Analyzing risk factors for post-acute recovery in older adults with Alzheimer's disease and related dementia: A new semi-parametric model for large-scale medicare claims.

Nearly 300,000 older adults experience a hip fracture every year, the majority of which occur following a fall. Unfortunately, recovery after fall-related trauma such as hip fracture is poor, where older adults diagnosed with Alzheimer's disease and related dementia (ADRD) spend a particularly long time in hospitals or rehabilitation facilities during the post-operative recuperation period. Because older adults value functional recovery and spending time at home versus facilities as key outcomes after hospitalization, identifying factors that influence days spent at home after hospitalization is imperative. While several individual-level factors have been identified, the characteristics of the treating hospital have recently been identified as contributors. However, few methodological rigorous approaches are available to help overcome potential sources of bias such as hospital-level unmeasured confounders, informative hospital size, and loss to follow-up due to death. This article develops a useful tool equipped with unsupervised learning to simultaneously handle statistical complexities that are often encountered in health services research, especially when using large administrative claims databases. The proposed estimator has a closed form, thus only requiring light computation load in a large-scale study. We further develop its asymptotic properties with stabilized inference assisted by unsupervised clustering. Extensive simulation studies demonstrate superiority of the proposed estimator compared to existing estimators.

A statistical framework for recovering pseudo-dynamic networks from static data.

MOTIVATION: The collection of temporal or perturbed data is often a prerequisite for reconstructing dynamic networks in most cases. However, these types of data are seldom available for genomic studies in medicine, thus significantly limiting the use of dynamic networks to characterize the biological principles underlying human health and diseases. RESULTS: We proposed a statistical framework to recover disease risk-associated pseudo-dynamic networks (DRDNet) from steady-state data. We incorporated a varying coefficient model with multiple ordinary differential equations to learn a series of networks. We analyzed the publicly available Genotype-Tissue Expression data to construct networks associated with hypertension risk, and biological findings showed that key genes constituting these networks had pivotal and biologically relevant roles associated with the vascular system. We also provided the selection consistency of the proposed learning procedure and evaluated its utility through extensive simulations. AVAILABILITY AND IMPLEMENTATION: DRDNet is implemented in the R language, and the source codes are available at https://github.com/chencxxy28/DRDnet/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Synthesizing secondary data into survival analysis to improve estimation efficiency.

The accelerated failure time (AFT) model and Cox proportional hazards (PH) model are broadly used for survival endpoints of primary interest. However, the estimation efficiency from those models can be further enhanced by incorporating the information from secondary outcomes that are increasingly available and highly correlated with primary outcomes. Those secondary outcomes could be longitudinal laboratory measures collected from doctor visits or cross-sectional disease-relevant variables, which are believed to contain extra information related to primary survival endpoints to a certain extent. In this paper, we develop a two-stage estimation framework to combine a survival model with a secondary model that contains secondary outcomes, named as the empirical-likelihood-based weighting (ELW), which comprises two weighting schemes accommodated to the AFT model (ELW-AFT) and the Cox PH model (ELW-Cox), respectively. This innovative framework is flexibly adaptive to secondary outcomes with complex data features, and it leads to more efficient parameter estimation in the survival model even if the secondary model is misspecified. Extensive simulation studies showcase more efficiency gain from ELW compared to conventional approaches, and an application in the Atherosclerosis Risk in Communities study also demonstrates the superiority of ELW by successfully detecting risk factors at the time of hospitalization for acute myocardial infarction.

Light and moderate intensity physical activity are associated with better ambulation, quality of life, and vascular measurements in patients with claudication.

