A Call for Caution When Using Network Methods to Study Multimorbidity: An Illustration Using Data from the Canadian Longitudinal Study on Aging (CLSA).

OBJECTIVE: To examine the impact of two key choices when conducting a network analysis (clustering methods and measure of association) on the number and type of multimorbidity clusters. STUDY DESIGN AND SETTING: Using cross-sectional self-reported data on 24 diseases from 30,097 community-living adults aged 45-85 from the Canadian Longitudinal Study on Aging, we conducted network analyses using 5 clustering methods and 11 association measures commonly used in multimorbidity studies. We compared the similarity among clusters using the adjusted Rand index (ARI); an ARI of 0 is equivalent to the diseases being randomly assigned to clusters and 1 indicates perfect agreement. We compared the network analysis results to disease clusters independently identified by two clinicians. RESULTS: Results differed greatly across combinations of association measures and cluster algorithms. The number of clusters identified ranged from 1 to 24, with low similarity of conditions within clusters. Compared to clinician-derived clusters, ARIs ranged from -0.02 to 0.24 indicating little similarity. CONCLUSION: These analyses demonstrate the need for a systematic evaluation of the performance of network analysis methods on binary clustered data like diseases. Moreover, in individual older adults, diseases may not cluster predictably, highlighting the need for a personalized approach to their care.

Financial Toxicity and Health-Related Quality of Life Profile of Patients With Hematologic Malignancies Treated in a Universal Health Care System.

PURPOSE: We investigated the association of financial toxicity (FT) with the health-related quality of life (HRQoL) profile of patients with hematologic malignancies treated in a universal health care system. METHODS: We did a secondary analysis of six multicenter studies enrolling patients with hematologic malignancies. FT was evaluated using the financial difficulties item of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Multivariable linear regression models were used to assess the mean differences in HRQoL scores between patients with or without FT, while adjusting for key potential confounding factors. We also examined the prevalence of clinically important problems and symptoms by the experience of FT, using established thresholds for the EORTC QLQ-C30. Multivariable binary logistic regression analysis was performed to explore the risk factors associated with FT. RESULTS: Overall, 1,847 patients were analyzed, of whom 441 (23.9%) reported FT. We observed statistically and clinically relevant worse scores for patients with FT compared with those without FT for all the EORTC QLQ-C30 scales. The three largest clinically relevant mean differences between patients with and without FT were observed in pain (∆ = 19.6 [95% CI, 15.7 to 23.5]; P < .001), social functioning (∆ = -18.9 [95% CI, -22.5 to -15.2]; P < .001), and role functioning (Δ = -17.7 [95% CI, -22.1 to -13.3]; P < .001). Patients with FT tended to report a higher prevalence of clinically important problems and symptoms across all EORTC QLQ-C30 scales. In the univariable and multivariable analyses, the presence of FT was associated with the presence of comorbidities, an Eastern Cooperative Oncology Group performance status ≥1, and not receiving a salary. CONCLUSION: Patients with hematologic malignancies treated in the setting of a universal health care system who experience FT have a worse HRQoL profile compared with those without FT.

An Exploration of Methods to Resolve Inconsistent Self-Reporting of Chronic Conditions and Impact on Multimorbidity in the Canadian Longitudinal Study on Aging.

OBJECTIVES: To quantify inconsistent self-reporting of chronic conditions between the baseline (2011-2015) and first follow-up surveys (2015-2018) in the Canadian Longitudinal Study on Aging (CLSA), and to explore methods to resolve inconsistent responses and impact on multimorbidity. METHODS: Community-dwelling adults aged 45-85 years in the baseline and first follow-up surveys were included (n = 45,184). At each survey, participants self-reported whether they ever had a physician diagnosis of 35 chronic conditions. Identifiable inconsistent responses were enumerated. RESULTS: 32-40% of participants had at least one inconsistent response across all conditions. Illness-related information (e.g., taking medication) resolved most inconsistent responses (>93%) while computer-assisted software asking participants to confirm their inconsistent disease status resolved ≤53%. Using these adjudication methods, multimorbidity prevalence at follow-up increased by ≤1.6% compared to the prevalence without resolving inconsistent responses. DISCUSSION: Inconsistent self-reporting of chronic conditions is common but may not substantially affect multimorbidity prevalence. Future research should validate methods to resolve inconsistencies.

