Use of Advanced Flexible Modeling Approaches for Survival Extrapolation from Early Follow-up Data in two Nivolumab Trials in Advanced NSCLC with Extended Follow-up.

OBJECTIVES: Immuno-oncology (IO) therapies are often associated with delayed responses that are deep and durable, manifesting as long-term survival benefits in patients with metastatic cancer. Complex hazard functions arising from IO treatments may limit the accuracy of extrapolations from standard parametric models (SPMs). We evaluated the ability of flexible parametric models (FPMs) to improve survival extrapolations using data from 2 trials involving patients with non-small-cell lung cancer (NSCLC). METHODS: Our analyses used consecutive database locks (DBLs) at 2-, 3-, and 5-y minimum follow-up from trials evaluating nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and nonsquamous (CheckMate-057) NSCLC. For each DBL, SPMs, as well as 3 FPMs-landmark response models (LRMs), mixture cure models (MCMs), and Bayesian multiparameter evidence synthesis (B-MPES)-were estimated on nivolumab overall survival (OS). The performance of each parametric model was assessed by comparing milestone restricted mean survival times (RMSTs) and survival probabilities with results obtained from externally validated SPMs. RESULTS: For the 2- and 3-y DBLs of both trials, all models tended to underestimate 5-y OS. Predictions from nonvalidated SPMs fitted to the 2-y DBLs were highly unreliable, whereas extrapolations from FPMs were much more consistent between models fitted to successive DBLs. For CheckMate-017, in which an apparent survival plateau emerges in the 3-y DBL, MCMs fitted to this DBL estimated 5-y OS most accurately (11.6% v. 12.3% observed), and long-term predictions were similar to those from the 5-y validated SPM (20-y RMST: 30.2 v. 30.5 mo). For CheckMate-057, where there is no clear evidence of a survival plateau in the early DBLs, only B-MPES was able to accurately predict 5-y OS (14.1% v. 14.0% observed [3-y DBL]). CONCLUSIONS: We demonstrate that the use of FPMs for modeling OS in NSCLC patients from early follow-up data can yield accurate estimates for RMST observed with longer follow-up and provide similar long-term extrapolations to externally validated SPMs based on later data cuts. B-MPES generated reasonable predictions even when fitted to the 2-y DBLs of the studies, whereas MCMs were more reliant on longer-term data to estimate a plateau and therefore performed better from 3 y. Generally, LRM extrapolations were less reliable than those from alternative FPMs and validated SPMs but remained superior to nonvalidated SPMs. Our work demonstrates the potential benefits of using advanced parametric models that incorporate external data sources, such as B-MPES and MCMs, to allow for accurate evaluation of treatment clinical and cost-effectiveness from trial data with limited follow-up. HIGHLIGHTS: Flexible advanced parametric modeling methods can provide improved survival extrapolations for immuno-oncology cost-effectiveness in health technology assessments from early clinical trial data that better anticipate extended follow-up.Advantages include leveraging additional observable trial data, the systematic integration of external data, and more detailed modeling of underlying processes.Bayesian multiparameter evidence synthesis performed particularly well, with well-matched external data.Mixture cure models also performed well but may require relatively longer follow-up to identify an emergent plateau, depending on the specific setting.Landmark response models offered marginal benefits in this scenario and may require greater numbers in each response group and/or increased follow-up to support improved extrapolation within each subgroup.

Real-world treatment patterns in resectable (stages I-III) non-small-cell lung cancer: a systematic literature review.

Aim: The aim of this systematic literature review was to describe treatment patterns in nonmetastatic non-small-cell lung cancer. Methods: A search was conducted in MEDLINE and EMBASE. Eligible studies were multicentered (>50 patients) and conducted after 2000 in North America, Europe and Asia. Results: Twenty studies met the eligibility criteria. Based on US and Canadian studies in the resectable population, the proportion of patients who received neoadjuvant chemotherapy/chemoradiotherapy and adjuvant chemotherapy/chemoradiotherapy increased with increasing stage (i.e., from <3% in stage I to about 40% in stage III and from 15% in stage I to 30% in stage III, respectively). Within the resectable population, the breakdown between bimodal and trimodal therapy was variable, suggesting that clinical practice is not uniform. Conclusion: Overall, studies were heterogeneous, precluding data extrapolation across regions. Despite heterogeneity and limited evidence, this review suggested an increase in neoadjuvant and adjuvant chemotherapy with increasing stage, generally in line with treatment guidelines.

