Multilevel modelling in the analysis of observational datasets in the health care setting

In health care-related research, many studies circle around the problem of identifying risk factors for clinical events of interest, with a potential for economic consequences, or risk factors for increased health care costs. Multivariate regression methods are typically used to analyse such studies and have become central for an efficient control of confounding and assessment of effect modification. However, most of the data used for this type of research are characterised by hierarchical (multilevel) data structures (e.g., patients are frequently nested within treating physicians or study centres). Standard multivariate regression methods tend to ignore this aspect and it has been shown that this may lead to a loss of statistical efficiency and, in some cases, to wrong conclusions. Multilevel regression modelling is an emerging statistical technique which claims to correctly address this type of data, and to make use of their full potential. The author conducted and/or analysed three observational studies of factors associated with clinical events or cost endpoints of interest. In all cases, conventional regression methods were primarily used. In a second step, multilevel re-analyses were performed and the results were compared. The first study addressed the effect of exacerbation status, disease severity and other covariates on the disease-specific health care costs of adult Swiss asthma patients. Among other factors, the occurrence of asthma exacerbations was confirmed to be independently associated with higher costs, and to interact with disease severity. The second study addressed the impact of gatekeeping, a technique widely used to manage the use of health care resources, on the health care costs accrued by a general Swiss population. In a situation characterised by ambiguous research findings, the author's study indicated substantial cost savings through gatekeeping as opposed to fee-for-service based health insurance. Finally, a combined dataset of six retrospective audits of breast cancer treatment from several Western European countries was used to estimate, for common chemotherapy regimen types, the frequency of chemotherapy-induced neutropenic events and to identify or confirm potential neutropenic event risk factors. Neutropenic events were shown to occur frequently in routine clinical practice. Several factors, including age, chemotherapy regimen type, planned chemotherapy dose intensity, and planned number of chemotherapy cycles, were shown to be potentially important elements of neutropenia risk models. Multilevel re-analysis showed higher level variation (i.e., variation at the level of the treating physicians or study centres) to be present in the asthma dataset and in the neutropenia dataset, but not in the gatekeeping dataset. In the first-mentioned cases, multilevel modelling allowed to quantify the amount of higher level variation; to identify its sources; to identify spurious findings by analysing influential higher level units; to achieve a gain in statistical precision; and to achieve a modest gain in predictive ability for out-of-sample observations whose corresponding higher level units contributed to model estimation. The main conclusions of the conventional analyses were confirmed. Based on these findings and in conjunction with published sources, it is concluded that multilevel modelling should be used systematically where hierarchical data structures are present, except if the higher level units must be regarded as distinct, unrelated entities or if their number is very small. Erroneous inferences will thus become more unlikely. Moreover, multilevel modelling is the only technique to date which allows to efficiently test hypotheses at different hierarchical levels, and hypotheses involving several levels, simultaneously. In the authors opinion, multilevel analysis is of particular interest where characteristics of health care providers, and clinical practice patterns in particular, may impact on health outcomes or health economic outcomes. It is only another facet of the same argument that multilevel modelling should also be used in multi-centre studies (including randomised clinical trials) to take into account study centre-specific characteristics and behaviours. In many instances, the use of the technique will be tentative and rule out the presence of substantial higher level variation. If so, simpler methods can again be used. Besides some technical issues, the main disadvantage of multilevel modelling is the complexity involved with the modelling process and with correctly interpreting the results. A careful approach is therefore needed. Multilevel modelling can be applied to datasets post hoc, as the author has done, but superior results can be expected from studies which are planned with the requirements of multilevel analysis (e.g., appropriate sample size, collection of relevant covariates at all hierarchical levels) in mind

Epidemiology and costs of gastroesophageal reflux disease in Switzerland: a population-based study

