The role of muscarinic cholinergic signaling in cost-benefit decision making

Thesis (Ph.D.)--University of Washington, 2016-08

Setting hospital infection control policy : a decision-making framework incorporating health economics and healthcare epidemiology

Background: Reducing rates of healthcare acquired infection has been identified by the Australian Commission on Safety and Quality in Health Care as a national priority. One of the goals is the prevention of central venous catheter-related bloodstream infection (CR-BSI). At least 3,500 cases of CR-BSI occur annually in Australian hospitals, resulting in unnecessary deaths and costs to the healthcare system between $25.7 and $95.3 million. Two approaches to preventing these infections have been proposed: use of antimicrobial catheters (A-CVCs); or a catheter care and management ‘bundle’. Given finite healthcare budgets, decisions about the optimal infection control policy require consideration of the effectiveness and value for money of each approach. Objectives: The aim of this research is to use a rational economic framework to inform efficient infection control policy relating to the prevention of CR-BSI in the intensive care unit. It addresses three questions relating to decision-making in this area: 1. Is additional investment in activities aimed at preventing CR-BSI an efficient use of healthcare resources? 2. What is the optimal infection control strategy from amongst the two major approaches that have been proposed to prevent CR-BSI? 3. What uncertainty is there in this decision and can a research agenda to improve decision-making in this area be identified? Methods: A decision analytic model-based economic evaluation was undertaken to identify an efficient approach to preventing CR-BSI in Queensland Health intensive care units. A Markov model was developed in conjunction with a panel of clinical experts which described the epidemiology and prognosis of CR-BSI. The model was parameterised using data systematically identified from the published literature and extracted from routine databases. The quality of data used in the model and its validity to clinical experts and sensitivity to modelling assumptions was assessed. Two separate economic evaluations were conducted. The first evaluation compared all commercially available A-CVCs alongside uncoated catheters to identify which was cost-effective for routine use. The uncertainty in this decision was estimated along with the value of collecting further information to inform the decision. The second evaluation compared the use of A-CVCs to a catheter care bundle. We were unable to estimate the cost of the bundle because it is unclear what the full resource requirements are for its implementation, and what the value of these would be in an Australian context. As such we undertook a threshold analysis to identify the cost and effectiveness thresholds at which a hypothetical bundle would dominate the use of A-CVCs under various clinical scenarios. Results: In the first evaluation of A-CVCs, the findings from the baseline analysis, in which uncertainty is not considered, show that the use of any of the four A-CVCs will result in health gains accompanied by cost-savings. The MR catheters dominate the baseline analysis generating 1.64 QALYs and cost-savings of $130,289 per 1.000 catheters. With uncertainty, and based on current information, the MR catheters remain the optimal decision and return the highest average net monetary benefits ($948 per catheter) relative to all other catheter types. This conclusion was robust to all scenarios tested, however, the probability of error in this conclusion is high, 62% in the baseline scenario. Using a value of $40,000 per QALY, the expected value of perfect information associated with this decision is $7.3 million. An analysis of the expected value of perfect information for individual parameters suggests that it may be worthwhile for future research to focus on providing better estimates of the mortality attributable to CR-BSI and the effectiveness of both SPC and CH/SSD (int/ext) catheters. In the second evaluation of the catheter care bundle relative to A-CVCs, the results which do not consider uncertainty indicate that a bundle must achieve a relative risk of CR-BSI of at least 0.45 to be cost-effective relative to MR catheters. If the bundle can reduce rates of infection from 2.5% to effectively zero, it is cost-effective relative to MR catheters if national implementation costs are less than $2.6 million ($56,610 per ICU). If the bundle can achieve a relative risk of 0.34 (comparable to that reported in the literature) it is cost-effective, relative to MR catheters, if costs over an 18 month period are below $613,795 nationally ($13,343 per ICU). Once uncertainty in the decision is considered, the cost threshold for the bundle increases to $2.2 million. Therefore, if each of the 46 Level III ICUs could implement an 18 month catheter care bundle for less than $47,826 each, this approach would be cost effective relative to A-CVCs. However, the uncertainty is substantial and the probability of error in concluding that the bundle is the cost-effective approach at a cost of $2.2 million is 89%. Conclusions: This work highlights that infection control to prevent CR-BSI is an efficient use of healthcare resources in the Australian context. If there is no further investment in infection control, an opportunity cost is incurred, which is the potential for a more efficient healthcare system. Minocycline/rifampicin catheters are the optimal choice of antimicrobial catheter for routine use in Australian Level III ICUs, however, if a catheter care bundle implemented in Australia was as effective as those used in the large studies in the United States it would be preferred over the catheters if it was able to be implemented for less than $47,826 per Level III ICU. Uncertainty is very high in this decision and arises from multiple sources. There are likely greater costs to this uncertainty for A-CVCs, which may carry hidden costs, than there are for a catheter care bundle, which is more likely to provide indirect benefits to clinical practice and patient safety. Research into the mortality attributable to CR-BSI, the effectiveness of SPC and CH/SSD (int/ext) catheters and the cost and effectiveness of a catheter care bundle in Australia should be prioritised to reduce uncertainty in this decision. This thesis provides the economic evidence to inform one area of infection control, but there are many other infection control decisions for which information about the cost-effectiveness of competing interventions does not exist. This work highlights some of the challenges and benefits to generating and using economic evidence for infection control decision-making and provides support for commissioning more research into the cost-effectiveness of infection control.