This literature review aimed to describe the treatment patterns in nonmetastatic non-small-cell lung cancer. This review was performed according to the highest methodological standards and searched published and unpublished records of stages I­III non-small-cell lung cancer treatment in North America, Europe and Asia. A limited number of studies were identified showing that in North America treatment with neoadjuvant and adjuvant chemotherapy (with or without radiotherapy) increased with stage. Identified studies in all regions showed that the treatment received, such as bimodal with surgery and chemotherapy compared with trimodal with surgery, chemotherapy and radiotherapy, was quite variable and that practice was not uniform. Overall, the studies were heterogeneous and data could not be extrapolated to practice across all regions. However, the studies suggested an increase in neoadjuvant and adjuvant usage with increasing stage, which is generally in line with treatment guidelines.

Role of IncP-1ß plasmids pWDL7::rfp and pNB8c in chloroaniline catabolism as determined by genomic and functional analyses.

Broad-host-range catabolic plasmids play an important role in bacterial degradation of man-made compounds. To gain insight into the role of these plasmids in chloroaniline degradation, we determined the first complete nucleotide sequences of an IncP-1 chloroaniline degradation plasmid, pWDL7::rfp and its close relative pNB8c, as well as the expression pattern, function, and bioaugmentation potential of the putative 3-chloroaniline (3-CA) oxidation genes. Based on phylogenetic analysis of backbone proteins, both plasmids are members of a distinct clade within the IncP-1ß subgroup. The plasmids are almost identical, but whereas pWDL7::rfp carries a duplicate inverted catabolic transposon, Tn6063, containing a putative 3-CA oxidation gene cluster, dcaQTA1A2BR, pNB8c contains only a single copy of the transposon. No genes for an aromatic ring cleavage pathway were detected on either plasmid, suggesting that only the upper 3-CA degradation pathway was present. The dcaA1A2B gene products expressed from a high-copy-number vector were shown to convert 3-CA to 4-chlorocatechol in Escherichia coli. Slight differences in the dca promoter region between the plasmids and lack of induction of transcription of the pNB8c dca genes by 3-CA may explain previous findings that pNB8C does not confer 3-CA transformation. Bioaugmentation of activated sludge with pWDL7::rfp accelerated removal of 3-CA, but only in the presence of an additional carbon source. Successful bioaugmentation requires complementation of the upper pathway genes with chlorocatechol cleavage genes in indigenous bacteria. The genome sequences of these plasmids thus help explain the molecular basis of their catabolic activities.

Payment, compensation and replacement--the ethics and motivation of blood and plasma donation.

The supply of blood and plasma to produce haemotherapies varies around the world, but all environments need donors to furnish the raw material. Many countries still lack adequate supply, and the question of what amounts of blood and plasma are required for optimal treatment is still unresolved. The issue of compensating donors has been a controversial and emotive one in blood transfusion for many decades. Donors are conventionally classified as paid, voluntary or replacement, and a level of stigma, based on safety and ethical considerations, has been attached to paid donation. This review points to evidence which renders many of these concerns redundant. Purist arguments against compensated donation have little basis in evidence and would lead to many of today's voluntary donors being designated as paid, because of the large range of incentives used to recruit and retain them. Misplaced application of 'Titmussian' volunteerism has precipitated its own safety and supply problems. Current systems of compensation and replacement are needed to maintain supplies of essential products and lead to safe products in controlled environments. We propose that a plurality of routes towards donation is an appropriate paradigm in the heterogeneous landscape of blood and plasma product supply.

Gestational diabetes mellitus screening and diagnosis: a prospective randomised controlled trial comparing costs of one-step and two-step methods.