OBJECTIVE: We sought to determine whether patients with claudication who reported performing either light intensity physical activity (LPA) or moderate-to-vigorous intensity physical activity (MVPA) would have higher levels of objectively determined physical activity and better physical function, health-related quality of life (HRQoL), and vascular measures, consisting of exercise time to minimum calf muscle oxygen saturation (StO2) and high-sensitivity C-reactive protein, than patients who reported being physically sedentary. METHODS: A total of 269 patients were assessed using the Johnson Space Center physical activity scale. The patients were grouped according to whether they performed no physical activities (n = 75), LPAs (n = 140), or MVPAs (n = 54). The primary measurements were the total daily steps obtained from a step activity monitor worn for 1 week, peak walking time obtained from a treadmill test, physical function score on the Medical Outcomes Study short-form 36-item survey to assess HRQoL, and high-sensitivity C-reactive protein. RESULTS: The total daily steps was significantly different among the groups. Both the LPA group (mean ± standard deviation, 7878 ± 2808 steps/d) and the MVPA group (mean, 8551 ± 3365 steps/d) had taken more daily steps (P < .01) than had the sedentary group (mean, 3323 ± 986 steps/d). The treadmill peak walking time was significantly different among the three groups. Both the LPA group (433 ± 296 seconds) and the MVPA group (548 ± 300 seconds) had had a greater peak walking time (P < .01) than that of the sedentary group (302 ± 210 seconds). The physical function score was also significantly different among the groups. The LPA group (44% ± 20%) and MVPA group (58% ± 19%) both had had higher scores (P < .01) than the sedentary group (36% ± 20%). In addition, the exercise time to the minimum calf muscle StO2 was significantly different among the groups. Both the LPA group (215 ± 238 seconds) and the MVPA group (377 ± 351 seconds) had had greater values (P < .05 and P < .01, respectively) than the sedentary group (147 ± 172 seconds). Finally, the high-sensitivity C-reactive protein level was significantly different among the groups. Both the LPA group (4.8 ± 5.5 mg/L) and the MVPA group (3.5 ± 3.6 mg/L) had had lower values (P < .01) than the sedentary group (8.6 ± 8.4 mg/L). CONCLUSIONS: Patients with claudication who reported performing LPA had greater amounts of objectively determined physical activity levels and better physical function, HRQoL, and vascular measures than those who reported being physically sedentary. Furthermore, these favorable results associated with LPA were even more pronounced for the patients who performed MVPA compared with those who were sedentary. The clinical significance is that our results have shown that engaging in any physical activity, even at relatively light intensity, is associated with favorable health and vascular measures for patients with claudication.

Cumulative Consumption of Sulfur Amino Acids and Risk of Diabetes: A Prospective Cohort Study.

BACKGROUND: Cross-sectional studies have suggested that consumption of sulfur amino acids (SAAs), including methionine and cysteine, is associated with a higher risk of type 2 diabetes (T2D) in humans and with T2D-related biomarkers in animals. But whether higher long-term SAA intake increases the risk of T2D in humans remains unknown. OBJECTIVES: We aimed to investigate the association between long-term dietary SAA intake and risk of T2D. METHODS: We analyzed data collected from 2 different cohorts of the Framingham Heart Study, a long-term, prospective, and ongoing study. The Offspring cohort (1991-2014) included participants from fifth through ninth examinations, and the Third-Generation cohort (2002-2011) included participants from first and second examinations. After excluding participants with a clinical history of diabetes, missing dietary data, or implausible total energy intake, 3222 participants in the Offspring cohort and 3205 participants in the Third-Generation cohort were included. Dietary intake was assessed using a validated FFQ. The relations between energy-adjusted total SAA (methionine and cysteine) intake or individual SAA intake (in quintiles) and risk of incident T2D were estimated via Cox proportional hazards models after adjusting for dietary and nondietary risk factors. Associations across the 2 cohorts were determined by direct combination and meta-analysis. RESULTS: During the 23 y of follow-up, 472 participants reported a new diagnosis of T2D in the 2 cohorts. In the meta-analysis, the HRs of T2D comparing the highest with the lowest intake of total SAAs, methionine, and cysteine were 1.8 (95% CI: 1.3, 2.5), 1.7 (95% CI: 1.2, 2.3), and 1.4 (95% CI: 1.0, 2.1), respectively. The association of SAA intake with T2D was attenuated after adjusting animal protein intake in sensitivity analyses. CONCLUSIONS: Our findings show that excess intake of SAAs is associated with higher risk of T2D. Dietary patterns that are low in SAAs could help in preventing T2D.

