Psychotropic, Anticonvulsant, and Opioid Use in Assisted Living Residents Before and During the COVID-19 Pandemic.

OBJECTIVES: To examine the associations between COVID-19 pandemic waves (1-4) and prevalent antipsychotic, antidepressant, benzodiazepine, anticonvulsant, and opioid use among assisted living (AL) residents, by setting (dementia care vs other). DESIGN: Population-based, repeated cross-sectional study. SETTING AND PARTICIPANTS: Linked clinical and health administrative databases for residents of all publicly subsidized AL homes (N = 256) in Alberta, Canada, examined from January 2018 to December 2021. Setting-specific quarterly cohorts of residents were derived for pandemic (starting March 1, 2020) and comparable historical (2018/2019 combined) periods. METHODS: The quarterly proportion of residents dispensed an antipsychotic, antidepressant, benzodiazepine, anticonvulsant, or opioid was examined for each setting and period. Log-binomial generalized estimating equations models estimated prevalence ratios (PR) for period (pandemic vs historical quarterly periods), setting (dementia care vs other AL), and period-setting interactions. RESULTS: On March 1, 2020, there were 2874 dementia care and 6611 other AL residents (mean age 82.4 vs 79.9 years, 68.2% vs 66.1% female, 93.5% vs 42.6% with dementia, respectively). Antipsychotic use increased during waves 2 to 4 for residents of both settings, but this increase was significantly greater for dementia care than other AL residents during waves 3 and 4 (eg, wave 3, PR 1.21, 95% CI 1.14-1.27 vs PR 1.12, 95% CI 1.07-1.17, interaction term P = .029). In both settings, there was a significant but modest increase in antidepressant use and a significant decrease in benzodiazepine use during several pandemic waves. For other AL residents only, there was a small statistically significant increase in anticonvulsant use during waves 2 to 4. No significant pandemic effect was observed for prevalent opioid use in either setting. CONCLUSIONS AND IMPLICATIONS: The persistence of the pandemic-associated increase in antipsychotic, antidepressant, and anticonvulsant use in AL residents, and greater increase in antipsychotic use for dementia care settings, raises concerns about the attendant risks for residents, especially those with dementia.

Causal inference for recurrent events via aggregated marginal odds ratio.

Researchers often work with treatments and outcomes that vary over time. For example, psychologists are interested in the curative effect of cognitive behavior therapies on patients' recurrent depression symptoms. While there are various causal effect measures designed for one-time treatment, the causal effect measures for time-varying treatment and recurrent events are relatively under-developed. In this article, a new causal measure is proposed to quantify the causal effect of time-varying treatments on recurrent events. We suggest estimators with robust standard errors that are based on various weight models for both conventional causal measures and the proposed measure in different time settings. We outline the approaches and describe how using some stabilized inverse probability weight models are more advantageous than others. We demonstrate that the proposed causal estimand can be consistently estimated for study periods of moderate length, and the estimation results are compared under different treatment settings with various weight models. We also find that the proposed method is suitable for both absorbing and nonabsorbing treatments. The methods are applied to the 1997 National Longitudinal Study of Youth as an illustrative example.

Greater Opioid Use Among Nursing Home Residents in Ontario, Canada During the First 2 Waves of the COVID-19 Pandemic.

OBJECTIVES: To examine the association between the COVID-19 pandemic and opioid use among nursing home residents followed up to March 2021, and possible variation by dementia and frailty status. DESIGN: Population-based cohort study with an interrupted time series analysis. SETTING AND PARTICIPANTS: Linked health administrative databases for residents of all nursing homes (n = 630) in Ontario, Canada were examined. Residents were divided into consecutive weekly cohorts (first observation week was March 5 to 11, 2017 and last was March 21 to March 27, 2021). METHODS: The weekly proportion of residents dispensed an opioid was examined overall and by strata defined by the presence of dementia and frailty. Autoregressive Integrated Moving Average models with step and ramp intervention functions tested for immediate level and slope changes in weekly opioid use after the onset of the pandemic (March 1, 2020) and were fit on prepandemic data for projected trends. RESULTS: The average weekly cohort ranged from 76,834 residents (prepandemic) to 69,359 (pandemic period), with a consistent distribution by sex (69% female) and age (54% age 85 + years). There was a statistically significant increased slope change in the weekly proportion of residents dispensed opioids (parameter estimate (ß) = 0.035; standard error (SE) = 0.005, P < .001). Although significant for all 4 strata, the increased slope change was more pronounced among nonfrail residents (ß = 0.038; SE = 0.008, P < .001) and those without dementia (ß = 0.044; SE = 0.008, P < .001). The absolute difference in observed vs predicted opioid use in the last week of the pandemic period ranged from 1.25% (frail residents) to 2.28% (residents without dementia). CONCLUSIONS AND IMPLICATIONS: Among Ontario nursing home residents, there was a statistically significant increase in opioid dispensations following the onset of the pandemic that persisted up to 1 year later. Investigations of the reasons for increased use, potential for long-term use and associated health consequences for residents are warranted.

