Supplemental material for Generalized causal mediation and path analysis: Extensions and practica... more Supplemental material for Generalized causal mediation and path analysis: Extensions and practical considerations by Jeffrey M Albert, Jang Ik Cho, Yiying Liu and Suchitra Nelson in Statistical Methods in Medical Research
Background: In phase 3 trials, ultra rapid lispro (URLi) showed superior postprandial glucose con... more Background: In phase 3 trials, ultra rapid lispro (URLi) showed superior postprandial glucose control and non-inferior HbA1c reduction compared to Humalog® (Lispro). However, infusion site reactions (combined; ISRs) were more frequent with URLi. Methods: We examined whether occurrence of ISRs was related to any intrinsic or extrinsic factors by analyzing data from the 16-week PRONTO-Pump-2 trial in patients with T1D (URLi, N=215; Humalog, N=217) between randomization and end of treatment period. Results: The most frequently reported adverse events (AEs) were infusion site reaction (URLi, n=41 [19.1%]; Humalog, n=15 [6.9%]) and infusion site pain (URLi, n=34 [15.8%]; Humalog, n=6 [2.8%]). ISRs were reported by 37.7% of patients on URLi and 10.1% on Humalog. Most ISRs with URLi started in the first 4 weeks after randomization, were primarily mild in severity (~76%) and lasted a median of 2-6 days, depending on the type of reaction. Individual ISRs resolved during the study, but anothe...
Background: In PRONTO-Pump-2, a Phase 3, 16-week, randomized, double-blind clinical trial in pati... more Background: In PRONTO-Pump-2, a Phase 3, 16-week, randomized, double-blind clinical trial in patients with type 1 diabetes on continuous subcutaneous insulin infusion (CSII), ultra rapid lispro (URLi; a novel mealtime insulin), showed superior postprandial glucose control and noninferior HbA1c reduction, with less hypoglycemia compared to Humalog® (Lispro). We assessed treatment satisfaction in patients enrolled in this trial (URLi, N=215; Humalog, N=217), using the Insulin Treatment Satisfaction Questionnaire (ITSQ). Methods: The ITSQ was administered to patients at baseline and endpoint (week 16 or early discontinuation). The 5 domains assessed were glycemic control, hypoglycemic control, insulin delivery device, inconvenience of regimen, and lifestyle flexibility. Domain scores were transformed to a scale of 0-100 for analysis, with higher scores indicating better treatment satisfaction. The change in each domain-specific and overall transformed score from baseline to endpoint (l...
Background: In PRONTO-Pump-2, a Phase 3, 16-week, randomized, double-blind clinical trial in pati... more Background: In PRONTO-Pump-2, a Phase 3, 16-week, randomized, double-blind clinical trial in patients with type 1 diabetes on continuous subcutaneous insulin infusion, ultra rapid lispro (URLi) showed superior postprandial glucose control and noninferior HbA1c reduction, with less hypoglycemia compared to Humalog® (Lispro). Although primarily reported as mild in severity, incidence of infusion site reactions was higher with URLi compared to Humalog (37.7% vs. 10.1%). We assessed patient-reported health status in the PRONTO-Pump-2 trial as an exploratory measure. Methods: The EQ-5D-5L (which includes a visual analogue scale rating perceived health [VAS; 0-100 from worst to best imaginable health state]) was administered at baseline and endpoint (week 16 or early discontinuation) to patients on URLi (N=215) or Humalog (N=217). The EQ-5D-5L assesses 5 dimensions of health status (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) for which a health state index ...
To evaluate the efficacy and safety of ultra rapid lispro (URLi) versus lispro (Humalog®) in peop... more To evaluate the efficacy and safety of ultra rapid lispro (URLi) versus lispro (Humalog®) in people with type 1 diabetes on continuous subcutaneous insulin infusion (CSII).
