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PubMed2003

Reduced dietary salt for prevention of cardiovascular disease.

BACKGROUND: Restricting sodium intake in elevated blood pressure over short periods of time reduces blood pressure. Long term effects (on mortality, morbidity or blood pressure) of advice to reduce salt in patients with elevated or normal blood pressure are unclear. OBJECTIVES: To assess in adults the long term effects (mortality, cardiovascular events, blood pressure, quality of life, weight, urinary sodium excretion, other nutrients and use of anti-hypertensive medications) of advice to restrict dietary sodium using all relevant randomised controlled trials. SEARCH STRATEGY: The Cochrane Library, MEDLINE, EMBASE, bibliographies of included studies and related systematic reviews were searched for unconfounded randomised trials in healthy adults aiming to reduce sodium intake over at least 6 months. Attempts were made to trace unpublished or missed studies and authors of all included trials were contacted. There were no language restrictions. SELECTION CRITERIA: Inclusion decisions were independently duplicated and based on the following criteria: 1) randomisation was adequate; 2) there was a usual or control diet group; 3) the intervention aimed to reduce sodium intake; 4) the intervention was not multifactorial; 5) the participants were not children, acutely ill, pregnant or institutionalised; 6) follow-up was at least 26 weeks; 7) data on any of the outcomes of interest were available. DATA COLLECTION AND ANALYSIS: Decisions on validity and data extraction were made independently by two reviewers, disagreements were resolved by discussion or if necessary by a third reviewer. Random effects meta-analysis, sub-grouping, sensitivity analysis and meta-regression were performed. MAIN RESULTS: Three trials in normotensives (n=2326), five in untreated hypertensives (n=387) and three in treated hypertensives (n=801) were included, with follow up from six months to seven years. The large, high quality (and therefore most informative) studies used intensive behavioural interventions. Deaths and cardiovascular events were inconsistently defined and reported; only 17 deaths equally distributed between intervention and control groups occurred. Systolic and diastolic blood pressures were reduced at 13 to 60 months in those given low sodium advice as compared with controls (systolic by 1.1 mm Hg, 95% CI 1.8 to 0.4, diastolic by 0.6 mm hg, 95% CI 1.5 to -0.3), as was urinary 24 hour sodium excretion (by 35.5 mmol/ 24 hours, 95% CI 47.2 to 23.9). Degree of reduction in sodium intake and change in blood pressure were not related. People on anti-hypertensive medications were able to stop their medication more often on a reduced sodium diet as compared with controls, while maintaining similar blood pressure control. REVIEWER'S CONCLUSIONS: Intensive interventions, unsuited to primary care or population prevention programmes, provide only minimal reductions in blood pressure during long-term trials. Further evaluations to assess effects on morbidity and mortality outcomes are needed for populations as a whole and for patients with elevated blood pressure. Evidence from a large and small trial showed that a low sodium diet helps in maintenance of lower blood pressure following withdrawal of antihypertensives. If this is confirmed, with no increase in cardiovascular events, then targeting of comprehensive dietary and behavioural programmes in patients with elevated blood pressure requiring drug treatment would be justified.

Antihypertensive Agents↗

PubMed1987

Analysis of p60v-src mutants carrying lesions involved in temperature sensitivity.

Analysis of the src genes of three temperature-sensitive (ts) mutants of Rous sarcoma virus (tsNY68, tsNY72-4, and PA104) showed that each has two C-terminal mutations in the kinase domain required for temperature sensitivity, as assayed by morphological alteration and anchorage-independent growth. In all three mutants, one of the mutations is a valine-to-methionine change at position 461. To assess the contribution of each mutation to the biochemical properties of the src protein, we analyzed the kinase activity and the interaction with cellular proteins p50 and p90 of recombinant src gene products in which only one mutation was combined with wild-type src sequences. Chimeric src protein containing only the Met-461 mutation was indistinguishable from the wild type by all criteria examined, while the effect of the second C-terminal mutation alone varied with the defectiveness of the parental ts mutant. The second mutation alone, while not sufficient to cause ts transformation, altered p60src complex formation with cellular proteins p50 and p90 and altered the in vitro thermolability of src kinase activity. The results indicate that these biochemical properties of p60src are more sensitive to mutation than others, such as in vivo kinase activity, which require more profound structural alterations.