Optimizing Catalytic Depolymerization of Lignin in Ethanol with a Day-Clustered Box-Behnken Design.

Lignin is a potential resource for biobased aromatics with applications in the field of fuel additives, resins, and bioplastics. Via a catalytic depolymerization process using supercritical ethanol and a mixed metal oxide catalyst (CuMgAlOx), lignin can be converted into a lignin oil, containing phenolic monomers that are intermediates to the mentioned applications. Herein, we evaluated the viability of this lignin conversion technology through a stage-gate scale-up methodology. Optimization was done with a day-clustered Box-Behnken design to accommodate the large number of experimental runs in which five input factors (temperature, lignin-to-ethanol ratio, catalyst particle size, catalyst concentration, and reaction time) and three output product streams (monomer yield, yield of THF-soluble fragments, and yield of THF-insoluble fragments and char) were considered. Qualitative relationships between the studied process parameters and the product streams were determined based on mass balances and product analyses. Linear mixed models with random intercept were employed to study quantitative relationships between the input factors and the outcomes through maximum likelihood estimation. The response surface methodology study reveals that the selected input factors, together with higher order interactions, are highly significant for the determination of the three response surfaces. The good agreement between the predicted and experimental yield of the three output streams is a validation of the response surface methodology analysis discussed in this contribution.

Short- and long-term outcomes after endarterectomy with autologous patching in endurance athletes with iliac artery endofibrosis.

OBJECTIVE: Endurance athletes such as cyclists may develop intermittent claudication owing to iliac artery endofibrosis after long-lasting extreme hemodynamic challenges. This study investigated short-term (<1.5 years) and long-term (>5 years) satisfaction and safety after a surgical endarterectomy and autologous patching. METHODS: Data of endurance athletes who underwent an endarterectomy for flow limitation of the iliac artery owing to endofibrosis between 1997 and 2015 in one center were studied. Maximal cycling exercise tests, ankle-brachial index with flexed hips, echo-Doppler examination (peak systolic velocity), and contrast-enhanced magnetic resonance angiography were performed before and 6 to 18 months after surgery. Short-term and long-term satisfaction were evaluated using questionnaires. Potential patch dilatation was assessed using echo-Doppler. RESULTS: Analysis of 68 patients (79 legs; 55.7% males, median age at the time of surgery, 34 years; interquartile range, 26-41 years) demonstrated that cycling workload at symptom onset improved from 226 ± 97 to 333 ± 101 (P < .001) Watts. Peak workload increased from 326 ± 111 to 352 ± 93 Watts (P < .001). Ankle-brachial index with flexed hips increased from 0.34 (interquartile range [IQR], 0.00-0.47) to 0.59 (IQR, 0.51-0.69; P < .001). Peak systolic velocity with extended and flexed hip decreased from 2.04 m·sec-1 (IQR, 1.52-2.56 m·3sec-1) to 1.25 m·sec-1 (IQR, 0.92-1.62 m·sec-1; P < .001) and 2.40 m·sec-1 (IQR, 1.81-2.81 m·sec-1) to 1.15 m·sec-1 (IQR, 0.97-1.60 m·sec-1; P < .001), respectively. Thirty-day major complication rate was 5.1% (hematoma requiring evacuation nLegs = 2, septic bleeding from deep infection nLegs = 1, and iliac occlusion requiring thrombectomy nLegs = 1). In the short term, 91.2% of patients reported symptom reduction with a 93.7% overall satisfaction rate. After a median of 11.1 years (IQR, 7.8-17.6 years), the overall satisfaction was 91.7%; 94.5% of patients reported persistent symptom reduction. Patch dilatation of >20 mm was observed in two patients. Linear mixed model analysis revealed no alarming patch dilatation in the long term. CONCLUSIONS: Endarterectomy with an autologous patch for intermittent claudication owing to iliac artery endofibrosis in endurance athletes shows high rates of patient satisfaction and symptom reduction in both the short and long term. The risk of surgical complications or patch dilatation is mild. A surgical intervention for flow limitation of the iliac artery owing to endofibrosis is safe and successful.

Determinants of information needs in patients with coronary artery disease receiving cardiac rehabilitation: a prospective observational study.