Summary: Objectives: Assessment of the prevalence, health care resource use and cost of gastroesophageal reflux disease in Switzerland. Methods: A population-based telephone survey was conducted in German and French speaking Switzerland. Reflux cases were defined using a questionnaire proposed by the German Gastro League and answered additional questions on their personal characteristics and resource use. Results: 1274 out of 7222 participants were positively screened. The prevalence of reflux disease in Swiss adults was estimated at 17.6% (95% CI: 15.6%-19.7%) or 993000 individuals. Regular treatment with medication was reported by 38.0% of the reflux positive sample. Reflux-induced general practitioner consultations during the last year were reported by 25.9%. On average, there were 0.84 general practitioner consultations, 0.19 specialist consultations, 0.08 gastroscopies and 0.01 hospitalisations annually. Mean direct medical costs, dominated by medication costs, were CHF 185 per patient-year (95 % CI: CHF 140-230) or 0.5% of Switzerland's total health care expenditures. Total costs were CHF 234 (95% CI: CHF 185-284) per patient-year. Conclusions: The prevalence of reflux disease in Switzerland is similar to that in other industrialised countries. Reflux disease causes considerable costs, in the medical system and at the societal leve

Human epidermal growth factor receptor 2 expression in early breast cancer patients: a Swiss cost-effectiveness analysis of different predictive assay strategies

Trastuzumab has conferred significant clinical benefits in HER-2-positive breast carcinomas. HER-2 status is determined by immunohistochemistry (IHC) and/or fluorescence in situ hybridisation (FISH), but appropriate assessment of HER2 status remains subject to considerable debate. Data on the health economic impact of HER-2 test strategies are limited. A life-long Markov state transition model was used to assess costs and effectiveness of HER-2 assay strategies (based on IHC, FISH, both combined or FISH confirmation of IHC2+) for a hypothetical cohort of early breast cancer patients from the perspective of the Swiss health system. We compared clinically relevant strategies of predictive testing and subsequent trastuzumab treatment of HER-2-positive patients only. FISH testing was the most cost-effective strategy with an incremental cost-effectiveness ratio of €12,245 per additional quality-adjusted life-year (QALY) gained, compared to no trastuzumab treatment. The next best strategy was parallel IHC and FISH, with costs of €400,154/QALY gained compared to FISH alone. FISH as primary HER-2 testing modality remained the preferred option in deterministic and probabilistic sensitivity analysis. Predictive testing to identify adjuvant breast cancer patients who benefit from trastuzumab treatment is a clinical and economic necessity. Our model identifies FISH as the most cost-effective approac

A model of osteoporosis impact in Switzerland 2000-2020

The aim of our study was to develop a modeling framework suitable to quantify the incidence, absolute number and economic impact of osteoporosis-attributable hip, vertebral and distal forearm fractures, with a particular focus on change over time, and with application to the situation in Switzerland from 2000 to 2020. A Markov process model was developed and analyzed by Monte Carlo simulation. A demographic scenario provided by the Swiss Federal Statistical Office and various Swiss and international data sources were used as model inputs. Demographic and epidemiologic input parameters were reproduced correctly, confirming the internal validity of the model. The proportion of the Swiss population aged 50 years or over will rise from 33.3% in 2000 to 41.3% in 2020. At the total population level, osteoporosis-attributable incidence will rise from 1.16 to 1.54 per 1,000 person-years in the case of hip fracture, from 3.28 to 4.18 per 1,000 person-years in the case of radiographic vertebral fracture, and from 0.59 to 0.70 per 1,000 person-years in the case of distal forearm fracture. Osteoporosis-attributable hip fracture numbers will rise from 8,375 to 11,353, vertebral fracture numbers will rise from 23,584 to 30,883, and distal forearm fracture numbers will rise from 4,209 to 5,186. Population-level osteoporosis-related direct medical inpatient costs per year will rise from 713.4million Swiss francs (CHF) to CHF946.2million. These figures correspond to 1.6% and 2.2% of Swiss health care expenditures in 2000. The modeling framework described can be applied to a wide variety of settings. It can be used to assess the impact of new prevention, diagnostic and treatment strategies. In Switzerland incidences of osteoporotic hip, vertebral and distal forearm fracture will rise by 33%, 27%, and 19%, respectively, between 2000 and 2020, if current prevention and treatment patterns are maintained. Corresponding absolute fracture numbers will rise by 36%, 31%, and 23%. Related direct medical inpatient costs are predicted to increase by 33%; however, this estimate is subject to uncertainty due to limited availability of input dat

Pneumococcal vaccination among adult risk patient with axial spondyloarthritis in Switzerland: Data from the survey of the ankylosing spondylitis association of Switzerland (SVMB)

