State of the art in selection of variables and functional forms in multivariable analysis-outstanding issues

Background: How to select variables and identify functional forms for continuous variables is a key concern when creating a multivariable model. Ad hoc ‘traditional’ approaches to variable selection have been in use for at least 50 years. Similarly, methods for determining functional forms for continuous variables were first suggested many years ago. More recently, many alternative approaches to address these two challenges have been proposed, but knowledge of their properties and meaningful comparisons between them are scarce. To define a state of the art and to provide evidence-supported guidance to researchers who have only a basic level of statistical knowledge, many outstanding issues in multivariable modelling remain. Our main aims are to identify and illustrate such gaps in the literature and present them at a moderate technical level to the wide community of practitioners, researchers and students of statistics. Methods: We briefly discuss general issues in building descriptive regression models, strategies for variable selection, different ways of choosing functional forms for continuous variables and methods for combining the selection of variables and functions. We discuss two examples, taken from the medical literature, to illustrate problems in the practice of modelling. Results: Our overview revealed that there is not yet enough evidence on which to base recommendations for the selection of variables and functional forms in multivariable analysis. Such evidence may come from comparisons between alternative methods. In particular, we highlight seven important topics that require further investigation and make suggestions for the direction of further research. Conclusions: Selection of variables and of functional forms are important topics in multivariable analysis. To define a state of the art and to provide evidence-supported guidance to researchers who have only a basic level of statistical knowledge, further comparative research is required

Radiographic joint damage in rheumatoid arthritis is associated with differences in cartilage turnover and can be predicted by serum biomarkers: an evaluation from 1 to 4 years after diagnosis

INTRODUCTION: The objective of this study was to determine whether serum biomarkers for degradation and synthesis of the extracellular matrix of cartilage are associated with, and can predict, radiographic damage in patients with rheumatoid arthritis (RA). METHODS: Clinical and radiographic data of 87 RA patients were recorded 1 year after disease onset and then annually up to four years. Serum concentrations of four cartilage biomarkers were determined at these time points: a neoepitope formed by collagenase cleavage of type II collagen (C2C), a neoepitope formed by collagenase cleavage of type II collagen as well as type I collagen (C1,2C), a carboxy propeptide of type II procollagen formed during synthesis (CPII), and a cartilage proteoglycan aggrecan turnover epitope (CS846-epitope). Biomarker concentrations between patients with rapid radiographic progression (>7.3 Sharp/van der Heijde units per year) and those with slow radiographic progression (<2.3 units per year) were compared. In addition, we evaluated the long-term and short-term predictive value of each biomarker for progression of radiographic damage. RESULTS: Patients with rapid radiographic progression had higher C2C, higher C1,2C, and higher CS846-epitope levels than slow progressors. CPII levels showed no differences. Most importantly, the long-term radiographic progression for C2C, for C1,2C, and for CS846-epitope can be predicted by the biomarker value at year 1 after disease onset. C2C was also a predictor for joint space narrowing and annual radiographic damage during the subsequent year. CONCLUSION: This study shows that the concentration of serum biomarkers of cartilage collagen breakdown and proteoglycan turnover, but not of collagen synthesis, are related to joint destruction in RA. The use of these biomarkers may be of value when studying progression of joint damage in patients with RA

A semi-parametric approach to estimate risk functions associated with multi-dimensional exposure profiles: application to smoking and lung cancer

A common characteristic of environmental epidemiology is the multi-dimensional aspect of exposure patterns, frequently reduced to a cumulative exposure for simplicity of analysis. By adopting a flexible Bayesian clustering approach, we explore the risk function linking exposure history to disease. This approach is applied here to study the relationship between different smoking characteristics and lung cancer in the framework of a population based case control study

Validation of population-based disease simulation models: a review of concepts and methods