Minimal clinically important differences in daily physical activity outcomes following supervised and home-based exercise in peripheral artery disease.

Introduction: We estimated minimal clinically important differences (MCID) for small, moderate, and large changes in daily step counts and time spent in moderate-to-vigorous physical activity (MVPA) following both supervised and home-based exercise programs in symptomatic patients with peripheral artery disease (PAD). Methods: Patients were randomized to either 12 weeks of a supervised exercise program (n = 60), a home-based exercise program (n = 60), or an attention-control group (n = 60). Results: Using the anchor-based method to determine MCID, the MCID value for a large change in health-related quality of life (HRQoL) was an increase of 1211 total daily steps and an increase in 11 minutes in the time spent in MVPA following 12 weeks of exercise intervention. Using the distribution-based method, the MCID values for small, moderate, and large changes in total daily steps in the home-based exercise group were 558, 1396, and 2233 steps/d, respectively, and the corresponding changes in the time spent in MVPA were 6, 15, and 23 minutes. Similar distribution-based MCID scores were noted for the supervised exercise group. Conclusion: Following 3 months of home-based and supervised exercise programs for patients with PAD and claudication, increases of 11 minutes in time spent in MVPA and 1211 total daily steps were associated with large anchor-based MCID increases in HRQoL. The clinical implication is that patients with PAD and claudication should be encouraged to increase daily steps, particularly by walking an additional 11 minutes each day in MVPA, which is associated with a large meaningful increase in HRQoL.

Semiparametric marginal methods for clustered data adjusting for informative cluster size with nonignorable zeros.

Clustered or longitudinal data are commonly encountered in clinical trials and observational studies. This type of data could be collected through a real-time monitoring scheme associated with some specific event, such as disease recurrence, hospitalization, or emergency room visit. In these contexts, the cluster size could be informative because of its potential correlation with disease status, since more frequency of observations may indicate a worsening health condition. However, for some clusters/subjects, there are no measures or relevant medical records. Under such circumstances, these clusters/subjects may have a considerably lower risk of an event occurrence or may not be susceptible to such events at all, indicating a nonignorable zero cluster size. There is a substantial body of literature using observations from those clusters with a nonzero informative cluster size only, but few works discuss informative nonignorable zero-sized clusters. To utilize the information from both event-free and event-occurring participants, we propose a weighted within-cluster-resampling (WWCR) method and its asymptotically equivalent method, dual-weighted generalized estimating equations (WWGEE) by adopting the inverse probability weighting technique. The asymptotic properties are rigorously presented theoretically. Extensive simulations and an illustrative example of the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study are performed to analyze the finite-sample behavior of our methods and to show their advantageous performance compared to the existing approaches.

Impact of radiation therapy facility volume on survival in patients with cancer.

BACKGROUND: This study examined whether radiation therapy facility volumes correlate with survival after curative intent treatment of solid tumors. METHODS: The National Cancer Database was queried for patients with solid tumors treated with curative-intent radiation therapy from 2004-2013. Facilities were stratified into 4 volume categories: low, intermediate, high, and very high. Primary cancer sites were divided into neoadjuvant, adjuvant, or definitive radiation subgroups. Kaplan-Meier curves of 5-year postradiation survival probability, stratified by facility volume, were generated with log-rank tests for group comparisons. Cox proportional hazard models were used to evaluate the effect of facility volume on survival, adjusted for multiple covariates. RESULTS: There were 253,422 patients treated at 1289 facilities: 6231 received neoadjuvant radiation, 147,980 received adjuvant radiation, and 99,211 received definitive radiation without surgery. Among patients receiving neoadjuvant radiation, survival correlated with facility volume for patients with rectal cancer (hazard ratio [HR], 0.75; 95% CI, 0.6-0.94; P = .01). For cancers of the breast and uterus, patients receiving adjuvant radiation at very high-volume facilities (vs low volume) had improved survival (HR, 0.83; 95% CI, 0.77-0.90; P < .001 and HR, 0.77, 95% CI, 0.62-0.97; P = .03, respectively). For patients receiving definitive radiation for prostate, non-small cell lung, pancreas, and head and neck cancer, there was an improvement in survival for patients treated at very high-volume centers (P < .05). CONCLUSIONS: For select cancer patients, treatment with curative radiation at higher volume facilities is associated with improved survival. In particular, patients receiving radiation therapy in the definitive setting without surgery may benefit most from treatment at high-volume centers.