While in Switzerland, pneumococcal vaccination is recommended for adult patients with axial spondyloarthritis (axSpA) treated with biological drugs, since 2014, little is known about the vaccination status of this specific patient population. This study assessed their vaccination status as part of a larger online survey by the ankylosing spondylitis association of Switzerland (SVMB). Out of 1560 who participated in the survey, 834 (53.5%) were eligible for the analysis. Vaccine coverage was low at 32.5% (271/834). Women and patients who got a flu shot every year were more likely to be covered. Age was negatively associated with being vaccinated. Most (54.2%; 147/271) were vaccinated by their general practitioner. Almost two-thirds of those who had not received the vaccine stated that it had not been offered to them (64.1%; 302/471). In summary, the vaccination coverage is low, but might be increased if the vaccine was offered systematically by general practitioners and specialists

Trends in Influenza Vaccination Coverage Rates in Germany over Six Seasons from 2001/02 to 2006/07

Abstract : Background and Purpose: : Influenza is a considerable health problem all over the world. Vaccination is the most important measure for preventing influenza and reducing morbidity and mortality. The aims of this study were to assess influenza vaccination coverage from 2001 to 2007 in Germany, to understand motivations and barriers to vaccination, and to identify vaccination intentions for season 2007/08. Methods: : In representative household surveys, 12,039 telephone interviews with individuals aged ≥ 14 years were conducted between 2001 and 2007. Essentially the same questionnaire was used in all seasons. Results: : In season 2006/07, the overall influenza vaccination coverage rate dropped from 32.5% in the previous season to 27.4%. In the elderly (≥ 60 years), the rate decreased from 51.6% to 44.7% and the odds ratio of being vaccinated, compared to those not belonging to a high-risk group, remained < 5. Chronically ill elderly persons had an odds ratio of vaccination of 7, while younger chronically ill persons and health-care workers had odds ratios of about 2. Perceiving influenza as a serious illness was the most frequent reason for getting vaccinated. 14% of those vaccinated in 2006/07 indicated the threat of avian flu as a reason. The main reason for not getting vaccinated was thinking not to be likely to catch the flu. A recommendation by the family doctor/nurse was perceived as the major encouraging factor for vaccination. A total of 44.7% of the respondents intended to get vaccinated against influenza in 2007/08. Conclusion: : A trend of increasing vaccination rates was observed from 2001 to 2006 in Germany, but the rates dipped by almost a sixth after 2005/06. The loss of media interest in the threat of avian influenza after February 2006 and stalling reimbursement programs may have contributed to the recent drop in vaccination rate

Direct medical costs of type 2 diabetes and its complications in Switzerland

Background: This paper analyses the direct medical costs of type 2 diabetes and its complications in Switzerland. Methods: Individual healthcare resource consumption related to type 2 diabetes and its complications was determined retrospectively in 1479 non-incident and non-dying patients over 12 months (1998-1999). Literature-derived attributable risks were used to correct for non-diabetes related macrovascular disease. Results: A total of 111 primary care physicians from 19 cantons throughout Switzerland participated. Their diabetic patients on average had 10.3 consultations per year related to this disease (95% CI: 10.0-10.7). Patients spent on average 2.7 days (95% CI: 2.2-3.3) per year in hospital due to diabetes and diabetes-related complications. Mean annual type 2 diabetes-related direct medical costs per patient amounted to CHF 3,508 / € 2,323 (95% CI: CHF 3,140-3,876 / € 2,080-2,567). They were particularly high in patients with insulin treatment or with complications. After application of attributable risks and a correction for the use of adjuvant materials, costs were CHF 3,324 / € 2,201. Assuming 250,000 patients with type 2 diabetes in Switzerland leads to an estimate of CHF 0.88 billion spent for this disease and its complications in 1998. This represents a share of about 2.2% of the country's total healthcare expenditures. Conclusion: These findings demonstrate the high economic importance of type 2 diabetes and its complications in Switzerlan

Geografische Unterschiede in der Inanspruchnahme von Gesundheitsleistungen

Geografische Variabilität der Inanspruchnahme von Gesundheitsleistungen hat vielfältige Ursachen. Sie kann auf Qualitätsprobleme im Gesundheitswesen hinweisen. Über die Situation in der Schweiz war bisher wenig bekannt. Die Studie «Geographic variation in the utilisation of health care inter­ventions: what is the role of recommendations and other influences?» widmete sich diesem Fragen­komplex