Comparison of Medication Prescribing Before and After the COVID-19 Pandemic Among Nursing Home Residents in Ontario, Canada.

Importance: COVID-19 has had devastating effects on the health and well-being of older adult residents and health care professionals in nursing homes. Uncertainty about the associated consequences of these adverse effects on the use of medications common to this care setting remains. Objective: To examine the association between the COVID-19 pandemic and prescription medication changes among nursing home residents. Design, Setting, and Participants: This population-based cohort study with an interrupted time-series analysis used linked health administrative data bases for residents of all nursing homes (N = 630) in Ontario, Canada. During the observation period, residents were divided into consecutive weekly cohorts. The first observation week was March 5 to 11, 2017; the last observation week was September 20 to 26, 2020. Exposures: Onset of the COVID-19 pandemic on March 1, 2020. Main Outcomes and Measures: Weekly proportion of residents dispensed antipsychotics, benzodiazepines, antidepressants, anticonvulsants, opioids, antibiotics, angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme (ACE) inhibitors. Autoregressive integrated moving average models with step and ramp intervention functions tested for level and slope changes in weekly medication use after the onset of the pandemic and were fit on prepandemic data for projected trends. Results: Across study years, the annual cohort size ranged from 75 850 to 76 549 residents (mean [SD] age, 83.4 [10.8] years; mean proportion of women, 68.9%). A significant increased slope change in the weekly proportion of residents who were dispensed antipsychotics (parameter estimate [ß] = 0.051; standard error [SE] = 0.010; P < .001), benzodiazepines (ß = 0.026; SE = 0.003; P < .001), antidepressants (ß = 0.046; SE = 0.013; P < .001), trazodone hydrochloride (ß = 0.033; SE = 0.010; P < .001), anticonvulsants (ß = 0.014; SE = 0.006; P = .03), and opioids (ß = 0.038; SE = 0.007; P < .001) was observed. The absolute difference in observed vs estimated use in the last week of the pandemic period ranged from 0.48% (for anticonvulsants) to 1.52% (for antipsychotics). No significant level or slope changes were found for antibiotics, ARBs, or ACE inhibitors. Conclusions and Relevance: In this population-based cohort study, statistically significant increases in the use of antipsychotics, benzodiazepines, antidepressants, anticonvulsants, and opioids followed the onset of the COVID-19 pandemic, although absolute differences were small. There were no significant changes for antibiotics, ARBs, or ACE inhibitors. Studies are needed to monitor whether changes in pharmacotherapy persist, regress, or accelerate during the course of the pandemic and how these changes affect resident-level outcomes.

A model averaging approach for estimating propensity scores by optimizing balance.

Many approaches, including traditional parametric modeling and machine learning techniques, have been proposed to estimate propensity scores. This paper describes a new model averaging approach to propensity score estimation in which parametric and nonparametric estimates are combined to achieve covariate balance. Simulation studies are conducted across different scenarios varying in the degree of interactions and nonlinearities in the treatment model. The results show that, based on inverse probability weighting, the proposed propensity score estimator produces less bias and smaller standard errors than existing approaches. They also show that a model averaging approach with the objective of minimizing the average Kolmogorov-Smirnov statistic leads to the best performing IPW estimator. The proposed approach is also applied to a real data set in evaluating the causal effect of formula or mixed feeding versus exclusive breastfeeding on a child's body mass index Z-score at age 4. The data analysis shows that formula or mixed feeding is more likely to lead to obesity at age 4, compared to exclusive breastfeeding.