Association between meeting daily step count goals with ambulatory function and quality of life in patients with claudication.

OBJECTIVE: To determine (a) whether patients with peripheral artery disease (PAD) who walked at least 7000 and 10,000 steps/day had better ambulatory function and health-related quality of life (HRQoL) than patients who walked less than 7000 steps/day, and (b) whether differences in ambulatory function and HRQoL in patients grouped according to these daily step count criteria persisted after adjusting for covariates. METHODS: Two hundred forty-eight patients were assessed on their daily ambulatory activity for 1 week with a step activity monitor, and were grouped according to daily step count targets. Patients who took fewer than 7000 steps/day were included in group 1 (n = 153), those who took 7000 to 9999 steps/day were included in group 2 (n = 57), and patients who took at least 10,000 steps/day were included in group 3 (n = 38). Primary outcomes were the 6-minute walk distance (6MWD) and Walking Impairment Questionnaire (WIQ) distance score, which is a disease-specific measurement of HRQoL. Patients were further characterized on demographic variables, comorbid conditions, and cardiovascular risk factors. RESULTS: The groups were significantly different on ankle-brachial index (P = .02), and on the prevalence of hypertension (P = .04), diabetes (P < .01), abdominal obesity (P < .01), arthritis (P = .04), and chronic obstructive pulmonary disease (P < .01). Thus, these variables served as covariates in adjusted analyses, along with age, weight, and sex. The 6MWD (mean ± standard deviation) was significantly different among the groups in unadjusted (P < .01) and adjusted (P < .01) analyses (group 1, 313 ± 90 m; group 2, 378 ± 84 m; and group 3, 414 ± 77 m), with groups 2 and 3 having a higher 6MWD than group 1 (P < .01). The WIQ distance score was significantly different among the groups in unadjusted (P < .01) and adjusted (P < .01) analyses (group 1, 30 ± 30%; group 2, 45 ± 35%; and group 3, 47 ± 34%), with groups 2 and 3 having higher WIQ distance scores than group 1 (P < .01). CONCLUSIONS: Patients with PAD who walked more than 7000 and 10,000 steps/day had greater ambulatory function and HRQoL than patients who walked fewer than 7000 steps/day. Second, the greater ambulatory function and HRQoL associated with walking 7000 and 10,000 steps/day persisted after adjusting for covariates. This study provides preliminary evidence that patients with PAD who walk more than 7000 steps/day have better ambulatory function and HRQoL than patients below this threshold.

Impact of Facility Surgical Volume on Survival in Patients With Cancer.

