Applying the estimand and target trial frameworks to external control analyses using observational data: a case study in the solid tumor setting.

Introduction: In causal inference, the correct formulation of the scientific question of interest is a crucial step. The purpose of this study was to apply causal inference principles to external control analysis using observational data and illustrate the process to define the estimand attributes. Methods: This study compared long-term survival outcomes of a pooled set of three previously reported randomized phase 3 trials studying patients with metastatic non-small cell lung cancer receiving front-line chemotherapy and similar patients treated with front-line chemotherapy as part of routine clinical care. Causal inference frameworks were applied to define the estimand aligned with the research question and select the estimator to estimate the estimand of interest. Results: The estimand attributes of the ideal trial were defined using the estimand framework. The target trial framework was used to address specific issues in defining the estimand attributes using observational data from a nationwide electronic health record-derived de-identified database. The two frameworks combined allow to clearly define the estimand and the aligned estimator while accounting for key baseline confounders, index date, and receipt of subsequent therapies. The hazard ratio estimate (point estimate with 95% confidence interval) comparing the randomized clinical trial pooled control arm with the external control was close to 1, which is indicative of similar survival between the two arms. Discussion: The proposed combined framework provides clarity on the causal contrast of interest and the estimator to adopt, and thus facilitates design and interpretation of the analyses.

Evaluation of US oncology electronic health record real-world data to reduce uncertainty in health technology appraisals: a retrospective cohort study.

OBJECTIVES: Examine whether data from early access to medicines in the USA can be used to inform National Institute for Health and Care Excellence (NICE) health technology assessments (HTA) in oncology. DESIGN: Retrospective cohort study. SETTING: Oncology-based community and academic treatment centres in the USA. PARTICIPANTS: Patients present in a nationwide electronic health record (EHR)-derived deidentified database. INTERVENTIONS: Cancer drugs that underwent NICE technology appraisal (TA) between 2014 and 2019. PRIMARY AND SECONDARY OUTCOME MEASURES: The count and follow-up time of US patients, available in the EHR, who were exposed to cancer drugs of interest in the period between Food and Drug Administration (FDA) approval and dates relevant to the NICE appraisal process. RESULTS: In 59 of 60 TAs analysed, the cancer therapy was approved in the USA before the final appraisal by NICE. The median time from FDA approval to the publication of NICE recommendations was 18.5 months, at which time the US EHR-derived database had, on average, 269 patients (SD=356) exposed to the new therapy, with a median of 75.3 person-years (IQR: 13.1-173) in time-at-risk. A case study generated evidence on real-world overall survival and treatment duration. CONCLUSIONS: Across different cancer therapies, there was substantial variability in US real-world data accumulated between FDA approval and NICE decision milestones. The applicability of these data to generate evidence for HTA decision-making should be assessed on a case-by-case basis depending on the intended HTA use case.

A pseudo-likelihood method for estimating misclassification probabilities in competing-risks settings when true-event data are partially observed.

Outcome misclassification occurs frequently in binary-outcome studies and can result in biased estimation of quantities such as the incidence, prevalence, cause-specific hazards, cumulative incidence functions, and so forth. A number of remedies have been proposed to address the potential misclassification of the outcomes in such data. The majority of these remedies lie in the estimation of misclassification probabilities, which are in turn used to adjust analyses for outcome misclassification. A number of authors advocate using a gold-standard procedure on a sample internal to the study to learn about the extent of the misclassification. With this type of internal validation, the problem of quantifying the misclassification also becomes a missing data problem as, by design, the true outcomes are only ascertained on a subset of the entire study sample. Although, the process of estimating misclassification probabilities appears simple conceptually, the estimation methods proposed so far have several methodological and practical shortcomings. Most methods rely on missing outcome data to be missing completely at random (MCAR), a rather stringent assumption which is unlikely to hold in practice. Some of the existing methods also tend to be computationally-intensive. To address these issues, we propose a computationally-efficient, easy-to-implement, pseudo-likelihood estimator of the misclassification probabilities under a missing at random (MAR) assumption, in studies with an available internal-validation sample. We present the estimator through the lens of studies with competing-risks outcomes, though the estimator extends beyond this setting. We describe the consistency and asymptotic distributional properties of the resulting estimator, and derive a closed-form estimator of its variance. The finite-sample performance of this estimator is evaluated via simulations. Using data from a real-world study with competing-risks outcomes, we illustrate how the proposed method can be used to estimate misclassification probabilities. We also show how the estimated misclassification probabilities can be used in an external study to adjust for possible misclassification bias when modeling cumulative incidence functions.