Cost-Effectiveness of Eplerenone in Patients with Left Ventricular Dysfunction after Myocardial Infarction—An Analysis of the EPHESUS Study from a Swiss Perspective

Objective: The EPHESUS study demonstrated that aldosterone blockade with eplerenone decreased mortality in patients with left ventricular systolic dysfunction (LVSD) and heart failure after acute myocardial infarction (AMI). The EPHESUS pharmacoeconomic analysis was performed to evaluate the cost-effectiveness of eplerenone in the Swiss setting. Materials and methods: A total of 6,632 patients with LVSD and heart failure after AMI were randomized to eplerenone or placebo and followed for a mean of 16months. The co-primary endpoints were all-cause death and the composite of cardiovascular death/cardiovascular hospitalization. The evaluation of resource use included hospitalizations, outpatient services, and medications. Survival beyond the trial period was estimated using data from the Framingham Heart Study, the Saskatchewan Health database, and the Worcester Heart Attack Registry. The incremental cost-effectiveness of eplerenone in cost per life-year and quality-adjusted life-year gained was estimated. The perspective of the Swiss third party payers was used. Daily treatment costs of eplerenone were set at CHF 3.88. All other resources were valued on the basis of official tariffs. Discounting of the results was performed at a rate of 3%. Results: The number of life-years gained with eplerenone was 0.1083 based on Framingham, 0.0661 with Saskatchewan and 0.1518 with Worcester survival estimates. Total costs were CHF 1,028 higher over the trial period in the eplerenone arm, due to drug cost. The incremental cost-effectiveness ratio was CHF 10,145 per life-year gained with Framingham, CHF 16,178 with Saskatchewan, and CHF 7,693 with Worcester survival estimates. The corresponding costs per QALY were CHF 15,219, CHF 23,965 and CHF 11,337, respectively. Conclusion: Eplerenone is effective in reducing mortality and, in Switzerland, is also cost-effective in increasing years of life for patients with LVSD after AM

Health-related quality of life and its association with medication adherence in active pulmonary tuberculosis– a systematic review of global literature with focus on South Africa

IntroductionTuberculosis (TB) is a leading cause of morbidity and mortality in South Africa. Clinical parameters are important objective outcomes in TB; however they often are not directly correlated with subjective well-being of the patient, but can be assessed using patient-reported outcome (PRO) measures. Health-related quality of life (HRQOL) is a specific PRO generally multi-dimensional in nature and includes physical, mental and social health domains. The inclusion of HRQOL PROs in trials and clinical practice can provide additional information beyondclinical and microbiological parameters. Furthermore, HRQOL may be associated with medication adherence. This review focuses on patient-reported HRQOL and its association with medication adherence in TB patients in South Africa.MethodsA comprehensive search strategy was developed focusing on the impact of TB on patient-reported HRQOL,the existence of a conceptual framework of TB-specific HRQOL, determinants of medication adherence and the association of HRQOL with medication adherence. Data were extracted from all identified articles and additionaldata extraction was performed by two independent reviewers with special focus on longitudinal studies in order to understand changes of HRQOL and adherence over time. Research gaps were identified with regard to patient-reported HRQOL and medication adherence.ResultsA total of 66 articles met the eligibility criteria. Ten HRQOL studies and one adherence study used a longitudinal design, none of these in South Africa. A variety of different generic and disease-specific HRQOL measures were identified in the articles. In South Africa four HRQOL and five adherence studies (non-longitudinal) were published. Similar factors (socio-demographic, socio-economic, disease-related, therapy-related and psycho-social aspects) affect HRQOL and adherence. Although standard TB treatment improved all health domains, psychological well-being and social functioning remained impaired in microbiologically cured patients after treatment.ConclusionWhile evidence of TB impact on HRQOL and medication adherence and their association exists, it is verylimited for the South African situation. No valid and reliable TB-specific HRQOL measures were identified in this systematicreview. An assessment of HRQOL in TB patients in South Africa is required as this may assist with improving current disease management programmes, medication adherence and national treatment guidelines.Electronic supplementary materialThe online version of this article (doi:10.1186/s12955-016-0442-6) contains supplementary material, which is available to authorized users