OBJECTIVES: Knowledge on information needs in cardiac rehabilitation (CR) patients is scarce. This study investigates determinants of information needs in patients with coronary artery disease (CAD). DESIGN: Prospective observational study. PARTICIPANTS: A total of 259 patients participated. SETTING: CR centre serving a general hospital in The Netherlands. METHODS: Patients with a coronary event and/or revascularisation referred for CR completed questionnaires assessing their level of information needs with respect to nutrition, physical activity, smoking, medication use and psychological well-being, and potential determinants of information needs (sociodemographic characteristics, health literacy, illness perceptions, anxiety, depression, Type D personality and quality of life). RESULTS: The majority (63%) of patients indicated a need for information on at least one of the four topics (nutrition, physical activity, medication use, psychological well-being), with considerable inter-individual variation. Female sex, being employed, higher socioeconomic status, higher levels of anxiety and higher illness perception were associated with higher information needs on specific topics. CONCLUSIONS: The majority of CR patients with CAD have a need for information, with considerable inter-individual variability. Several demographic, socioeconomic and psychosocial characteristics were related to their preference for information topics. These results underline the need for personalised information strategies in patients undergoing CR.

Surgical shortening of lengthened iliac arteries in endurance athletes: Short-term and long-term satisfaction.

OBJECTIVE: Endurance athletes are prone to develop flow limitations in iliac arteries (FLIA). Especially in cyclists and ice speed skaters, excessive hemodynamic loading coupled with hip hyperflexion may cause kinking in lengthened iliac arteries necessitating surgical correction. This study investigated the short-term (≤1.5 years) and long-term (≥5 years) satisfaction of operative shortening of the iliac artery in endurance athletes. METHODS: All patients who were diagnosed and operated for FLIA owing to lengthened and kinked iliac arteries between 1997 and 2015 in one center were analyzed. Short-term follow-up consisted of an incremental maximal cycling test, ankle-brachial index with flexed hips, echo-Doppler examination with peak systolic velocity measurements and contrast-enhanced magnetic resonance angiography before and 6 to 18 months after surgery. Both short- and long-term satisfaction were assessed using questionnaires. RESULTS: A total of 83 patients (90 operated legs; 96.7% males; median age of 34 years at the time of surgery; interquartile range [IQR], 29-47) were analyzed. In the short-term, 87.5% reported symptom reduction with an 86.4% overall satisfaction rate. Symptom-free cycling improved from 272 ± 84 W to 384 ± 101 W (P < .001), whereas the maximal workload increased from 419 ± 72 W to 428 ± 67 W (P = .01). The ankle-brachial index with flexed hips increased from 0.55 (IQR, 0.45-0.65) to 0.62 (IQR, 0.52-0.74; P = .008), and the peak systolic velocity measured with hips flexed decreased from 2.50 m/s (IQR, 1.77-3.13 m/s) to 1.57 m/s (IQR, 1.20-2.04 m/s; P < .001). After a median of 12 years (IQR, 9.0-15.4 years), symptoms were still decreased in 84.1% of patients with an 81.2% overall satisfaction rate (79.5% response rate). Three patients needed a reintervention (recurrent FLIA, n = 2; failure, n = 1). CONCLUSIONS: Operative shortening of a lengthened and kinked iliac artery causing FLIA is successful both in the short- and long-term.

Short- and long-term results of operative iliac artery release in endurance athletes.