Genomic markers for decision making:What is preventing us from using markers?

The advent of novel genomic technologies that enable the evaluation of genomic alterations on a genome-wide scale has significantly altered the field of genomic marker research in solid tumors. Researchers have moved away from the traditional model of identifying a particular genomic alteration and evaluating the association between this finding and a clinical outcome measure to a new approach involving the identification and measurement of multiple genomic markers simultaneously within clinical studies. This in turn has presented additional challenges in considering the use of genomic markers in oncology, such as clinical study design, reproducibility and interpretation and reporting of results. This Review will explore these challenges, focusing on microarray-based gene-expression profiling, and highlights some common failings in study design that have impacted on the use of putative genomic markers in the clinic. Despite these rapid technological advances there is still a paucity of genomic markers in routine clinical use at present. A rational and focused approach to the evaluation and validation of genomic markers is needed, whereby analytically validated markers are investigated in clinical studies that are adequately powered and have pre-defined patient populations and study endpoints. Furthermore, novel adaptive clinical trial designs, incorporating putative genomic markers into prospective clinical trials, will enable the evaluation of these markers in a rigorous and timely fashion. Such approaches have the potential to facilitate the implementation of such markers into routine clinical practice and consequently enable the rational and tailored use of cancer therapies for individual patients. © 2010 Macmillan Publishers Limited. All rights reserved.

Does uncertainty cause inertia in decision making? An experimental study of the role of regret aversion and indecisiveness

Previous research has shown that often there is clear inertia in individual decision making---that is, a tendency for decision makers to choose a status quo option. I conduct a laboratory experiment to investigate two potential determinants of inertia in uncertain environments: (i) regret aversion and (ii) ambiguity-driven indecisiveness. I use a between-subjects design with varying conditions to identify the effects of these two mechanisms on choice behavior. In each condition, participants choose between two simple real gambles, one of which is the status quo option. I find that inertia is quite large and that both mechanisms are equally important.

Decision-making in a phase II clinical trial: a new approach combining Bayesian and frequentist concepts

The aim of a phase H clinical trial is to decide whether or not to develop an experimental therapy further through phase III clinical evaluation. In this paper, we present a Bayesian approach to the phase H trial, although we assume that subsequent phase III clinical trials will hat,e standard frequentist analyses. The decision whether to conduct the phase III trial is based on the posterior predictive probability of a significant result being obtained. This fusion of Bayesian and frequentist techniques accepts the current paradigm for expressing objective evidence of therapeutic value, while optimizing the form of the phase II investigation that leads to it. By using prior information, we can assess whether a phase II study is needed at all, and how much or what sort of evidence is required. The proposed approach is illustrated by the design of a phase II clinical trial of a multi-drug resistance modulator used in combination with standard chemotherapy in the treatment of metastatic breast cancer. Copyright (c) 2005 John Wiley & Sons, Ltd.