OBJECTIVE: To conduct a cost minimisation analysis of three methods of gestational diabetes mellitus (GDM) screening and diagnosis. DESIGN: Prospective randomised controlled trial. SETTING: University teaching hospital. POPULATION: Pregnant women (n = 1594) presenting for GDM screening. METHODS: Women presenting for GDM screening, who consented to participate, were randomised to GR1 [1-hour, 50-g glucose screen (GS) +/- 3-hour, 100-g oral glucose tolerance test (OGTT)], GR2 (50-g GS +/- 2-hour, 75-g OGTT) or GR3 (2-hour, 75-g OGTT). Demographics, health and time/travel cost information were assessed for each glucose testing visit. MAIN OUTCOME MEASURES: Costs (direct and indirect) and prevalence of GDM diagnosis. RESULTS: The direct sampling costs of the glucose tests per woman were as follows: GS, CAN$12.57; 75-g OGTT, $36.10; 100-g OGTT, CAN$48.13. Among women in the two-step method groups diagnosed with GDM, 39% of the GR1 and 61% of the GR2 groups were diagnosed at the first step by GS > or = 10.3 mmol/l, according to the Canadian Diabetes Association recommendations, contributing to a lower total cost in these groups. The total costs per woman screened were as follows: GR1, CAN$91.61; GR2, CAN$89.03; GR3, CAN$108.38. The GDM prevalence was similar (3.7%, 3.7% and 3.6%, respectively). The higher costs of GR3 were related to more blood draws and the time required for all women to undergo the 2-hour OGTT. CONCLUSIONS: Careful consideration should be given to an internationally recommended method of universal screening for GDM which minimises the burden and cost for individual women and the healthcare system, yet provides diagnostic efficacy. The two-step method (GS +/- OGTT) accomplished this better than the one-step method (75-g OGTT).

Cost-effectiveness of mandibular two-implant overdentures and conventional dentures in the edentulous elderly.

Implementation of new therapies is usually governed by financial considerations, so efficacy studies should also include cost comparisons. The cost and effectiveness of mandibular conventional dentures (CD, n = 30) and two-implant overdentures (IOD, n = 30) were compared in elderly subjects. Effectiveness (Oral Health Impact Profile, OHIP-20) and cost were measured up to one year post-treatment. Data for subsequent years were estimated by the Delphi method. Using an average life expectancy of 17.9 years, the equalized annual costs (in Canadian dollars) were dollar 399 for CD and dollar 625 for IOD (p < 0.001), and the equalized annual values for the outcome (OHIP-20) were 47.0 for CD and 31.3 for IOD treatment (p < 0.05). These values translate into a yearly additional cost for IOD treatment of dollar 14.41 per OHIP-20 point. These results are key to the implementation of programs to provide this form of therapy for edentulous adults.

The systemic lupus erythematosus tri-nation study: longitudinal changes in physical and mental well-being.

OBJECTIVE: We have shown that SLE patients in Canada and the UK incurred 20% and 13% lower health costs than those in the US, respectively, but did not experience worse outcomes as expressed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. We now compare change in quality of life in these patients. PATIENTS AND METHODS: Seven hundred and fifteen SLE patients (Canada 231, US 269, UK 215) completed the SF-36 annually over four years. The annual change in the SF-36 Physical and Mental Component Summary (PCS and MCS) scores over the course of the study were summarized by estimating a linear trend for each individual patient using hierarchical modelling. Cross-country comparison of the slopes in the PCS and MCS scores was then performed using simultaneous regressions. RESULTS: The estimated mean annual changes (95% credible interval [CrI]) in the PCS scores in Canada, the US, and the UK were 0.18 (-0.07, 0.43), -0.05 (-0.27, 0.17), and 0.03 (-0.20, 0.27), respectively; the mean annual changes in the MCS scores were 0.15 (-0.04, 0.34), 0.23 (0.09, 0.37), and 0.08 (-0.10, 0.27), respectively. Regression results showed that the mean annual changes in PCS and MCS scores did not substantially differ across countries. CONCLUSION: Quality of life remained stable across countries. Despite Canadian and British patients incurring lower health costs, on average, patients experienced similar changes in physical and mental well-being.

Co-morbidity and physician use in fibromyalgia.

OBJECTIVE: To describe comorbidity in women with FM, and to examine the effects of different types of comorbidity on physician use. METHODS: Women (n = 180) with primary FM were evaluated at baseline and 6 months later for self-reported health resource use and covariates. Reported comorbidity was classified into 4 categories: medical, psychiatric, "functional", and unknown. The category for "functional" conditions included disorders that have been classified by previous authors as medically unexplained symptoms such as the irritable bowel and chronic fatigue syndromes. Logistic regression models were developed to examine associations between types of comorbidity and physician use. RESULTS: Comorbid conditions were reported by over 90% of the sample. Total number of comorbid complaints was associated with high number of physician visits. In logistic regression models (controlling for age, ethnicity, education, disability, pain, and psychological vulnerability) medical comorbidity was a much stronger determinant of high number of physician visits than was "functional" comorbidity. CONCLUSIONS: Comorbidity with other disorders, both functional and medical, was high in this sample. Medical and psychiatric comorbidity were stronger determinants of high physician use than "functional" comorbidity.

The systemic lupus erythematosus Tri-nation Study: absence of a link between health resource use and health outcome.