Abstract Background Computer simulation models are used increasingly to support public health research and policy, but questions about their quality persist. The purpose of this article is to review the principles and methods for validation of population-based disease simulation models. Methods We developed a comprehensive framework for validating population-based chronic disease simulation models and used this framework in a review of published model validation guidelines. Based on the review, we formulated a set of recommendations for gathering evidence of model credibility. Results Evidence of model credibility derives from examining: 1) the process of model development, 2) the performance of a model, and 3) the quality of decisions based on the model. Many important issues in model validation are insufficiently addressed by current guidelines. These issues include a detailed evaluation of different data sources, graphical representation of models, computer programming, model calibration, between-model comparisons, sensitivity analysis, and predictive validity. The role of external data in model validation depends on the purpose of the model (e.g., decision analysis versus prediction). More research is needed on the methods of comparing the quality of decisions based on different models. Conclusion As the role of simulation modeling in population health is increasing and models are becoming more complex, there is a need for further improvements in model validation methodology and common standards for evaluating model credibility

The use of Systemic Lupus Erythematosus Disease Activity Index-2000 to define active disease and minimal clinically meaningful change based on data from a large cohort of systemic lupus erythematosus patients

Objectives. To examine SLEDAI-2000 cut-off scores for definition of active SLE and to determine the sensitivity to change of SLEDAI-2000 for the assessment of SLE disease activity and minimal clinically meaningful changes in score

Quality of life and satisfaction with life in SLE patients—the importance of clinical manifestations

To assess the correlation between quality of life (QoL) and satisfaction with life (SL) in SLE patients and correlate both with clinical symptoms of the disease. The study was performed in 83 patients. QoL was assessed by Short Form 36, and SL was assessed by the Satisfaction with Life Scale. Clinical manifestations presented at the time of examination were taken into consideration. SLE patients assessed their QoL and SL as rather low. Those with photosensitivity as well as neurological symptoms presented lower QoL in particular domains, while those with renal manifestation of SLE assessed their QoL as higher. Similar observations were made for SL only in relation to neurological symptoms. Moreover, our findings show that although SL is a part of QoL, both these parameters should be distinguished in order to fully assess the state of the patient

Flares after hydroxychloroquine reduction or discontinuation: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort

OBJECTIVES: To evaluate systemic lupus erythematosus (SLE) flares following hydroxychloroquine (HCQ) reduction or discontinuation versus HCQ maintenance. METHODS: We analysed prospective data from the Systemic Lupus International Collaborating Clinics (SLICC) cohort, enrolled from 33 sites within 15 months of SLE diagnosis and followed annually (1999-2019). We evaluated person-time contributed while on the initial HCQ dose ('maintenance'), comparing this with person-time contributed after a first dose reduction, and after a first HCQ discontinuation. We estimated time to first flare, defined as either subsequent need for therapy augmentation, increase of ≥4 points in the SLE Disease Activity Index-2000, or hospitalisation for SLE. We estimated adjusted HRs (aHRs) with 95% CIs associated with reducing/discontinuing HCQ (vs maintenance). We also conducted separate multivariable hazard regressions in each HCQ subcohort to identify factors associated with flare. RESULTS: We studied 1460 (90% female) patients initiating HCQ. aHRs for first SLE flare were 1.20 (95% CI 1.04 to 1.38) and 1.56 (95% CI 1.31 to 1.86) for the HCQ reduction and discontinuation groups, respectively, versus HCQ maintenance. Patients with low educational level were at particular risk of flaring after HCQ discontinuation (aHR 1.43, 95% CI 1.09 to 1.87). Prednisone use at time-zero was associated with over 1.5-fold increase in flare risk in all HCQ subcohorts. CONCLUSIONS: SLE flare risk was higher after HCQ taper/discontinuation versus HCQ maintenance. Decisions to maintain, reduce or stop HCQ may affect specific subgroups differently, including those on prednisone and/or with low education. Further study of special groups (eg, seniors) may be helpful

QUARITE (quality of care, risk management and technology in obstetrics): a cluster-randomized trial of a multifaceted intervention to improve emergency obstetric care in Senegal and Mali