URLi is a novel prandial insulin lispro formulation developed to more closely match physiological... more URLi is a novel prandial insulin lispro formulation developed to more closely match physiological insulin secretion and improve PPG control. In PRONTO-T1D, a phase 3, 26-week, treat-to-target study comparing URLi to Humalog in patients with T1D on a multiple daily injection regimen with insulin glargine or degludec, mealtime URLi was non-inferior to mealtime Humalog for change from baseline HbA1c and superior for PPG control, with a similar safety profile to Humalog. Randomization to treatment was stratified by basal insulin type, baseline HbA1c and prandial insulin dosing plan (carb counting, yes/no). The impact of these subgroups and baseline 2-hour PPG on the efficacy and safety of URLi was assessed from the double-blind treatment groups: mealtime URLi (n=451) and mealtime Humalog (n=442). No significant treatment-subgroup interactions were noted (all p>0.1) but occasional treatment differences were seen within each subgroup (p<0.05) (Table 1.). Numerically, results suggest...
PRONTO T1D was a phase 3 study evaluating ultra rapid lispro (URLi) in adults with type 1 diabete... more PRONTO T1D was a phase 3 study evaluating ultra rapid lispro (URLi) in adults with type 1 diabetes (T1D) for 52 weeks. Subjects were randomized to double-blind mealtime URLi, Humalog, or open-label postmeal URLi with insulin degludec or glargine for the first 26 weeks. Subjects on URLi (n=451) and Humalog (n=442) given 0-2 minutes before meals continued for another 26-weeks to assess long-term safety and efficacy. Mean HbA1c at 52 weeks (7.47% URLi; 7.54% Humalog) increased significantly (p<.001) from baseline in both groups (+0.13% [URLi] vs. +0.20% [Humalog]) and showed an estimated treatment difference (ETD) [95% confidence interval (CI)] (ETD: -0.06 [-0.16, 0.03]) that was similar to that previously reported at 26-weeks. Proportions of patients with HbA1c <7% at Week 52 were similar (URLi, 26.8%; Humalog, 24.5%). At Week 52, self-monitored blood glucose profiles (mg/dL) showed that 1-hour (ETD: -13.5 [-19.4, -7.5]) and 2- hour (ETD: -8.4 [-14.1, -2.7]) postmeal daily mean ...
Causal mediation analysis seeks to decompose the effect of a treatment or exposure among multiple... more Causal mediation analysis seeks to decompose the effect of a treatment or exposure among multiple possible paths and provide casually interpretable path-specific effect estimates. Recent advances have extended causal mediation analysis to situations with a sequence of mediators or multiple contemporaneous mediators. However, available methods still have limitations, and computational and other challenges remain. The present paper provides an extended causal mediation and path analysis methodology. The new method, implemented in the new R package, gmediation (described in a companion paper), accommodates both a sequence (two stages) of mediators and multiple mediators at each stage, and allows for multiple types of outcomes following generalized linear models. The methodology can also handle unsaturated models and clustered data. Addressing other practical issues, we provide new guidelines for the choice of a decomposition, and for the choice of a reference group multiplier for the r...
Background and objectives: Tibetans have distinctively low hemoglobin concentrations at high alti... more Background and objectives: Tibetans have distinctively low hemoglobin concentrations at high altitudes compared with visitors and Andean highlanders. This study hypothesized that natural selection favors an unelevated hemoglobin concentration among Tibetans. It considered nonheritable sociocultural factors affecting reproductive success and tested the hypotheses that a higher percent of oxygen saturation of hemoglobin (indicating less stress) or lower hemoglobin concentration (indicating dampened response) associated with higher lifetime reproductive success. Methodology: We sampled 1006 post-reproductive ethnically Tibetan women residing at 3000-4100 m in Nepal. We collected reproductive histories by interviews in native dialects and noninvasive physiological measurements. Regression analyses selected influential covariates of measures of reproductive success: the numbers of pregnancies, live births and children surviving to age 15. Results: Taking factors such as marriage status, ...