Nonparametric analysis of dependently interval-censored failure time data.

Failure time studies based on observational cohorts often have to deal with irregular intermittent observation of individuals, which produces interval-censored failure times. When the observation times depend on factors related to a person's failure time, the failure times may be dependently interval censored. Inverse-intensity-of-visit weighting methods have been developed for irregularly observed longitudinal or repeated measures data and recently extended to parametric failure time analysis. This article develops nonparametric estimation of failure time distributions using weighted generalized estimating equations and monotone smoothing techniques. Simulations are conducted for examination of the finite sample performance of proposed estimators. This research is motivated in part by the Toronto Psoriatic Arthritis Cohort Study, and the proposed methodology is applied to this study.

Estimation of parametric failure time distributions based on interval-censored data with irregular dependent follow-up.

Event history studies based on disease clinic data often face several complications. Specifically, patients may visit the clinic irregularly, and the intermittent observation times could depend on disease-related variables; this can cause a failure time outcome to be dependently interval-censored. We propose a weighted estimating function approach so that dependently interval-censored failure times can be analysed consistently. A so-called inverse-intensity-of-visit weight is employed to adjust for the informative inspection times. Left truncation of failure times can also be easily handled. Additionally, in observational studies, treatment assignments are typically non-randomized and may depend on disease-related variables. An inverse-probability-of-treatment weight is applied to estimating functions to further adjust for measured confounders. Simulation studies are conducted to examine the finite sample performances of the proposed estimators. Finally, the Toronto Psoriatic Arthritis Cohort Study is used for illustration. Copyright © 2017 John Wiley & Sons, Ltd.

Development of a decision tree to classify the most accurate tissue-specific tissue to plasma partition coefficient algorithm for a given compound.

Physiologically based pharmacokinetic (PBPK) modeling is a tool used in drug discovery and human health risk assessment. PBPK models are mathematical representations of the anatomy, physiology and biochemistry of an organism and are used to predict a drug's pharmacokinetics in various situations. Tissue to plasma partition coefficients (Kp), key PBPK model parameters, define the steady-state concentration differential between tissue and plasma and are used to predict the volume of distribution. The experimental determination of these parameters once limited the development of PBPK models; however, in silico prediction methods were introduced to overcome this issue. The developed algorithms vary in input parameters and prediction accuracy, and none are considered standard, warranting further research. In this study, a novel decision-tree-based Kp prediction method was developed using six previously published algorithms. The aim of the developed classifier was to identify the most accurate tissue-specific Kp prediction algorithm for a new drug. A dataset consisting of 122 drugs was used to train the classifier and identify the most accurate Kp prediction algorithm for a certain physicochemical space. Three versions of tissue-specific classifiers were developed and were dependent on the necessary inputs. The use of the classifier resulted in a better prediction accuracy than that of any single Kp prediction algorithm for all tissues, the current mode of use in PBPK model building. Because built-in estimation equations for those input parameters are not necessarily available, this Kp prediction tool will provide Kp prediction when only limited input parameters are available. The presented innovative method will improve tissue distribution prediction accuracy, thus enhancing the confidence in PBPK modeling outputs.

Inverse probability weighted estimating equations for randomized trials in transfusion medicine.

Thrombocytopenia is a condition characterized by extremely low platelet counts, which puts patients at elevated risk of morbidity and mortality because of bleeding. Trials in transfusion medicine are routinely designed to assess the effect of experimental platelet products on patients' platelet counts. In such trials, patients may receive multiple platelet transfusions over a predefined period of treatment, and a response is available from each such administration. The resulting data comprised multiple responses per patient, and although it is natural to want to use this data in testing for treatment effects, naive analyses of the multiple responses can yield biased estimates of the probability of response and associated treatment effects. These biases arise because only subsets of the patients randomized contribute response data on the second and subsequent administrations of therapy and the balance between treatment groups with respect to potential confounding factors is lost. We discuss the design and analysis issues involved in this setting and make recommendations for the design of future platelet transfusion trials.

Early and late mortality after diagnosis of wilms tumor.