Mortality Among People With HIV Treated for Tuberculosis Based on Positive, Negative, or No Bacteriologic Test Results for Tuberculosis: The IeDEA Consortium.

BACKGROUND: In resource-constrained settings, many people with HIV (PWH) are treated for tuberculosis (TB) without bacteriologic testing. Their mortality compared with those with bacteriologic testing is uncertain. METHODS: We conducted an observational cohort study among PWH ≥15 years of age initiating TB treatment at sites affiliated with 4 International epidemiology Databases to Evaluate AIDS consortium regions from 2012 to 2014: Caribbean, Central and South America, and Central, East, and West Africa. The exposure of interest was the TB bacteriologic test status at TB treatment initiation: positive, negative, or no test result. The hazard of death in the 12 months after TB treatment initiation was estimated using a Cox proportional hazard model. Missing covariate values were multiply imputed. RESULTS: In 2091 PWH, median age 36 years, 53% had CD4 counts ≤200 cells/mm3, and 52% were on antiretroviral therapy (ART) at TB treatment initiation. The adjusted hazard of death was higher in patients with no test compared with those with positive test results (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.08-2.26). The hazard of death was also higher among those with negative compared with positive tests but was not statistically significant (HR, 1.28; 95% CI, 0.91-1.81). Being on ART, having a higher CD4 count, and tertiary facility level were associated with a lower hazard for death. CONCLUSIONS: There was some evidence that PWH treated for TB with no bacteriologic test results were at higher risk of death than those with positive tests. Research is needed to understand the causes of death in PWH treated for TB without bacteriologic testing.

Hospital outcomes in non-surgical patients identified at risk for OSA.

BACKGROUND: In-hospital respiratory outcomes of non-surgical patients with undiagnosed obstructive sleep apnea (OSA), particularly those with significant comorbidities are not well defined. Undiagnosed and untreated OSA may be associated with increased cardiopulmonary morbidity. STUDY OBJECTIVES: Evaluate respiratory failure outcomes in patients identified as at-risk for OSA by the Berlin Questionnaire (BQ). METHODS: This was a retrospective study conducted using electronic health records at a large health system. The BQ was administered at admission to screen for OSA to medical-service patients under the age of 80 years old meeting the following health system criteria: (1) BMI greater than 30; (2) any of the following comorbid diagnoses: hypertension, heart failure, acute coronary syndrome, pulmonary hypertension, arrhythmia, cerebrovascular event/stroke, or diabetes. Patients with known OSA or undergoing surgery were excluded. Patients were classified as high-risk or low-risk for OSA based on the BQ score as follows: low-risk (0 or 1 category with a positive score on the BQ); high-risk (2 or more categories with a positive score on BQ). The primary outcome was respiratory failure during index hospital stay defined by any of the following: orders for conventional ventilation or intubation; at least two instances of oxygen saturation less than 88% by pulse oximetry; at least two instances of respiratory rate over 30 breaths per minute; and any orders placed for non-invasive mechanical ventilation without a previous diagnosis of sleep apnea. Propensity scores were used to control for patient characteristics. RESULTS: Records of 15,253 patients were assessed. There were no significant differences in the composite outcome of respiratory failure by risk of OSA (high risk: 11%, low risk: 10%, p = 0.55). When respiratory failure was defined as need for ventilation, more patients in the low-risk group experienced invasive mechanical ventilation (high-risk: 1.8% vs. low-risk: 2.3%, p = 0.041). Mortality was decreased in patients at high-risk for OSA (0.86%) vs. low risk for OSA (1.53%, p < 0.001). CONCLUSIONS: Further prospective studies are needed to understand the contribution of undiagnosed OSA to in-hospital respiratory outcomes.

