 was noted for proximal, mid and distal ureteral calculi, respectively. One-way sensitivity analysis showed that the cost of ureteroscopy would have to increase by more than $1,400, $1,700 and $1,850, and the success rate would have to decrease by 28%, 36% and 39% for proximal, mid and distal stones, respectively, before reaching cost equivalence with shock wave lithotripsy. Likewise, the cost of shock wave lithotripsy would have to decrease by more than $1,489 to achieve cost equivalence with ureteroscopy. Overall ureteroscopy was more cost-effective at all stone sites regardless of the success rate of shock wave lithotripsy. CONCLUSIONS: Ureteroscopy is the most cost-effective treatment strategy for ureteral stones at all locations after observation fails. The high cost of purchasing and maintaining a lithotriptor is responsible for the high treatment cost associated with shock wave lithotripsy. However, cost is only one of a number of important factors that are considered when determining an appropriate treatment strategy.

Cost-Benefit Analysis↗
PubMed2006

Simplification and its consequences in biological modelling: conclusions from a study of calcium oscillations in hepatocytes.

Systems Biology requires that biological modelling is scaled up from small components to system level. This can produce exceedingly complex models, which obscure understanding rather than facilitate it. The successful use of highly simplified models would resolve many of the current problems faced in Systems Biology. This paper questions whether the conclusions of simple mathematical models of biological systems are trustworthy. The simplification of a specific model of calcium oscillations in hepatocytes is examined in detail, and the conclusions drawn from this scrutiny generalized. We formalize our choice of simplification approach through the use of functional 'building blocks'. A collection of models is constructed, each a progressively more simplified version of a well-understood model. The limiting model is a piecewise linear model that can be solved analytically. We find that, as expected, in many cases the simpler models produce incorrect results. However, when we make a sensitivity analysis, examining which aspects of the behaviour of the system are controlled by which parameters, the conclusions of the simple model often agree with those of the richer model. The hypothesis that the simplified model retains no information about the real sensitivities of the unsimplified model can be very strongly ruled out by treating the simplification process as a pseudo-random perturbation on the true sensitivity data. We conclude that sensitivity analysis is, therefore, of great importance to the analysis of simple mathematical models in biology. Our comparisons reveal which results of the sensitivity analysis regarding calcium oscillations in hepatocytes are robust to the simplifications necessarily involved in mathematical modelling. For example, we find that if a treatment is observed to strongly decrease the period of the oscillations while increasing the proportion of the cycle during which cellular calcium concentrations are rising, without affecting the inter-spike or maximum calcium concentrations, then it is likely that the treatment is acting on the plasma membrane calcium pump.

Animals↗
PubMed2005

A validated mathematical model of cell-mediated immune response to tumor growth.

Mathematical models of tumor-immune interactions provide an analytic framework in which to address specific questions about tumor-immune dynamics. We present a new mathematical model that describes tumor-immune interactions, focusing on the role of natural killer (NK) and CD8+ T cells in tumor surveillance, with the goal of understanding the dynamics of immune-mediated tumor rejection. The model describes tumor-immune cell interactions using a system of differential equations. The functions describing tumor-immune growth, response, and interaction rates, as well as associated variables, are developed using a least-squares method combined with a numerical differential equations solver. Parameter estimates and model validations use data from published mouse and human studies. Specifically, CD8+ T-tumor and NK-tumor lysis data from chromium release assays as well as in vivo tumor growth data are used. A variable sensitivity analysis is done on the model. The new functional forms developed show that there is a clear distinction between the dynamics of NK and CD8+ T cells. Simulations of tumor growth using different levels of immune stimulating ligands, effector cells, and tumor challenge are able to reproduce data from the published studies. A sensitivity analysis reveals that the variable to which the model is most sensitive is patient specific, and can be measured with a chromium release assay. The variable sensitivity analysis suggests that the model can predict which patients may positively respond to treatment. Computer simulations highlight the importance of CD8+ T-cell activation in cancer therapy.

Animals↗
PubMed2003

Feasibility and cost-effectiveness of sentinel lymph node radiolocalization in stage N0 head and neck cancer.