Animals↗

PubMed2002

Benefit-cost analysis of addiction treatment: methodological guidelines and empirical application using the DATCAP and ASI.

OBJECTIVE: To provide detailed methodological guidelines for using the Drug Abuse Treatment Cost Analysis Program (DATCAP) and Addiction Severity Index (ASI) in a benefit-cost analysis of addiction treatment. DATA SOURCES/STUDY SETTING: A representative benefit-cost analysis of three outpatient programs was conducted to demonstrate the feasibility and value of the methodological guidelines. STUDY DESIGN: Procedures are outlined for using resource use and cost data collected with the DATCAP. Techniques are described for converting outcome measures from the ASI to economic (dollar) benefits of treatment. Finally, principles are advanced for conducting a benefit-cost analysis and a sensitivity analysis of the estimates. DATA COLLECTION/EXTRACTION METHODS: The DATCAP was administered at three outpatient drug-free programs in Philadelphia, PA, for 2 consecutive fiscal years (1996 and 1997). The ASI was administered to a sample of 178 treatment clients at treatment entry and at 7-months postadmission. PRINCIPAL FINDINGS: The DATCAP and ASI appear to have significant potential for contributing to an economic evaluation of addiction treatment. The benefit-cost analysis and subsequent sensitivity analysis all showed that total economic benefit was greater than total economic cost at the three outpatient programs, but this representative application is meant to stimulate future economic research rather than justifying treatment per se. CONCLUSIONS: This study used previously validated, research-proven instruments and methods to perform a practical benefit-cost analysis of real-world treatment programs. The study demonstrates one way to combine economic and clinical data and offers a methodological foundation for future economic evaluations of addiction treatment.

Ambulatory Care↗

PubMed2000

When is pelvic lymph node dissection necessary before radical prostatectomy? A decision analysis.

PURPOSE: In recent years the role of pelvic lymph node dissection before or at radical prostatectomy has been questioned. We compared the outcome of performing or omitting pelvic lymph node dissection in patients undergoing radical retropubic prostatectomy by formal decision analysis. MATERIALS AND METHODS: We created a decision tree for patients undergoing radical retropubic prostatectomy that accounts for all possible branch points and outcomes. Outcome probabilities applied to the model were derived from published data. Utility values were determined for each outcome state by a panel of experts. Decision analysis was done using decision analysis computer software. Sensitivity analysis was performed to determine which elements in the model were most important and to calculate threshold values. RESULTS: Using probability data from the literature and our assigned outcome values, decision analysis initially favored omitting pelvic lymph node dissection. Sensitivity analysis revealed that the threshold values for the incidence of positive lymph nodes and the sensitivity of lymph node dissection and frozen section analysis at which outcomes were equivalent were 18% and 80%, respectively. Analysis was insensitive to the pelvic lymph node dissection complication rate. CONCLUSIONS: We performed formal decision analysis to determine the incidence of lymph node metastasis below which pelvic lymph node dissection is not warranted at radical retropubic prostatectomy. Our results suggest that lymph node dissection is unnecessary in the subset of patients in which the risk of lymph node involvement is less than 18%.

Decision Support Techniques↗

PubMed2005

Efficient pipeline for image-based patient-specific analysis of cerebral aneurysm hemodynamics: technique and sensitivity.

Hemodynamic factors are thought to be implicated in the progression and rupture of intracranial aneurysms. Current efforts aim to study the possible associations of hemodynamic characteristics such as complexity and stability of intra-aneurysmal flow patterns, size and location of the region of flow impingement with the clinical history of aneurysmal rupture. However, there are no reliable methods for measuring blood flow patterns in vivo. In this paper, an efficient methodology for patient-specific modeling and characterization of the hemodynamics in cerebral aneurysms from medical images is described. A sensitivity analysis of the hemodynamic characteristics with respect to variations of several variables over the expected physiologic range of conditions is also presented. This sensitivity analysis shows that although changes in the velocity fields can be observed, the characterization of the intra-aneurysmal flow patterns is not altered when the mean input flow, the flow division, the viscosity model, or mesh resolution are changed. It was also found that the variable that has the greater impact on the computed flow fields is the geometry of the vascular structures. We conclude that with the proposed modeling pipeline clinical studies involving large numbers cerebral aneurysms are feasible.