Supplemental material for Generalized causal mediation and path analysis: Extensions and practica... more Supplemental material for Generalized causal mediation and path analysis: Extensions and practical considerations by Jeffrey M Albert, Jang Ik Cho, Yiying Liu and Suchitra Nelson in Statistical Methods in Medical Research
Background: In phase 3 trials, ultra rapid lispro (URLi) showed superior postprandial glucose con... more Background: In phase 3 trials, ultra rapid lispro (URLi) showed superior postprandial glucose control and non-inferior HbA1c reduction compared to Humalog® (Lispro). However, infusion site reactions (combined; ISRs) were more frequent with URLi. Methods: We examined whether occurrence of ISRs was related to any intrinsic or extrinsic factors by analyzing data from the 16-week PRONTO-Pump-2 trial in patients with T1D (URLi, N=215; Humalog, N=217) between randomization and end of treatment period. Results: The most frequently reported adverse events (AEs) were infusion site reaction (URLi, n=41 [19.1%]; Humalog, n=15 [6.9%]) and infusion site pain (URLi, n=34 [15.8%]; Humalog, n=6 [2.8%]). ISRs were reported by 37.7% of patients on URLi and 10.1% on Humalog. Most ISRs with URLi started in the first 4 weeks after randomization, were primarily mild in severity (~76%) and lasted a median of 2-6 days, depending on the type of reaction. Individual ISRs resolved during the study, but anothe...
Background: In PRONTO-Pump-2, a Phase 3, 16-week, randomized, double-blind clinical trial in pati... more Background: In PRONTO-Pump-2, a Phase 3, 16-week, randomized, double-blind clinical trial in patients with type 1 diabetes on continuous subcutaneous insulin infusion (CSII), ultra rapid lispro (URLi; a novel mealtime insulin), showed superior postprandial glucose control and noninferior HbA1c reduction, with less hypoglycemia compared to Humalog® (Lispro). We assessed treatment satisfaction in patients enrolled in this trial (URLi, N=215; Humalog, N=217), using the Insulin Treatment Satisfaction Questionnaire (ITSQ). Methods: The ITSQ was administered to patients at baseline and endpoint (week 16 or early discontinuation). The 5 domains assessed were glycemic control, hypoglycemic control, insulin delivery device, inconvenience of regimen, and lifestyle flexibility. Domain scores were transformed to a scale of 0-100 for analysis, with higher scores indicating better treatment satisfaction. The change in each domain-specific and overall transformed score from baseline to endpoint (l...
Background: In PRONTO-Pump-2, a Phase 3, 16-week, randomized, double-blind clinical trial in pati... more Background: In PRONTO-Pump-2, a Phase 3, 16-week, randomized, double-blind clinical trial in patients with type 1 diabetes on continuous subcutaneous insulin infusion, ultra rapid lispro (URLi) showed superior postprandial glucose control and noninferior HbA1c reduction, with less hypoglycemia compared to Humalog® (Lispro). Although primarily reported as mild in severity, incidence of infusion site reactions was higher with URLi compared to Humalog (37.7% vs. 10.1%). We assessed patient-reported health status in the PRONTO-Pump-2 trial as an exploratory measure. Methods: The EQ-5D-5L (which includes a visual analogue scale rating perceived health [VAS; 0-100 from worst to best imaginable health state]) was administered at baseline and endpoint (week 16 or early discontinuation) to patients on URLi (N=215) or Humalog (N=217). The EQ-5D-5L assesses 5 dimensions of health status (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) for which a health state index ...
To evaluate the efficacy and safety of ultra rapid lispro (URLi) versus lispro (Humalog®) in peop... more To evaluate the efficacy and safety of ultra rapid lispro (URLi) versus lispro (Humalog®) in people with type 1 diabetes on continuous subcutaneous insulin infusion (CSII).