OBJECTIVES: To determine the feasibility of sentinal lymph node (SN) radiolocalization and to assess the cost-effectiveness of the SN navigation surgery strategy in patients with stage N0 squamous cell carcinoma (SCC) of the head and neck. Patients Eleven consecutive patients with stage N0 SCC of the head and neck. METHODS: Head and neck lymphoscintigraphy was performed 2 hours after the injection of technetium Tc 99m tin colloid or phytate. A handheld gamma probe was used to detect the SN before and directly after making a skin incision. Nodes were evaluated histopathologically for micrometastasis. To determine the expected cost savings, a decision tree sensitivity analysis was designed based on the 2 competing strategies: ipsilateral neck dissection vs SN navigation surgery. The costs referred to billed costs based on the Japanese national insurance reimbursement system. RESULTS: The sensitivity of SN navigation surgery in our series was 100% (11/11) on a patient-by-patient basis and 94% (17/18) on a node-by-node basis. Micrometastasis was found in 36% (4/11). Assuming the micrometastasis prevalence, sensitivity, and specificity of navigation surgery for detecting SN to be 30%, 90%, and 100%, respectively, the decision tree sensitivity analysis showed that introduction of SN navigation surgery in place of ipsilateral neck dissection would yield cost savings of $1218 (US) per stage N0 patient in Japan and avoid 7 surgical deaths per 1000 patients who are supposed to undergo neck dissection in the neck dissection strategy. Break-even point analysis for the SN navigation surgery strategy showed that the threshold value required more than 41 patients for the savings to begin to accrue. CONCLUSION: Our results indicate that SN navigation surgery using radiolocalization is feasible and cost-effective, based on decision tree sensitivity analysis, in patients with stage N0 SCC of the head and neck.

Adult↗
PubMed2003

Thermodynamic and kinetic analysis of sensitivity amplification in biological signal transduction.

Based on a thermodynamic analysis of the kinetic model for the protein phosphorylation-dephosphorylation cycle, we study the ATP (or GTP) energy utilization of this ubiquitous biological signal transduction process. It is shown that the free energy from hydrolysis inside cells, DeltaG (phosphorylation potential), controls the amplification and sensitivity of the switch-like cellular module; the response coefficient of the sensitivity amplification approaches the optimal 1 and the Hill coefficient increases with increasing DeltaG. We discover that zero-order ultrasensitivity is mathematically equivalent to allosteric cooperativity. Furthermore, we show that the high amplification in ultrasensitivity is mechanistically related to the proofreading kinetics for protein biosynthesis. Both utilize multiple kinetic cycles in time to gain temporal cooperativity, in contrast to allosteric cooperativity that utilizes multiple subunits in a protein.

Allosteric Regulation↗
PubMed1993

Parameter sensitivity of a model of viral epidemics simulated with Monte Carlo techniques. I. Illness attack rates.

This is the first of a series of papers concerning sensitivity analyses of stochastic micropopulation models. A model of epidemic spread of viral infection is used in this series to illustrate the principles and performance of the sensitivity analysis system. For these studies the analysis system now known as SENSEN was redesigned and extended to use the principles and modules of the SUMMERS simulation shell. The latter was used in the implementation of the epidemic model as well as a number of others. The SENSEN system can be used with any of these. The advantages of sensitivity analysis for stochastic micropopulation models are discussed. Its general form and operation are illustrated by a comparison of illness attack rates with infection attack rates.

Adult↗
PubMed2002

Cost-effectiveness of Helicobacter pylori eradication therapy at a company occupational health clinic in Japan.

Peptic ulcer disease (PUD) is a common disorder that follows a chronically relapsing course. Many clinical trials have proven the efficacy of H2-blockers in the long-term management of chronic relapsing PUD. On the other hand, 30% of patients with duodenal ulcer (DU) receiving maintenance therapy with H2-blockers experience ulcer recurrence yearly. Helicobacter pylori (H. pylori) is now recognized as the major cause of PUD. We estimated the cost-effectiveness of H. pylori eradication in comparison to maintenance therapy with H2-blocker in a 1-year period at a company occupational health clinic. Ninety-nine with PUD tested for H. pylori were positive. Forty-nine patients received H. pylori eradication, and the remaining 50 patients were treated with ranitidine (RAN) 150 mg for 1 year according to their demands. H. pylori was successfully eradicated in 42 patients (86%), and 41 (98%) of these 42 patients remained free of symptoms for the remainder of the study period. The lifetable probability of ulcer recurrence during 1 year was significantly lower for patients who received eradication (6.1%) compared with those who received RAN alone (24.0%). The total cost for H. pylori eradication was lower than that for maintenance therapy along our study design (102,664 yen vs 150,356 yen). A decision tree was illustrated and the total cost were calculated by using sensitivity analysis. When we used baseline probabilities in sensitivity analysis, the total cost for eradication was lower than that for maintenance therapy (104,647 yen vs 154,468 yen). H. pylori eradication is cost-effective therapy for patients with PUD in comparison to maintenance therapy with RAN at an on-site occupational health clinic in Japan.

Adult↗