PURPOSE: To assess rates and causes of mortality in patients with Wilms tumor (WT). METHODS: Through 2002, 6,185 patients enrolled onto the National Wilms Tumor Study between 1969 and 1995 were actively observed. Deaths were classified on the basis of medical records as the result of original disease, late effects (including second malignant neoplasms [SMNs], cardiac causes, pulmonary disease, and renal failure), or other causes. Standardized mortality ratios (SMRs) and Cox regression were used to assess the effects of sex, age, and calendar period of diagnosis on mortality. RESULTS: Within 5 years of WT diagnosis, 819 deaths occurred, and 159 deaths occurred among 4,972 known 5-year survivors. The SMR was 24.3 (95% CI, 22.6 to 26.0) for the first 5 years, was 12.6 (95% CI, 10.0 to 15.7) for the next 5 years, and remained greater than 3.0 thereafter. For deaths in the first 5 years, the mortality risk decreased by 5-year calendar period of diagnosis (rate ratio [RR] = 0.78 per period). No such trend occurred for later deaths. Among 5-year survivors, 62 deaths were attributed to late effects of treatment or disease, including 27 to SMNs. A trend of decreased risk with calendar period of diagnosis was observed for late-effects mortality (RR = 0.86; 95% CI, 0.67 to 1.10) and for SMN mortality (RR = 0.82; 95% CI, 0.55 to 1.21). CONCLUSION: Although the survival outlook for WT patients has improved greatly over time, survivors remain at elevated risk for death many years after their original diagnosis.

Synchronous bilateral Wilm's tumor with complete radiographic response managed without surgical resection: a report from the National Wilm's Tumor Study 4.

PURPOSE: We reviewed the long-term local tumor control in patients with bilateral Wilm's tumor (BWT) who received no definitive surgical therapy to one kidney after complete radiographic resolution after initial chemotherapy. METHODS: National Wilm's Tumor Study 4 (NWTS-4) enrolled 3335 patients (pts) during the period August 1986 to August 1994. There were 188 pts with BWT or 5.6% of the total enrolled. The treatment records and imaging reports were reviewed to ascertain those children who had documented tumors without definitive surgical therapy after initial treatment. Patients who did not have renal surgery because of progression of tumor were excluded from this study. RESULTS: Eleven children had no definitive surgical treatment of renal lesions in one kidney (right, 6; left, 5) after initial treatment with chemotherapy and/or radiation therapy. The pretreatment size of the lesions were less than 3 cm (4 pts), 3 to 6 cm (5 pts), more than 6 cm (1 pt), and unknown (1 pt). Prechemotherapy biopsy was performed in 6 of 11 patients. Lesions were less than 3 cm (1 pt), 3 to 6 cm (3 pts), more than 6 cm (1 pt), and unknown (1 pt). Four biopsy specimens showed favorable Wilm's histologic findings. One lesion (4 cm) showed an intralobar nephrogenic rest, another lesion of unknown size was read as favorable histologic findings vs perilobar nephrogenic rest. Biopsy was not performed on 5 lesions (4 pts, <1 cm; 1 pt, 3cm). Only 2 children in this study received radiation treatment. One child received 1050 cGy whole abdominal radiation, and 1 child received 1060 cGy to the left flank postnephrectomy. Radiation therapy was not given to any patient because of failure of the tumor to respond to chemotherapy. Five patients received treatment regimen EE-4A, dactinomycin, and vincristine. The duration of therapy ranged from 24 to 102 weeks for an average of 55.6 weeks. Three patients received treatment regimen DD-4A, dactinomycin, vincristine, and doxorubicin for 28, 52, and 52 weeks, respectively. Three patients received 2 separate regimens of chemotherapy. One child was treated with dactinomycin, vincristine, and cyclophosphamide for 60 weeks and then received regimen EE-4A for 24 weeks. Another patient received regimen EE-4A for 16 weeks and then regimen DD4-A for 36 weeks. One child received regimen EE-4-A for 12 weeks and then regimen DD4A for 40 weeks. Management of the contralateral kidney was complete nephrectomy in all 11 patients. There were no local relapses in the renal tumor bed. All patients were alive at a median follow-up of 9 years (range, 9 months to 15 years). CONCLUSION: Children with synchronous BWT or Wilm's tumor and contralateral nephrogenic rests that have radiographic resolution, after initial treatment, have a low risk for local relapse. These children should be followed by serial imaging.

Treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D, and doxorubicin. A report from the National Wilms Tumor Study Group.

OBJECTIVE: We evaluated the use of alternating cycles of cyclophosphamide/etoposide and carboplatin/etoposide in children entered on National Wilms Tumor Study (NWTS)-5 who were diagnosed between August 1, 1995 and May 31, 2002 and who relapsed after chemotherapy with vincristine, actinomycin D, and doxorubicin (VAD) and radiation therapy (DD-4A). PATIENTS AND METHODS: One hundred three patients who relapsed or had progressive disease after initial VAD chemotherapy and radiation therapy were registered on stratum C of the NWTS-5 Relapse protocol. Twelve patients were not evaluable: five due to insufficient data, six due to major protocol violations, and one for refusal of therapy. Among the 91 remaining patients, 14 with stage V Wilms tumor (WT), 1 with contralateral relapse, and 16 who did not achieve a complete response (CR) to the initial three-drug chemotherapy were not included in this analysis. Relapse treatment included alternating courses of the drug pairs cyclophosphamide/etoposide and carboplatin/etoposide, surgery, and radiation therapy. RESULTS: The outcomes of 60 patients were analyzed. The lung was the only site of relapse for 33 patients; other sites of relapse included the operative bed, the abdomen, and liver. Four-year event-free survival (EFS) and overall survival (OS) were 42.3 and 48.0% respectively for all patients and were 48.9 and 52.8% for those who relapsed in the lungs only. Thrombocytopenia was the most frequent toxicity. CONCLUSION: These results demonstrate that approximately one-half of children with unilateral WT who relapse after initial treatment with VAD and radiation therapy can be successfully retreated.

Mortality ascertainment of participants in the National Wilms Tumor Study using the National Death Index: comparison of active and passive follow-up results.

Long term studies of childhood cancer survivors are hampered by difficulties in tracking young adult participants. After performing a National Death Index (NDI) search we sought to identify which factors best predicted a match among known decedents from the National Wilms Tumor Study (NWTS) and to determine if record linkage could substitute for missing follow-up in a cohort of NWTS survivors. To our knowledge, this is the first study to compare passive mortality follow-up using the NDI to active follow-up of a childhood and young adult population. Records for 984 known decedents and 3,406 subjects whose January 1, 2002 vital status was unknown were sent to the NDI in June 2003. In April 2005 NWTS follow-up records were used to reassess January 1, 2002 vital status. Matches were established for 709 of 789 known decedents (sensitivity 89.9%) with a date of death between 1979 and 2001, the calendar period covered by the NDI at the time of the search. No matches were identified among 1,052 subjects known to be alive in 2002 (specificity 100%). Factors associated with decreased sensitivity were an unknown social security number (sensitivity 87.8%), Hispanic ethnicity (76.4%) and foreign birth (56.5%). For 2,351 subjects with 2002 vital status unknown who had 13,166 pre 2002 person-years of missing observation, only 18 deaths were ascertained by the NDI whereas 79.3 were expected based on NWTS mortality data. Mortality analyses based strictly on NDI search results and those based on NWTS follow-up augmented with NDI search results yielded inflated estimates of the 15 year survival rate when compared with estimates based on NWTS active follow-up. Match rates were comparable to those observed in adult populations. Since the same selection factors were likely associated with NDI failure to match and NWTS loss to follow-up, use of the NDI to fill in missing follow-up data appears unwarranted.

Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: a report from the National Wilms Tumor Study Group.

PURPOSE: NWTS-5 was a multi-institutional clinical trial for patients less than 16 years of age at diagnosis with specific renal neoplasms who were diagnosed between August 1, 1995 and May 31, 2002. A uniform approach to the treatment of patients with relapse was employed. PATIENTS AND METHODS: Seventy-two patients who relapsed after immediate nephrectomy (stages I and II), initial chemotherapy with vincristine (VCR) and actinomycin D and no radiation therapy were registered on stratum B of the NWTS-5 relapse protocol. Four patients were not evaluable: one due to insufficient data and three due to major protocol violations. Among the 68 remaining patients, one who was 19 years of age at initial diagnosis of Wilms tumor, five with bilateral Wilms tumor at diagnosis, three who developed a contralateral relapse, and one with persistent disease were not included in this analysis. Relapse treatment included surgical excision, when feasible, radiation therapy and alternating courses of VCR, doxorubicin and cyclophosphamide and etoposide and cyclophosphamide. RESULTS: The outcomes of 58 patients were analyzed. The lung was the only site of relapse for 31 patients. Event-free survival 4 years after relapse was 71.1% and 4-year overall survival was 81.8% for all patients and were 67.8 and 81.0% for those who relapsed only to their lungs. The most frequent toxicities were hematological. CONCLUSIONS: These results demonstrate that a significant proportion of children with Wilms tumor who relapse after initial treatment with VCR and actinomycin D can be successfully re-treated.