BACKGROUND: Increased facility surgical treatment volume is sometimes associated with improved survival in patients with cancer; however, published studies evaluating volume are heterogeneous and disparate in their patient inclusion and definition of volume. The purpose of this work was to evaluate uniformly the impact of surgical facility volume on survival in patients with cancer. METHODS: The National Cancer Database was searched for patients diagnosed in 2004 through 2013 with the 12 cancers most commonly treated surgically. Facilities were stratified by 4 categories using the overall population (low, intermediate, high, and very high), each including 25% of patients, and then stratified by each individual disease site. Five-year postsurgery survival was estimated using both the Kaplan-Meier method and corresponding log-rank tests for group comparisons. Cox proportional hazard models were used to evaluate the effects of facility volume on 5-year postsurgery survival further, adjusted for multiple covariates. RESULTS: A total of 3,923,618 patients who underwent surgery were included from 1,139 facilities. Of these, 40.4% had breast cancer, 12.8% prostate cancer, and 10.0% colon cancer. Most patients were female (65.0%), White (86.4%), and privately insured (51.6%) with stage 0-III disease (64.8%). For all cancers, the risk of death for patients undergoing surgery at very high-volume facilities was 88% of that for those treated at low-volume facilities. Hazard ratios (HRs) were greatest (very high vs low volume) for cancer of the prostate (HR, 0.66; 95% CI, 0.63-0.69), pancreas (HR, 0.75; 95% CI, 0.71-0.78), and esophagus (HR, 0.78; 95% CI, 0.73-0.83), and for melanoma (HR, 0.81; 95% CI, 0.78-0.84); differences were smallest for uterine and non-small cell lung cancers. Overall survival differences were greatest for cancers of the brain, pancreas, and esophagus. CONCLUSIONS: Patients treated surgically at higher-volume facilities consistently had improved overall survival compared with those treated at low-volume centers, although the magnitude of difference was cancer-specific.

A multiple robust propensity score method for longitudinal analysis with intermittent missing data.

Longitudinal data are very popular in practice, but they are often missing in either outcomes or time-dependent risk factors, making them highly unbalanced and complex. Missing data may contain various missing patterns or mechanisms, and how to properly handle it for unbiased and valid inference still presents a significant challenge. Here, we propose a novel semiparametric framework for analyzing longitudinal data with both missing responses and covariates that are missing at random and intermittent, a general and widely encountered situation in observational studies. Within this framework, we consider multiple robust estimation procedures based on innovative calibrated propensity scores, which offers additional relaxation of the misspecification of missing data mechanisms and shows more satisfactory numerical performance. Also, the corresponding robust information criterion on consistent variable selection for our proposed model is developed based on empirical likelihood-based methods. These advocated methods are evaluated in both theory and extensive simulation studies in a variety of situations, showing competing properties and advantages compared to the existing approaches. We illustrate the utility of our approach by analyzing the data from the HIV Epidemiology Research Study.

Joint modeling of longitudinal data with informative cluster size adjusted for zero-inflation and a dependent terminal event.

Repeated measures are often collected in longitudinal follow-up from clinical trials and observational studies. In many situations, these measures are adherent to some specific event and are only available when it occurs; an example is serum creatinine from laboratory tests for hospitalized acute kidney injuries. The frequency of event recurrences is potentially correlated with overall health condition and hence may influence the distribution of the outcome measure of interest, leading to informative cluster size. In particular, there may be a large portion of subjects without any events, thus no longitudinal measures are available, which may be due to insusceptibility to such events or censoring before any events, and this zero-inflation nature of the data needs to be taken into account. On the other hand, there often exists a terminal event that may be correlated with the recurrent events. Previous work in this area suffered from the limitation that not all these issues were handled simultaneously. To address this deficiency, we propose a novel joint modeling approach for longitudinal data adjusting for zero-inflated and informative cluster size as well as a terminal event. A three-stage semiparametric likelihood-based approach is applied for parameter estimation and inference. Extensive simulations are conducted to evaluate the performance of our proposal. Finally, we utilize the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study for illustration.

Association between calf muscle oxygen saturation with ambulatory function and quality of life in symptomatic patients with peripheral artery disease.