URLi is a novel prandial insulin lispro formulation developed to more closely match physiological... more URLi is a novel prandial insulin lispro formulation developed to more closely match physiological insulin secretion and improve PPG control. In PRONTO-T1D, a phase 3, 26-week, treat-to-target study comparing URLi to Humalog in patients with T1D on a multiple daily injection regimen with insulin glargine or degludec, mealtime URLi was non-inferior to mealtime Humalog for change from baseline HbA1c and superior for PPG control, with a similar safety profile to Humalog. Randomization to treatment was stratified by basal insulin type, baseline HbA1c and prandial insulin dosing plan (carb counting, yes/no). The impact of these subgroups and baseline 2-hour PPG on the efficacy and safety of URLi was assessed from the double-blind treatment groups: mealtime URLi (n=451) and mealtime Humalog (n=442). No significant treatment-subgroup interactions were noted (all p>0.1) but occasional treatment differences were seen within each subgroup (p<0.05) (Table 1.). Numerically, results suggest...
PRONTO T1D was a phase 3 study evaluating ultra rapid lispro (URLi) in adults with type 1 diabete... more PRONTO T1D was a phase 3 study evaluating ultra rapid lispro (URLi) in adults with type 1 diabetes (T1D) for 52 weeks. Subjects were randomized to double-blind mealtime URLi, Humalog, or open-label postmeal URLi with insulin degludec or glargine for the first 26 weeks. Subjects on URLi (n=451) and Humalog (n=442) given 0-2 minutes before meals continued for another 26-weeks to assess long-term safety and efficacy. Mean HbA1c at 52 weeks (7.47% URLi; 7.54% Humalog) increased significantly (p<.001) from baseline in both groups (+0.13% [URLi] vs. +0.20% [Humalog]) and showed an estimated treatment difference (ETD) [95% confidence interval (CI)] (ETD: -0.06 [-0.16, 0.03]) that was similar to that previously reported at 26-weeks. Proportions of patients with HbA1c <7% at Week 52 were similar (URLi, 26.8%; Humalog, 24.5%). At Week 52, self-monitored blood glucose profiles (mg/dL) showed that 1-hour (ETD: -13.5 [-19.4, -7.5]) and 2- hour (ETD: -8.4 [-14.1, -2.7]) postmeal daily mean ...
Causal mediation analysis seeks to decompose the effect of a treatment or exposure among multiple... more Causal mediation analysis seeks to decompose the effect of a treatment or exposure among multiple possible paths and provide casually interpretable path-specific effect estimates. Recent advances have extended causal mediation analysis to situations with a sequence of mediators or multiple contemporaneous mediators. However, available methods still have limitations, and computational and other challenges remain. The present paper provides an extended causal mediation and path analysis methodology. The new method, implemented in the new R package, gmediation (described in a companion paper), accommodates both a sequence (two stages) of mediators and multiple mediators at each stage, and allows for multiple types of outcomes following generalized linear models. The methodology can also handle unsaturated models and clustered data. Addressing other practical issues, we provide new guidelines for the choice of a decomposition, and for the choice of a reference group multiplier for the r...
Background and objectives: Tibetans have distinctively low hemoglobin concentrations at high alti... more Background and objectives: Tibetans have distinctively low hemoglobin concentrations at high altitudes compared with visitors and Andean highlanders. This study hypothesized that natural selection favors an unelevated hemoglobin concentration among Tibetans. It considered nonheritable sociocultural factors affecting reproductive success and tested the hypotheses that a higher percent of oxygen saturation of hemoglobin (indicating less stress) or lower hemoglobin concentration (indicating dampened response) associated with higher lifetime reproductive success. Methodology: We sampled 1006 post-reproductive ethnically Tibetan women residing at 3000-4100 m in Nepal. We collected reproductive histories by interviews in native dialects and noninvasive physiological measurements. Regression analyses selected influential covariates of measures of reproductive success: the numbers of pregnancies, live births and children surviving to age 15. Results: Taking factors such as marriage status, ...
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