<p>Abstract</p> <p>Background</p> <p>Maternal and perinatal mortality are major problems for which progress in sub-Saharan Africa has been inadequate, even though childbirth services are available, even in the poorest countries. Reducing them is the aim of two of the main Millennium Development Goals. Many initiatives have been undertaken to remedy this situation, such as the Advances in Labour and Risk Management (ALARM) International Program, whose purpose is to improve the quality of obstetric services in low-income countries. However, few interventions have been evaluated, in this context, using rigorous methods for analyzing effectiveness in terms of health outcomes. The objective of this trial is to evaluate the effectiveness of the ALARM International Program (AIP) in reducing maternal mortality in referral hospitals in Senegal and Mali. Secondary goals include evaluation of the relationships between effectiveness and resource availability, service organization, medical practices, and satisfaction among health personnel.</p> <p>Methods/Design</p> <p>This is an international, multi-centre, controlled cluster-randomized trial of a complex intervention. The intervention is based on the concept of evidence-based practice and on a combination of two approaches aimed at improving the performance of health personnel: 1) Educational outreach visits; and 2) the implementation of facility-based maternal death reviews.</p> <p>The unit of intervention is the public health facility equipped with a functional operating room. On the basis of consent provided by hospital authorities, 46 centres out of 49 eligible were selected in Mali and Senegal. Using randomization stratified by country and by level of care, 23 centres will be allocated to the intervention group and 23 to the control group. The intervention will last two years. It will be preceded by a pre-intervention one-year period for baseline data collection. A continuous clinical data collection system has been set up in all participating centres. This, along with the inventory of resources and the satisfaction surveys administered to the health personnel, will allow us to measure results before, during, and after the intervention. The overall rate of maternal mortality measured in hospitals during the post-intervention period (Year 4) is the primary outcome. The evaluation will also include cost-effectiveness.</p> <p>Trial Registration</p> <p>The QUARITE trial is registered on the Current Controlled Trials website under the number ISRCTN46950658 <url>http://www.controlled-trials.com/</url>.</p

Associations of education with 30 year life course blood pressure trajectories: Framingham Offspring Study

Background: Education is inversely associated with cardiovascular disease incidence in developed countries. Blood pressure may be an explanatory biological mechanism. However few studies have investigated educational gradients in longitudinal blood pressure trajectories, particularly over substantial proportions of the life course. Study objectives were to determine whether low education was associated with increased blood pressure from multiple longitudinal assessments over 30 years. Furthermore, we aimed to separate antecedent effects of education, and other related factors, that might have caused baseline differences in blood pressure, from potential long-term effects of education on post-baseline blood pressure changes. Methods: The study examined 3890 participants of the Framingham Offspring Study (mean age 36.7 years, 52.0% females at baseline) from 1971 through 2001 at up to 7 separate examinations using multivariable mixed linear models. Results: Mixed linear models demonstrated that mean systolic blood pressure (SBP) over 30 years was higher for participants with ≤12 vs. ≥17 years education after adjusting for age (3.26 mmHg, 95% CI: 1.46, 5.05 in females, 2.26 mmHg, 95% CI: 0.87, 3.66 in males). Further adjustment for conventional covariates (antihypertensive medication, smoking, body mass index and alcohol) reduced differences in females and males (2.86, 95% CI: 1.13, 4.59, and 1.25, 95% CI: -0.16, 2.66 mmHg, respectively). Additional analyses adjusted for baseline SBP, to evaluate if there may be educational contributions to post-baseline SBP. In analyses adjusted for age and baseline SBP, females with ≤12 years education had 2.69 (95% CI: 1.09, 4.30) mmHg higher SBP over follow-up compared with ≥17 years education. Further adjustment for aforementioned covariates slightly reduced effect strength (2.53 mmHg, 95% CI: 0.93, 4.14). Associations were weaker in males, where those with ≤12 years education had 1.20 (95% CI: -0.07, 2.46) mmHg higher SBP over follow-up compared to males with ≥17 years of education, after adjustment for age and baseline blood pressure; effects were substantially reduced after adjusting for aforementioned covariates (0.34 mmHg, 95% CI: -0.90, 1.68). Sex-by-education interaction was marginally significant (p = 0.046). Conclusion: Education was inversely associated with higher systolic blood pressure throughout a 30-year life course span, and associations may be stronger in females than males.Eric B Loucks, Michal Abrahamowicz, Yongling Xiao, John W Lync