OBJECTIVE: Endurance athletes can develop intermittent claudication due to sports-related flow limitations of the iliac artery (FLIA) caused by arterial kinking. In the present study, we investigated the short- and long-term efficacy of an operative release for iliac artery kinking. METHODS: Between 1996 and 2015, all patients with a diagnosis of FLIA due to iliac artery kinking without substantial arterial stenosis (<15%) or an excessive arterial length (vessel length to straight ratio, <1.25) who had undergone surgery were included. The short-term follow-up protocol consisted of cycling tests, the ankle brachial index with a flexed hip, and Doppler echography examinations to determine the peak systolic velocity before and 6 to 18 months after surgery. Additionally, the short- and long-term efficacy were evaluated using questionnaires. RESULTS: A total of 142 endurance athletes (155 legs; 88.4% male; median age, 26 years; interquartile range [IQR], 22-31 years) were available for analysis. In the short term, the symptoms had decreased in 83.9% of the patients, with an overall 80.3% satisfaction rate. Power during a maximal cycling test had improved from 420 W (IQR, 378-465 W) to 437 W (IQR, 392-485 W; P < .001). The symptom-free workload had increased from 300 W (IQR, 240-340 W) to 400 W (IQR, 330-448 W; P < .001). The postexercise ankle brachial index with a flexed hip had increased from 0.53 (IQR, 0.40-0.61) to 0.57 (IQR, 0.47-0.64; P = .002), and the peak systolic velocity with a flexed hip had decreased from 1.88 m/s (IQR, 1.45-2.50 m/s) to 1.52 m/s (IQR, 1.19-2.07 m/s; P < .001). Postoperative imaging studies revealed some degree kinking in 33.9%, mostly asymptomatic. The long-term results were evaluated after a median of 15.2 years (IQR, 10.9-19.5 years). The athletes had cycled an additional 125.500 km (IQR, 72.00-227.500 km), which was approximately equal to the 131.000 km (IQR, 98.250-220.000 km) cycled before the diagnosis of FLIA. On the long term, 63.9% of the athletes reported persistent reduction of complaints, with an overall 59.1% satisfaction rate. Eight patients had required reintervention, six because of treatment failure and two because of newly developed FLIA. CONCLUSIONS: Operative iliac artery release for sports-related functional kinking in the absence of stenosis or an excessive vessel length was effective for most athletes in the short and long term.

Predictors of non-participation in a cardiac telerehabilitation programme: a prospective analysis.

Aims: Current cardiac telerehabilitation (CTR) interventions are insufficiently tailored to the preferences and competences of individual patients, which raises the question whether their implementation will increase overall participation and adherence to cardiac rehabilitation (CR). However, research on patient-specific factors that influence participation and adoption of CTR interventions is scarce. The aim of this study was to evaluate which patient-related characteristics influence participation in a novel CTR intervention in patients with coronary artery disease. Methods and results: This prospective observational substudy of the SmartCare-CAD randomized controlled trial evaluated patient characteristics of study participants as proxy for participation in a CTR intervention. We compared demographic, geographic, and health-related characteristics between trial participants and non-participants to determine which characteristics influenced trial participation. A total of 699 patients (300 participants and 399 non-participants; 84% male, mean age 64.3 ± 10.5 years) were included. Most of the non-participants refused participation because of insufficient technical skills or lack of interest in digital health (26%), or preferred centre-based CR (21%). Variables independently associated with non-participation included: higher age, lower educational level, shorter travelling distance, smoking, positive family history for cardiovascular disease, having undergone coronary artery bypass grafting; and a higher blood pressure, worse exercise capacity, and higher risk of depression before the start of CR. Conclusion: Participation in CTR is strongly influenced by demographic and health-related factors such as age, educational level, smoking status, and both physical and mental functioning. Cardiac telerehabilitation interventions should therefore be redesigned with the involvement of these currently underrepresented patient subgroups.

Improved One-Class Modeling of High-Dimensional Metabolomics Data via Eigenvalue-Shrinkage.

One-class modelling is a useful approach in metabolomics for the untargeted detection of abnormal metabolite profiles, when information from a set of reference observations is available to model "normal" or baseline metabolite profiles. Such outlying profiles are typically identified by comparing the distance between an observation and the reference class to a critical limit. Often, multivariate distance measures such as the Mahalanobis distance (MD) or principal component-based measures are used. These approaches, however, are either not applicable to untargeted metabolomics data, or their results are unreliable. In this paper, five distance measures for one-class modeling in untargeted metabolites are proposed. They are based on a combination of the MD and five so-called eigenvalue-shrinkage estimators of the covariance matrix of the reference class. A simple cross-validation procedure is proposed to set the critical limit for outlier detection. Simulation studies are used to identify which distance measure provides the best performance for one-class modeling, in terms of type I error and power to identify abnormal metabolite profiles. Empirical evidence demonstrates that this method has better type I error (false positive rate) and improved outlier detection power than the standard (principal component-based) one-class models. The method is illustrated by its application to liquid chromatography coupled to mass spectrometry (LC-MS) and nuclear magnetic response spectroscopy (NMR) untargeted metabolomics data from two studies on food safety assessment and diagnosis of rare diseases, respectively.