Algorithms↗

PubMed2006

Cost-minimization analysis of a phase III trial comparing concurrent versus sequential radiochemotherapy for locally advanced non-small-cell lung cancer (GFPC-GLOT 95-01).

BACKGROUND: We conducted an economic analysis of a phase III clinical trial comparing sequential radiochemotherapy (RT-CT) with concurrent RT-CT in patients with locally advanced non-small-cell lung cancer. PATIENTS AND METHODS: The trial was a randomized multicenter study comparing three cycles of chemotherapy (arm A) followed by radiotherapy against an RT-CT combination (two cycles of platinum etoposide) followed by two cycles of platinum-vinorelbine (arm B). The economic analysis adopted the payer's perspective and only included direct costs. Costs (euro, 1996-2003) were recorded until the cut-off date. A cost minimization analysis and a sensitivity analysis were carried out. RESULTS: Data from 173 patients were used in the economic study. Protocol costs tended to be higher in arm B, while relapse costs were significantly higher in arm A. The total number of hospital days was higher in arm B. The average total cost per patient was euro16,074 in arm A and euro15,245 in arm B (P=0.15). The cost minimization analysis favored arm B. This advantage persisted in the sensitivity analysis. CONCLUSIONS: Concurrent RT-CT was not the more costly strategy in this phase III trial, despite lengthier hospitalization for toxicity. Other studies of similar design are needed to confirm these results in future randomized trials.

Adolescent↗

PubMed2005

Automated oncogene detection in complex protein networks with applications to the MAPK signal transduction pathway.

Activation of the extracellular signal-regulated kinases (ERK1/2; p42/p44 mitogen-activated protein kinase (MAPK)) is one of the most extensively studied signaling pathways not least because it occurs downstream of oncogenic RAS. Here, we take advantage of the wealth of experimental data available on the canonical RAS/RAF/MEK/ERK pathway of Bhalla et al. to test the utility of a newly developed nonlinear analysis algorithm designed to predict likelihood of cellular transformation. By using ERK phosphorylation as an "output signal", the method analyzes experimentally determined kinetic data and predicts putative oncogenes and tumor suppressor gene products impacting the RAS/MAPK module using a purely theoretical approach. This analysis identified several modifiers of ERK/MAPK activation described previously. In addition, several novel enzymes are identified which are not previously described to affect ERK/MAPK phosphorylation. Importantly, the nonlinear analysis enables a ranking of modifiers of MAPK activation predicting their relative importance in RAS-dependent oncogenesis. The results are compared with a linearized analysis based on sensitivity analysis about the steady state or metabolic control analysis (MCA). The results are favorable, pointing to the utility of first-order sensitivity analysis and MCA in the analysis of complex signaling networks for oncogenes.

Automation↗

PubMed2004

Cost-minimization analysis of two algorithms for diagnosing acute pulmonary embolism.

INTRODUCTION: Pulmonary embolism is a common disorder that often requires extensive diagnostic testing. We hypothesized that an algorithmic approach to diagnosis of pulmonary embolism based upon clinical risk stratification and D-dimer testing would be less costly than a standard approach. MATERIALS AND METHODS: We constructed a decision tree based upon two published algorithms for diagnosing acute pulmonary embolism. Branch point probabilities were obtained from the best available published literature. Costs were based upon Medicare charges. From this we obtained a base-case analysis and conducted sensitivity analysis. RESULTS: Our base-case analysis revealed that the cost-per-patient for diagnostic testing were US$216.52 for the algorithm based upon pre-test probability and D-dimer testing and US$538.62 for the standard algorithm. The cost difference per patient evaluated was US$322.10. One- and two-way sensitivity analyses did not reveal any instances in which the clinical risk algorithm was more costly than the standard algorithm. Two-way sensitivity analysis revealed several scenarios in which the standard algorithm would be less costly; however, the conditions required for these scenarios are rarely encountered in clinical practice. CONCLUSIONS: Costs of testing using an algorithm based on clinical pre-test probability and D-dimer testing are less than with a standard approach for evaluating suspected acute pulmonary embolism. This new algorithm has previously been shown to be safe and has the potential for large cost savings if widely applied.