OBJECTIVE: Health consumption and health status in SLE in three countries with different health funding structures were compared. METHODS: Seven hundred and fifteen SLE patients (Canada 231, USA 269, UK 215) were surveyed semi-annually over 4 yr for health resource utilization and health status. Cross-country comparisons of (i) cumulative health expenditure (calculated by applying 2002 Canadian prices to resources in all countries) and (ii) disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, SLICC/ACR DI) at study conclusion were performed after adjustment. Missing expenditure and damage data were managed through multiple imputation using best predictive regressions with all available data from all patients as potential covariates. RESULTS: Four hundred and eighty-five patients provided data at study entry and conclusion and at least four resource questionnaires (Canada 162, USA 157, UK 166); 41 died (Canada 13, USA 18, UK 10); 189 withdrew, were lost to follow-up or provided data at entry and conclusion but fewer than four resource questionnaires (Canada 56, USA 94, UK 39). At conclusion, after imputation, in Canada, the USA and the UK respectively, mean cumulative costs per patient over 4 yr [95% confidence interval (CI)] were $15,845 (13,509, 18,182), $20,244 (17,764, 22,724) and $17,647 (15,557, 19,737) and mean changes in SLICC/ACR DI were 0.49 (0.39, 0.60), 0.63 (0.52, 0.74) and 0.48 (0.39, 0.57). After adjustment for baseline differences, on average (95% CI), Canadian and British patients utilized 20% (8%, 32%) and 13% (1%, 24%) less resources than patients in the USA respectively, but experienced similar health outcomes. CONCLUSION: Despite patients in the USA incurring higher health expenditures, they did not experience superior health outcomes.

Radiographic damage in rheumatoid arthritis correlates with functional disability but not direct medical costs.

OBJECTIVE: Few longitudinal data exist on the relationship between radiographic damage and self-reported functional disability and direct medical costs in rheumatoid arthritis (RA). We assessed these relationships. METHODS: One hundred thirty patients with RA (at time of the first available radiograph, mean age 56.6 yrs, 16.9% male, mean disease duration 16.8 yrs) were followed for up to 13.4 years. Semiannually, they reported on functional disability (0 = no difficulty, 3 = unable to do), global severity (0 = very well, 100 = very poor), pain (0 = no pain, 3 = severe pain), and health services utilization through completion of the Stanford Health Assessment Questionnaire (HAQ). Concurrent hand radiographs were scored for erosions and joint space narrowing using the Genant method and a single score summing both erosions and joint space narrowing for both hands was calculated (0 = no damage, 200 = maximum damage). The univariate association of functional disability, global severity, pain, or direct medical costs with concurrent radiographic damage was assessed through Spearman correlations and hierarchical regression models. The hierarchical models permit exploitation of the between-patient and within-patient variation present in our longitudinal data. RESULTS: At the time of the first available radiograph, mean (SD) levels of functional disability, global severity, and pain were 1.3 (0.7), 39.4 (21.0), and 1.1 (0.7), respectively. At entry into the study, the average radiograph score was 49.7 and upon leaving the study it was 66.9. Patients were followed an average of 6.7 years, with radiograph scores increasing at an average rate of 2.5 units/yr. The Spearman correlation [95% confidence interval (CI)] between average per-patient radiograph score and average per-patient HAQ disability index, average per-patient global severity, average per-patient pain score, and average per-patient direct medical costs was, respectively, 0.42 (0.26, 0.55), 0.23 (0.06, 0.39), 0.20 (0.03, 0.36), and 0.06 (-0.11, 0.23). The mean slope (95% CI) for disability on radiograph score was 0.0186 (0.0132, 0.0226), for severity on radiographs 0.1889 (0.1295, 0.2498), and for pain on radiographs 0.0057 (0.0027, 0.0084). As an example, over 10 years, a 25 unit (i.e., 50%) increase in radiograph scores would, on average, be associated with a 0.46 unit (i.e., 35%) increase in disability, a 4.72 unit (12%) increase in global severity score, and a 0.14 unit (13%) increase in pain, all expressed on the HAQ scales. There was little association between radiograph score and direct medical costs. CONCLUSION: A clinically meaningful association exists between radiographic damage and self-reported functional disability, suggesting that interventions that slow radiographic progression may improve the patient's health status. Such a relationship was not observed between radiographic damage and direct medical costs.

An exploration and advancement of the concept of trust.