Treatment of anaplastic histology Wilms' tumor: results from the fifth National Wilms' Tumor Study.

PURPOSE: An objective of the fifth National Wilms' Tumor Study (NWTS-5) was to evaluate the efficacy of treatment regimens for anaplastic histology Wilms' tumor (AH). PATIENTS AND METHODS: Prospective single-arm studies were conducted. Patients with stage I AH were treated with vincristine and dactinomycin for 18 weeks. Patients with stages II to IV diffuse AH were treated with vincristine, doxorubicin, cyclophosphamide, and etoposide for 24 weeks plus flank/abdominal radiation. RESULTS: A total of 2,596 patients with Wilms' tumor were enrolled onto NWTS-5, of whom 281 (10.8%) had AH. Four-year event-free survival (EFS) and overall survival (OS) estimates for assessable patients with stage I AH (n = 29) were 69.5% (95% CI, 46.9 to 84.0) and 82.6% (95% CI, 63.1 to 92.4). In comparison, 4-year EFS and OS estimates for patients with stage I favorable histology (FH; n = 473) were 92.4% (95% CI, 89.5 to 94.5) and 98.3% (95% CI, 96.4 to 99.2). Four-year EFS estimates for patients who underwent immediate nephrectomy with stages II (n = 23), III (n = 43), and IV (n = 15) diffuse AH were 82.6% (95% CI, 60.1 to 93.1), 64.7% (95% CI, 48.3 to 77.7), and 33.3% (95% CI, 12.2 to 56.4), respectively. OS was similar to EFS for these groups. There were no local recurrences among patients with stage II AH. Four-year EFS and OS estimates for patients with bilateral AH (n = 29) were 43.8% (95% CI, 24.2 to 61.8) and 55.2% (95% CI, 34.8 to 71.7), respectively. CONCLUSION: The prognosis for patients with stage I AH is worse than that for patients with stage I FH. Novel treatment strategies are needed to improve outcomes for patients with AH, especially those with stage III to V disease.

Bilateral Wilms' tumors with progressive or nonresponsive disease.

BACKGROUND: To provide guidelines for future cooperative group trials, we reviewed the outcomes of children with bilateral Wilms' tumors (BWTs) treated on National Wilms Tumor Study-4 (NWTS-4) who had progressive or nonresponsive disease (PNRD). METHODS: NWTS-4 enrolled 3335 patients from August 1986 to September 1994 including 188 patients with BWT (5.6%). Treatment and outcome data were collected on patients with BWT. Treatment guidelines were outlined in the protocol, but patients were not on study. RESULTS: Thirty-eight children with BWT had PNRD. Preoperative chemotherapy was given for a median of 7 months (range, 2-29 months) before definitive resection. After the initial chemotherapy regimen, 36 children went on to a second regimen, and of these, 21 children received a third regimen before resection. Eleven patients received irradiation to one or both kidneys. Pathology at resection revealed previously undiagnosed anaplasia in 3 patients (2 diffuse and 1 focal) treated for 14, 15, and 15 months before resection. A fourth patient developed a diffusely anaplastic tumor 13 months after therapy. Other pathological findings included rhabdomyomatous (4 patients) or differentiated stromal elements (10 patients) and complete necrosis (1 patient). Ten kidneys from 7 patients lacked biopsy at presentation or pathology review of those specimens. CONCLUSIONS: BWT patients with PNRD received prolonged courses of chemotherapy. Early and sequential biopsies to establish the reason for failure to respond should be obtained. This will identify anaplastic tumors managed best by early nephrectomy and intensive chemotherapy and will also distinguish differentiated tumors that are best managed with early resection, but less intensive therapy after nephrectomy.