Contrast-enhanced 3-D MRA in decision making for carotid endarterectomy: a 6-year experience

BACKGROUND: Systematic need for angiography in diagnosis of carotid artery stenosis and indication of surgical therapy is still debated. Noninvasive imaging techniques such as MR angiography (MRA) or CT angiography (CTA) offer an alternative to digital subtraction angiography (DSA) and are increasingly used in clinical practice. In this study, we present the radiological characteristics and clinical results of a series of patients operated on the basis of combined ultrasonography (US)/MRA. METHODS: This observational study included all the patients consecutively operated for a carotid stenosis in our Department from October 1998 to December 2004. The applied MRA protocol had previously been established in a large correlation study with DSA. DSA was used only in case of discordance between US and MRA. The preoperative radiological information furnished by MRA was compared with intraoperative findings. The outcome of the operation was assessed according to ECST criteria. RESULTS: Among 327 patients, preoperative MRA was performed in 278 (85%), DSA in 44 (13.5%) and CT angiography in 5 (1.5%). Most of DSA studies were performed as emergency for preparation of endovascular therapy or for reasons other than carotid stenosis. Eleven additional DSA (3.3%) complemented US/MRA, mostly because diverging diagnosis of subocclusion of ICA. No direct morbidity or intraoperative difficulty was related to preoperative MRA. Combined mortality/major morbidity rate was 0.9% (3 patients) and minor morbidity rate 5.5% (18 patients). CONCLUSIONS: This observational study describes a well-established practice of carotid surgery and supports the exclusive use of non invasive diagnostic imaging for indicating and deciding the operation.

[Role of coronary artery bypass grafting in the treatment of coronary artery disease - a well-balanced information of the patients and objective decision making are welcome]

Most recently discussion about the optimal treatment for different subsets of patients suffering from coronary artery disease has re-emerged, mainly because of the uncertainty caused by doctors and patients regarding the phenomenon of unpredictable early and late stent thrombosis. Surgical revascularization using multiple arterial bypass grafts has repeatedly proven its superiority compared to percutaneous intervention techniques, especially in patients suffering from left main stem disease and coronary 3-vessels disease. Several prospective randomized multicenter studies comparing early and mid-term results following PCI and CABG have been really restrictive, with respect to patient enrollment, with less than 5% of all patients treated during the same time period been enrolled. Coronary artery bypass grafting allows the most complete revascularization in one session, because all target coronary vessels larger than 1 mm can be bypassed in their distal segments. Once the patient has been turn-off for surgery, surgeons have to consider the most complete arterial revascularization in order to decrease the long-term necessity for re-revascularization; for instance patency rate of the left internal thoracic artery grafted to the distal part left anterior descending artery may be as high as 90-95% after 10 to 15 years. Early mortality following isolated CABG operation has been as low as 0.6 to 1% in the most recent period (reports from the University Hospital Berne and the University Hospital of Zurich); beside these excellent results, the CABG option seems to be less expensive than PCI with time, since the necessity for additional PCI is rather high following initial PCI, and the price of stent devices is still very high, particularly in Switzerland. Patients, insurance and experts in health care should be better and more honestly informed concerning the risk and costs of PCI and CABG procedures as well as about the much higher rate of subsequent interventions following PCI. Team approach for all patients in whom both options could be offered seems mandatory to avoid unbalanced information of the patients. Looking at the recent developments in transcatheter valve treatments, the revival of cardiological-cardiosurgical conferences seems to a good option to optimize the cooperation between the two medical specialties: cardiology and cardiac surgery.