OBJECTIVE: The objective of this study was to determine whether calf muscle hemoglobin oxygen saturation (Sto2) obtained during a standardized treadmill test is associated with ambulatory function and health-related quality of life (HRQoL) in patients with symptomatic peripheral artery disease (PAD). We hypothesized that a rapid decline in calf muscle Sto2 during walking is associated with impaired ambulatory function and HRQoL and that these associations are independent of ankle-brachial index (ABI). METHODS: Calf muscle Sto2, peak walking time, and claudication onset time were obtained during a treadmill test in 151 symptomatic men and women with PAD. Patients were further characterized by demographic variables, comorbid conditions, cardiovascular risk factors, ABI, 6-minute walk distance, daily ambulatory activity, Walking Impairment Questionnaire (WIQ) score, and Medical Outcomes Study 36-Item Short Form Health Survey physical function score to assess HRQoL. RESULTS: The median calf muscle Sto2 value at rest was 52%, which declined to 22% after only 1 minute of walking during the treadmill test and reached a minimum value of 9% after a median time of 87 seconds of walking. Of the various calf muscle Sto2 measurements obtained during the treadmill test, the exercise time to the minimum calf muscle Sto2 value (log transformed) had the strongest univariate associations with peak walking time (r = 0.56; P < .001), claudication onset time (r = 0.49; P < .001), 6-minute walk distance (r = 0.31; P < .001), WIQ distance score (r = 0.33; P < .001), WIQ speed score (r = 0.39; P < .001), WIQ stair-climbing score (r = 0.37; P < .001), and Medical Outcomes Study 36-Item Short Form Health Survey physical function score (r = 0.32; P < .001). In adjusted multiple regression models, these associations persisted (P < .001) after adjustment for demographic measures, cardiovascular risk factors, comorbid conditions, and ABI. CONCLUSIONS: More rapid decline in oxygen saturation of the calf musculature during walking, indicative of impaired microcirculation, is predictive of impaired ambulatory function and HRQoL in patients with symptomatic PAD. Of particular importance, these associations are independent of ABI and other common health burdens, highlighting the clinical relevance that the microcirculation has on ambulatory function and HRQoL in patients with symptomatic PAD.

Diet is associated with ankle-brachial index, inflammation, and ambulation in patients with intermittent claudication.

OBJECTIVE: The aims of this investigation were to determine whether the daily dietary intake of nutrients by patients with peripheral artery disease (PAD) and intermittent claudication (IC) met recommended levels for adults older than 50 years and to determine whether meeting recommended levels of nutrients was associated with ankle-brachial index (ABI), inflammation, and ambulation of patients with PAD and IC. METHODS: A total of 48 patients were assessed on their dietary intake of 20 nutrients during a 3-day period. Patients were further characterized on demographic variables, comorbid conditions, cardiovascular risk factors, ABI, 6-minute walk distance (6MWD), and high-sensitivity C-reactive protein (hsCRP) concentration. RESULTS: Few patients met the daily recommended intakes for calcium (4%), fiber (6%), vitamin E (6%), trans fatty acids (13%), vitamin A (15%), total sugars (19%), potassium (23%), sodium (29%), saturated fat (29%), and vitamin C (31%), and none of the patients met the daily recommended intake of vitamin D (0%). Overall, patients met few of the 20 dietary recommendations as the median score was seven recommendations. Only 17 of 48 patients met more than seven of the recommendations. For the ABI regression model adjusted for age, sex, race, smoking, hypertension, dyslipidemia, body mass index, and percentage body fat, the only significant predictor was total sugars (P < .001); patients who did not meet the recommendation had lower ABI values. For the hsCRP-adjusted regression model, the strongest significant predictor was omega-3 polyunsaturated fatty acids (P = .001), indicating that those who did not meet the recommendation had higher hsCRP values. Finally, for the 6MWD-adjusted regression model, folate (P = .011) and dietary score index (P = .014) were significant predictors; those who did not meet the recommendation for folate and those who met 5 or fewer of the 20 recommendations had shorter 6MWD. CONCLUSIONS: Patients with PAD and IC consume a low-nutrient-dense diet that is deficient in many vitamins, calcium, fruits, and vegetables and contains too much added sugar, saturated and trans fats, and processed foods. In addition, more severe PAD, greater inflammation, and ambulatory dysfunction are independently associated with aspects of a low-nutrient-dense diet, such as too much intake of added sugars, low intake of omega-3 polyunsaturated fatty acids and folate, and meeting the recommended intakes of only five or fewer nutrients.