BACKGROUND: Trust is a concept used both in everyday language and in the scientific realm. An exploration of the conceptualizations of trust within the disciplines of nursing, medicine, psychology and sociology, revealed that trust is an ambiguous scientific concept. AIMS: In order to increase the pragmatic utility of the concept of trust for scientific application, further clarification and development of the concept was undertaken. METHODS: First, a concept analysis was conducted with the aim of clarifying the state of the science of discipline-specific conceptualizations of trust. The criterion-based method of concept analysis as described by Morse and colleagues was used (Morse et al. 1996a, 1996b, Morse 2000). This analytic process enabled the assessment of the scientific maturity of the concept of trust. The interdisciplinary concept of trust was found to be immature. Based on this level of maturity it was determined that in order to advance the concept of trust toward greater maturity, techniques of concept development using the literature as data were applied. In this process, questions were "asked of the data" (in this case, the selected disciplinary literatures) to identify the conceptual components of trust. RESULTS: The inquiry into the concept of trust led to the development of an expanded interdisciplinary conceptual definition by merging the most coherent commonalties from each discipline. CONCLUSIONS: The newly developed interdisciplinary conceptualization advances the concept toward maturity, that is, a more refined, pragmatic and higher-order concept. The refined concept of trust transcends the contextual boundaries of each discipline in a truly interdisciplinary scientific fashion.

A comparison of life satisfaction and mood in nursing home residents and community-dwelling elders.

This study compared life satisfaction and mood in a sample of 138 cognitively intact and ambulatory elders, including 70 who lived in nursing homes and 68 who lived independently in the community. Community-dwelling elders reported greater life satisfaction, and scored higher on the Vigor-Activity subscale of the Profile of Mood States (POMS) than those who lived in a nursing home. Nursing home residents scored higher on the Depression-Dejection, Tension-Anxiety, and Confusion-Bewilderment subscales of the POMS. No between group differences were shown on the Anger-Hostility and Fatigue-Inertia subscales of the POMS. The diminished life satisfaction and high depression found in the nursing home residents hold immediate implications for professionals who work in this area.

Geographic variation in determinants of Medicare managed care enrollment.

OBJECTIVE: To examine the effect of adjusted average per capita cost (AAPCC) rate and volatility on Medicare risk plan enrollment at the county level. DATA SOURCES: Secondary data from the Health Care Financing Administration's office of managed care and other sources were merged to create comprehensive data on all Medicare risk plans in 3,069 of the 3,112 U. S. counties in December 1996. STUDY DESIGN: A two-step least squares regression was estimated to examine the effects of AAPCC rate and volatility, commercial HMO enrollment, market factors, and characteristics of the county population on Medicare HMO enrollment. The model was also used to simulate the effects of the Balanced Budget Act of 1997. Data from the Health Care Financing Administration were merged with other sources at the county level. The Federal Information Processing Standards code and a crosswalk file matching that code with the county name linked the data across sources. PRINCIPLE FINDINGS: The AAPCC rate has a small positive effect on the probability of Medicare HMO availability and enrollment. However, commercial HMO enrollment has a much stronger positive effect on Medicare HMO enrollment. Volatility has a negative effect on the probability of any Medicare HMO enrollment. CONCLUSIONS: The results suggest that payment changes enacted as part of the Balanced Budget Act will have a limited effect on Medicare HMO enrollment, especially in rural areas. Other policy changes are needed to stimulate Medicare HMO enrollment.

Refinement of the concept of uncertainty.

AIMS: To analyse the conceptual maturity of uncertainty; to develop an expanded theoretical definition of uncertainty; to advance the concept using methods of concept refinement; and to analyse congruency with the conceptualization of uncertainty presented in the theory of hope, enduring, and suffering. BACKGROUND: Uncertainty is of concern in nursing as people experience complex life events surrounding health. In an earlier nursing study that linked the concepts of hope, enduring, and suffering into a single theoretical scheme, a state best described as 'uncertainty' arose. This study was undertaken to explore how this conceptualization fit with the scientific literature on uncertainty and to refine the concept. DESIGN/METHODS: Initially, a concept analysis using advanced methods described by Morse, Hupcey, Mitcham and colleagues was completed. The concept was determined to be partially mature. A theoretical definition was derived and techniques of concept refinement using the literature as data were applied. FINDINGS: The refined concept was found to be congruent with the concept of uncertainty that had emerged in the model of hope, enduring and suffering. CONCLUSIONS: Further investigation is needed to explore the extent of probabilistic reasoning and the effects of confidence and control on feelings of uncertainty and certainty.