Decision-making in aortic root surgery in Marfan syndrome: bleeding, thromboembolism and risk of reintervention after valve-sparing or mechanical aortic root replacement†

OBJECTIVES Valve-sparing root replacement (VSRR) is thought to reduce the rate of thromboembolic and bleeding events compared with aortic root replacement using a mechanical aortic root replacement (MRR) with a composite graft by avoiding oral anticoagulation. But as VSRR carries a certain risk for subsequent reinterventions, decision-making in the individual patient can be challenging. METHODS Of 100 Marfan syndrome (MFS) patients who underwent 169 aortic surgeries and were followed at our institution since 1995, 59 consecutive patients without a history of dissection or prior aortic surgery underwent elective VSRR or MRR and were retrospectively analysed. RESULTS VSRR was performed in 29 (David n = 24, Yacoub n = 5) and MRR in 30 patients. The mean age was 33 ± 15 years. The mean follow-up after VSRR was 6.5 ± 4 years (180 patient-years) compared with 8.8 ± 9 years (274 patient-years) after MRR. Reoperation rates after root remodelling (Yacoub) were significantly higher than after the reimplantation (David) procedure (60 vs 4.2%, P = 0.01). The need for reinterventions after the reimplantation procedure (0.8% per patient-year) was not significantly higher than after MRR (P = 0.44) but follow-up after VSRR was significantly shorter (P = 0.03). There was neither significant morbidity nor mortality associated with root reoperations. There were no neurological events after VSRR compared with four stroke/intracranial bleeding events in the MRR group (log-rank, P = 0.11), translating into an event rate of 1.46% per patient-year following MRR. CONCLUSION The calculated annual failure rate after VSRR using the reimplantation technique was lower than the annual risk for thromboembolic or bleeding events. Since the perioperative risk of reinterventions following VSRR is low, patients might benefit from VSRR even if redo surgery may become necessary during follow-up.

End-of-life decision making in Europe and Australia - A physician survey

Background: The frequencies with which physicians make different medical end-of-life decisions (ELDs) may differ between countries, but comparison between countries has been difficult owing to the use of dissimilar research methods. Methods: A written questionnaire was sent to a random sample of physicians from 9 specialties in 6 European countries and Australia to investigate possible differences in the frequencies of physicians' willingness to perform ELDs and to identify predicting factors. Response rates ranged from 39% to 68% (N= 10 139). Using hypothetical cases, physicians were asked whether they would ( probably) make each of 4 ELDs. Results: In all the countries, 75% to 99% of physicians would withhold chemotherapy or intensify symptom treatment at the request of a patient with terminal cancer. In most cases, more than half of all physicians would also be willing to deeply sedate such a patient until death. However, there was generally less willingness to administer drugs with the explicit intention of hastening death at the request of the patient. The most important predictor of ELDs was a request from a patient with decisional capacity (odds ratio, 2.1-140.0). Shorter patient life expectancy and uncontrollable pain were weaker predictors but were more stable across countries and across the various ELDs (odds ratios, 1.1-2.4 and 0.9-2.4, respectively). Conclusion: Cultural and legal factors seem to influence the frequencies of different ELDs and the strength of their determinants across countries, but they do not change the essence of decision making.

Supporting decision-making for self-adaptive systems:from goal models to dynamic decision networks

Context/Motivation - Different modeling techniques have been used to model requirements and decision-making of self-adaptive systems (SASs). Specifically, goal models have been prolific in supporting decision-making depending on partial and total fulfilment of functional (goals) and non-functional requirements (softgoals). Different goalrealization strategies can have different effects on softgoals which are specified with weighted contribution-links. The final decision about what strategy to use is based, among other reasons, on a utility function that takes into account the weighted sum of the different effects on softgoals. Questions/Problems - One of the main challenges about decisionmaking in self-adaptive systems is to deal with uncertainty during runtime. New techniques are needed to systematically revise the current model when empirical evidence becomes available from the deployment. Principal ideas/results - In this paper we enrich the decision-making supported by goal models by using Dynamic Decision Networks (DDNs). Goal realization strategies and their impact on softgoals have a correspondence with decision alternatives and conditional probabilities and expected utilities in the DDNs respectively. Our novel approach allows the specification of preferences over the softgoals and supports reasoning about partial satisfaction of softgoals using probabilities. We report results of the application of the approach on two different cases. Our early results suggest the decision-making process of SASs can be improved by using DDNs. © 2013 Springer-Verlag.

Fatigue is associated with excess mortality in the general population : results from the EPIC-Norfolk study

This work was supported by programme grants from the Medical Research Council G1000143 and the Cancer Research UK 8257. Funders have no roles in study design, analysis, and interpretation of the findings.