Empirical-likelihood-based criteria for model selection on marginal analysis of longitudinal data with dropout missingness.

Longitudinal data are common in clinical trials and observational studies, where missing outcomes due to dropouts are always encountered. Under such context with the assumption of missing at random, the weighted generalized estimating equation (WGEE) approach is widely adopted for marginal analysis. Model selection on marginal mean regression is a crucial aspect of data analysis, and identifying an appropriate correlation structure for model fitting may also be of interest and importance. However, the existing information criteria for model selection in WGEE have limitations, such as separate criteria for the selection of marginal mean and correlation structures, unsatisfactory selection performance in small-sample setups, and so forth. In particular, there are few studies to develop joint information criteria for selection of both marginal mean and correlation structures. In this work, by embedding empirical likelihood into the WGEE framework, we propose two innovative information criteria named a joint empirical Akaike information criterion and a joint empirical Bayesian information criterion, which can simultaneously select the variables for marginal mean regression and also correlation structure. Through extensive simulation studies, these empirical-likelihood-based criteria exhibit robustness, flexibility, and outperformance compared to the other criteria including the weighted quasi-likelihood under the independence model criterion, the missing longitudinal information criterion, and the joint longitudinal information criterion. In addition, we provide a theoretical justification of our proposed criteria, and present two real data examples in practice for further illustration.

A Cartographic Tool to Predict Disease Risk-associated Pseudo-Dynamic Networks from Tissue-specific Gene Expression.

Understanding how genes are differentially expressed across tissues is key to reveal the etiology of human diseases. Genes are never expressed in isolation, but rather co-expressed in a community; thus, they co-act through intricate but well-orchestrated networks. However, existing approaches cannot coalesce the full properties of gene-gene communication and interactions into networks. In particular, the unavailability of dynamic gene expression data might impair the application of existing network models to unleash the complexity of human diseases. To address this limitation, we developed a statistical pipeline named DRDNetPro to visualize and trace how genes dynamically interact with each other across diverse tissues, to ascertain health risk from static expression data. This protocol contains detailed tutorials designed to learn a series of networks, with the illustration example from the Genotype-Tissue Expression (GTEx) project. The proposed toolbox relies on the method developed in our published paper ( Chen et al., 2022 ), coding all genes into bidirectional, signed, weighted, and feedback looped networks, which will provide profound genomic information enabling medical doctors to design precise medicine. Graphical abstract Flowchart illustrating the use of DRDNetPro. The left panel contains the summarized pipeline of DRDNetPro and the right panel contains one pseudo-illustrative example. See the Equipment and Procedure sections for detailed explanations.

Diabetes Is Negatively Associated With Meeting Physical Activity Time-Intensity Guidelines in Patients With Claudication.

PURPOSES: We determined the percentage of patients with peripheral artery disease (PAD) and claudication who meet the 2018 physical activity (PA) time-intensity guidelines, and we identified the clinical characteristics associated with the status of meeting the guidelines. METHODS: Five hundred seventy-two patients were assessed on their daily ambulatory activity for 1 wk with a step activity monitor, and were evaluated on whether or not they achieved 150 min/wk of moderate-intensity PA. RESULTS: Thirty-one percent (n = 175) of the patients with PAD met the PA time-intensity guidelines and 69% (n = 397) did not. In a final multivariable logistic regression model identifying the independent predictors of meeting the PA time-intensity guidelines from clinical characteristics, diabetes was the only significant variable entered (OR = 0.310: 95% CI, 0.175-0.538; P < .001) and was associated with a 69% lower chance of meeting the guidelines. Patients with diabetes spent less daily time in moderate-intensity ambulatory PA than patients without diabetes (15 ± 13 vs 23 ± 20 min/d; P < .001). CONCLUSIONS: Thirty-one percent of patients with PAD and claudication met the PA time-intensity guidelines. Furthermore, patients with diabetes were least likely to meet the PA time-intensity guidelines, as they had a 69% lower chance than patients without diabetes. The clinical significance is that PAD patients who have diabetes are particularly susceptible to being physically sedentary, and are therefore prime patients who should be encouraged to increase their daily PA.