Algorithms↗

PubMed2003

Cost analysis of ropinirole versus levodopa in the treatment of Parkinson's disease.

BACKGROUND: Not all patients with Parkinson's disease (PD) respond to levodopa and others develop dyskinesias. Ropinirole, a dopamine agonist, is associated with fewer dyskinesias than levodopa. OBJECTIVE: To examine the economic impact of reducing dyskinesias using ropinirole instead of levodopa plus benserazide in PD was examined. The research question addressed was: is the added cost of ropinirole offset by savings due to avoided cases of dyskinesia? METHODS: A cost-minimisation analysis was performed from both the societal and Ministry of Health (MoH) of Ontario, Canada perspectives, using 5-year data from a study of dyskinesia outcomes comparing ropinirole with levodopa plus benserazide. A predictive model was developed to capture resource utilisation over 5 years, such as medication costs, medical consultations, hospital admissions, nursing home admissions, caregiver time and productivity loss. The model was based on a previously reported clinical trial which determined dyskinesia rates to be 20% for ropinirole and 45% for levodopa. Standard costing lists were used, and costs were discounted at various rates. Constant 1999 Canadian dollars ($Can) were applied, and no increases were assumed over the time horizon of the analysis. A multivariate sensitivity analysis with changes in key parameters was also performed. RESULTS: From a societal perspective, ropinirole was cost saving. From the MoH perspective, the analysis yielded an incremental expected daily cost/patient of $Can4.41 for substituting levodopa plus benserazide with ropinirole. Ropinirole resulted in daily savings/patient of $Can0.17 in non-drug healthcare costs. In the sensitivity analysis, the direction of results did not change despite changes of 15 to 20% in key parameters, suggesting robustness of the model. CONCLUSIONS: From the societal perspective, in comparison with levodopa plus benserazide, the added cost of ropinirole is offset by savings due to avoided cases of dyskinesia.

Adult↗

PubMed1995

Cost-benefit analysis of screening for toxoplasmosis during pregnancy.

Congenital toxoplasmosis is a risk for fetus both in 'low' and 'high risk' areas. A cost-benefit analysis based on data from a Finnish prospective study (20.3% seropositivity of pregnant mothers and incidence of 2.4/1,000 seronegative pregnancies) and on Finnish cost data was performed to compare the no-screening and screening alternatives for primary toxoplasma infections during pregnancy. A maternal-feto transmission risk of 40%, effectiveness of treatment of 50%, and discount rate of 4% were used as other baseline probabilities. The calculations were carried out by decision analysis combined with sensitivity analysis. The total annual costs of congenital toxoplasmosis without screening amount to US$ 128/pregnancy/year, and with systematic serological screening, US$ 95/pregnancy. Thus screening reduces the costs by 25%. The present value of net savings in Finland would be US$ 2.1 million every year. A one-way sensitivity analysis showed that screening together with health education is preferable to health education without screening if the incidence of maternal primary infections exceeds 1.1/1,000 and effectiveness of treatment is better than 22.1%. Screening for toxoplasma infections during pregnancy is economically worthwhile even in a country with a low incidence. A scheme of systematic screening for maternal primary toxoplasma infections combined with health education should be considered.

Cost-Benefit Analysis↗

PubMed2024

Causal effect of the age at first birth with depression: a mendelian randomization study.

BACKGROUND: This study aimed to explore the causal relationship between age at first birth (AFB) and depression. METHODS: Using the univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) methods to examine the potential correlation between age at first birth (AFB) and major depressive disorder and postpartum depression. A public database was used to obtain the genome-wide association studies (GWAS) summary data. We put inverse-variance-weighted (IVW) as the primary method in Mendelian randomization (MR) analysis and used sensitivity analysis to confirm the robustness of our result. RESULTS: We found a significant causal association between AFB and major depressive disorder by using the IVW algorithm (odd ratio [OR] 0.826; 95% confidence interval [CI] 0.793 - 0.861; P = 4.51 × 10- 20). MR-Egger, weighted median, simple mode and weighted mode method concluded the same result (P < 0.05). During the sensitivity analysis, the heterogeneity test (Q-value = 55.061, df = 48, P = 2.81 × 10- 01, I2 = 12.82%) and the leave-one-out plot analysis confirmed the stability of the results. The outcomes of the pleiotropy test (MR-Egger intercept = 8.932 × 10- 3. SE = 6.909 × 10- 3. P = 2.02 × 10- 01) and MR_PRESSO global test (P = 2.03 × 10- 01) indicated there is no pleiotropy. CONCLUSION: There is solid evidence that a higher age at first birth is associated with a lower risk of major depressive disorder.