Association Between Daily Steps at Moderate Cadence and Vascular Outcomes in Patients With Claudication.

PURPOSE: We determined whether patients with peripheral artery disease (PAD) and claudication grouped according to tertiles of community-based daily steps taken at a moderate cadence had differences in vascular function and biomarkers and whether group differences in vascular function and biomarkers persisted after adjusting for demographic variables, comorbid conditions, and severity of PAD. METHODS: Two hundred sixty-three patients were evaluated for 1 wk on steps taken at a moderate cadence (exceeding 60 steps/min), and patients were placed into low (group 1), intermediate (group 2), and high (group 3) tertiles. RESULTS: Ankle/brachial index (ABI) at 1 min after exercise (mean ± SD) was significantly higher in groups 2 and 3 than in group 1 in unadjusted (P < .01) and adjusted (P < .01) analyses (group 1: 0.34 ± 0.25; group 2: 0.38 ± 0.27; and group 3: 0.44 ± 0.28). Exercise time to reach the minimum calf muscle oxygen saturation (StO2) value during treadmill exercise was significantly longer in groups 2 and 3 than in group 1 in unadjusted (P < .01) and adjusted (P < .01) analyses (group 1: 127 ± 127 sec; group 2: 251 ± 266 sec; and group 3: 310 ± 323 sec). Fibrinogen was significantly lower in group 3 than in group 1 in unadjusted (P = .02) and adjusted (P = .05) analyses (group 1: 3.5 ± 1.2 g/L; group 2: 3.6 ± 1.5 g/L; and group 3: 3.0 ± 1.1 g/L). CONCLUSIONS: Compared with patients with claudication in the lowest tertile of community-based daily steps taken at a moderate cadence, patients in the second and third tertiles had better calf muscle StO2 and ABI values during and immediately after exercise. Second, the most active group had lower fibrinogen levels than the least active group.

Association Between Meeting Physical Activity Time-Intensity Guidelines With Ambulation, Quality of Life, and Inflammation in Claudication.

PURPOSE: The aim of this investigation was to determine if meeting the 2018 physical activity (PA) time-intensity guidelines was associated with better ambulatory function, health-related quality of life (HRQoL), vascular function, and inflammation than failing to meet the guidelines in patients with peripheral artery disease and claudication. Second, we determined the optimal number of total steps/d and steps taken at moderate cadence needed to meet the PA time-intensity guidelines. METHODS: Five hundred seventy-two patients were assessed on daily ambulatory activity for 1 wk with a step activity monitor, and were grouped according to whether they achieved <150 min/wk of moderate-intensity PA (group 1 = do not meet guidelines; n = 397) or whether they were above this threshold (group 2 = meet guidelines; n = 175). RESULTS: Treadmill peak walking time (mean ± SD) was higher ( P < .001) in group 2 (709 ± 359 sec) than in group 1 (427 ± 281 sec). The physical function HRQoL score was higher ( P < .001) in group 2 (61 ± 22%) than in group 1 (44 ± 21%). High-sensitivity C-reactive protein was lower ( P < .001) in group 2 (3.6 ± 4.5 mg/L) than in group 1 (5.9 ± 6.1 mg/L). Finally, ≥7675 total steps/d and ≥1660 steps/d at moderate cadence were optimal thresholds associated with meeting PA guidelines. CONCLUSIONS: Patients with claudication who meet the 2018 PA time-intensity guidelines for US adults had better ambulation, HRQoL, and vascular outcomes than those who failed to meet the PA guidelines. Patients with claudication best achieved the PA time-intensity guidelines by taking ≥7675 total steps/d, and ≥1660 steps/d at a moderate cadence.