Humans↗

PubMed2001

Visualization methods in analysis of detailed chemical kinetics modelling.

Sensitivity analysis, principal component analysis of the sensitivity matrix, and rate-of-production analysis are useful tools in interpreting detailed chemical kinetics calculations. This paper deals with the practical use and communication of the sensitivity analysis and the related methods are discussed. Some limitations of sensitivity analysis, originating from the mathematical concept (e.g. first-order or brute force methods) or from the software-specific implementation of the method, are discussed. As supplementary tools to the current methods, three novel visual tools for analysis of detailed chemical kinetics mechanisms are introduced: (a) scaled sensitivity analysis which is especially suited for studying initiation reactions where the span of reaction rates is high; (b) automated generation of reaction pathway plots which provides an immediate graphical illustration of the chemical processes occurring; (c) explorative (or chemometric) analysis of accumulated rate of progress matrices which assist in the identification of reaction subsets. The application of these tools are demonstrated by analysing NOx enhanced oxidation of methane at 700-1200 K.

Journal Article↗

PubMed2001

Estimation of kinetic parameters in a structured yeast model using regularisation.

In this work, a procedure for estimating kinetic parameters in biochemically structured models was developed. The approach is applicable when the structure of a kinetic model has been set up and the kinetic parameters should be estimated. The procedure consists of five steps. First, initial values were found in or calculated from literature. Hereafter using sensitivity analysis the most sensitive parameters were identified. In the third step physiological knowledge was combined with the parameter sensitivities to manually tune the most sensitive parameters. In step four, a global optimisation routine was applied for simultaneous estimation of the most sensitive parameters identified during the sensitivity analysis. Regularisation was included in the simultaneous estimation to reduce the effect of insensitive parameters. Finally, confidence intervals for the estimated parameters were calculated. This parameter estimation approach was demonstrated on a biochemically structured yeast model containing 11 reactions and 37 kinetic constants as a case study.

Algorithms↗

PubMed2002

The cost utility of bisphosphonate treatment in established osteoporosis.

BACKGROUND: Hip fracture is an important and costly problem. Bisphosphonate therapy prevents hip and other fractures among women with established osteoporosis, but there are few published economic evaluations of this treatment. AIM: To assess the cost-effectiveness of risedronate, a recently launched bisphosphonate for the prevention of fractures among women with established osteoporosis. METHODS: A state transition Markov model of established post-menopausal osteoporosis based upon randomized clinical trial data was developed. Uncertainty underlying model parameters and outcomes was dealt with using traditional sensitivity analysis and stochastic sensitivity analysis to produce quasi-95%CIs. We focussed on patients aged approximately 75 years, since this population most closely matches the randomized controlled trial, and is typical of osteoporosis patients in the UK. RESULTS: The baseline model of treating a cohort of 1000 75-year-old women for 3 years with risedronate and then modelling the costs and benefits over their expected lifetimes, produced net savings of pound sterling 786 000 for the treatment group per 1000 treated women, (95%CI pound sterling 1.55m savings to pound sterling 47000 extra costs). Restricting the horizon of the analysis to only three years led to a small net cost of pound sterling 138 000 per 1000 treated women (95%CI pound sterling 196 000 savings to pound sterling 477 000 extra costs) with a net increment in Quality Adjusted Life years (QALYs) of 16 per 1000 treated women. This resulted in a cost per QALY of pound sterling 8625 per treated woman. CONCLUSIONS: In this example, the use of risedronate therapy in 75-year-old women at high risk of hip fracture leads to an improvement in quality of life with possible cost savings. Restricting the analysis to a time horizon of only three years leads to a QALY gain at a modest net cost.

Aged↗

PubMed2006

Cost-effectiveness strategies to treat osteoporosis in elderly women.

BACKGROUND: Comparing the cost-effectiveness of various antiosteoporotic drugs has not been defined. METHODS: We determined the cost-effectiveness of calcitonin, raloxifene, bisphosphates and PTH in a base-case cohort of women aged 65 or older with osteoporosis. After bone densitometry, women were stratified into groups of treatment or no treatment. Our outcome goal was a value of dollars 100,000 or less per quality-adjusted life years (QALY). A sensitivity analysis varied nonvertebral fracture reduction and compliance between the two most effective strategies to test various cost per QALY thresholds. RESULTS: Bisphosphonates displayed the most favorable incremental cost saving and prevented more fractures in our base-case analysis. In a sensitivity analysis, virtually all values of bisphosphonates were under dollars 100,000 per QALY and parathyroid hormone (PTH) was between dollars 100,000 and dollars 200,000 per QALY. CONCLUSIONS: Only bisphosphonates are cost-effective for fracture prevention in osteoporotic women aged 65 or older and this economic advantage is also maintained in subsets who have a lower relative risk of future fracture.

Aged↗

PubMed2006

Costs and benefits of combining probation and substance abuse treatment.

AIMS OF THE STUDY: We compared seamless combination of probation and treatment (where the probation officer is co-located with treatment provider or is actively engaged in treatment) to traditional probation where treatment is left to the client's choice. METHODS: Clients were randomly assigned to either seamless or traditional probation. We used a decision analytic approach which had two advantages: First it separated estimation of probability of adverse events (e.g. hospitalization) from the daily cost of the adverse event, thereby allowing use of estimates of daily costs available within the literature. Second, the reliance on daily probability of various adverse events also had the benefit of reflecting both length of the event and its intermittent re-occurrence. Subjects were 272 clients on probation in Northern Virginia and Maryland in the United States. Clients were randomly assigned to seamless and traditional probation and were followed for an average of 2.75 years (arrest information was only available for 1 year); 77% of clients participated in the follow-up interviews. At baseline, there was no statistically significant difference among the clients. RESULTS: During the follow-up period, clients in the seamless probation had less recidivism but the cost savings from this component (dollar 2.31 per client per follow-up day) was not sufficient to overcome increased costs due to mental hospitalization of seamless clients (dollar 13.50 per client per follow-up day), cost of delivery of seamless probation (dollar 2.58 per client per follow-up day), more frequent use of jail/prison for clients in the seamless group (dollar 2.08 per client per follow-up day) and additional treatment costs (dollar 1.24 per client per follow-up day). The expected cost of seamless probation and its consequences was dollar 38.84 per follow-up day. The expected cost of traditional probation and its consequences was dollar 21.60 per follow-up day. Seamless probation was dollar 6,293 more expensive than traditional probation per client per year. DISCUSSION: Sensitivity analysis suggested that the analysis was not sensitive to small change in any single cost or probability estimate. Sensitivity analysis suggested that increased supervision intensity and use of sanctions had contributed to lower cost-effectiveness. IMPLICATIONS: One possible way of improving seamless probation is to improve the intensity of the substance abuse treatment while reducing the intensity of supervision to its traditional levels. This analysis was limited to 2.75 years follow-up period and does not address cost savings that might occur after this period.

Adult↗

PubMed1977

Rapid sensitive fluorometric analysis of cephalosporin antibiotics.

A rapid and sensitive fluorometric analysis for cephalosporins, which can also be applied to penicillins, is presented. The method involves reaction with 0.1 N sodium hydroxide at 100 degrees, producing stable fluorescent products. This method was applied to cephalexin and ampicillin with detection at concentrations as low as 0.01 mug/ml.

Ampicillin↗

PubMed1984

Genetic predisposition to hypertension, elevated blood pressure and pain sensitivity: a functional analysis.

Pain sensitivity was examined in Dahl hypertension-sensitive (DS) and Dahl hypertension-resistant (DR) rats. The results indicated that hypertensive DS rats had a reduced sensitivity to painful stimulation compared to normotensive DS rats or compared to DR rats. Furthermore, the lower pain sensitivity of even normotensive DS vis-a-vis normotensive DR rats was not due to genetic factors but due to slight variations in blood pressure between lines. These results provide additional experimental support for the contention that elevations in blood pressure result in decreased pain sensitivity.

Animals↗