Response and Overall Survival for Yttrium-90 Radioembolization of Hepatic Sarcoma: A Multicenter Retrospective Study.

PURPOSE: To evaluate the effectiveness and safety of yttrium-90 transarterial radioembolization (TARE) for the treatment of primary and metastatic soft tissue sarcoma (STS) of the liver. MATERIALS AND METHODS: A retrospective review of 39 patients with primary (n = 2) and metastatic (n = 37) hepatic STS treated with TARE at 4 institutions was performed. Fourteen STS subtypes were included, with leiomyosarcoma being the most common (51%). TARE with glass (22 patients) or resin (17 patients) microspheres was performed, with single lobe (17 patients) or bilobar treatment (22 patients) based on disease burden. Adverse events of treatment, overall survival (OS), and tumor response at 3, 6, and 12 months after TARE were assessed per the Response Evaluation Criteria in Solid Tumors. RESULTS: Fourteen patients demonstrated either partial or complete response to therapy, with an objective response rate of 36%. Thirty patients (77%) demonstrated disease control (DC)-either stable disease or response to treatment. Median OS was 30 months (95% confidence interval 12-43 months) for all patients. DC at 3 months was associated with an increased median OS (44 months) compared with progressive disease (PD) (7.5 months; P < .0001). Patients with DC at 6 months also demonstrated an increased median OS (38 months) compared to patients with PD (17 months; P = .0443). Substantial adverse events included 1 liver abscess, 1 gastric ulceration, and 1 pneumonitis. CONCLUSIONS: Patients with hepatic STS treated with TARE demonstrated a high rate of DC and a median OS of 30 months, which suggests a role for TARE in the palliation of hepatic STS.

The Relationship Between Hard Tissue and Soft Tissue Dimensions of the Nose in Children: A 3D Cone Beam Computed Tomography Study.

This study using three-dimensional cone beam computed tomography (CBCT) images of children determined relationships between nasal skeletal and soft tissue measurements and assessed the association with sex, age, and skeletal maturation stage. Following reliability studies, skeletal and soft tissue parameters were measured on coded CBCTs of 73 children (28M:45F;6-13 yoa). Pearson and Mantel correlations were used to analyze associations between skeletal and soft tissues. Partial Mantel correlations were used to study the associations between skeletal and soft tissue, adjusting for sex, age, and skeletal maturation. Linear regression analyses were used to predict soft tissues sizes. Logistic regression was used to study the relationships between soft and skeletal tissue symmetry. Except for nasal aperture width and interalar width, skeletal landmarks best predicted corresponding soft tissue landmarks. Significant positive associations existed between skeletal and soft tissues after adjusting for sex, skeletal maturation, and age. Children's nasal skeletal tissues predicted nasal soft tissue reasonably well.

Effects of a Care Coordination Intervention with Children with Neurodevelopmental Disabilities and Their Families.

: Care coordination is integral to improving the health of children and families. Using a Shared Plan of Care (SPoC) as a care coordination activity is recommended, but related research on outcomes in pediatric populations with complex medical conditions is scarce. OBJECTIVE: This study explores family outcomes associated with implementation of a care coordination/SPoC intervention with a population of children with neurodevelopmental disabilities and their families. METHODS: Children aged 2 to 10 years with a neurodevelopmental disability (autism spectrum disorder: 60.9%; global developmental delay/intellectual disability: 39.1%) were referred by pediatric subspecialty programs for care coordination. The intervention included previsit assessments, planned care visits, SPoC development, and 6-month care coordination. A single-group, repeated-measures design was used to evaluate model feasibility and effects on care coordination access, SPoC use, family/clinician goals and needs met, family-professional partnerships, family empowerment, and worry. Times 1 and 2 survey data were collected from a total of 70 families. RESULTS: Analysis shows significant improvement in care coordination access, SPoC use, goals achieved, needs met, family empowerment, and reduced worry. There was no significant change in family-professional partnerships and reported SPoC use. CONCLUSION: Findings provide preliminary evidence that a care coordination model using a family-centered, goal-oriented SPoC is a feasible and effective approach with a cohort of children with complex neurodevelopmental disorders and is associated with improved family outcomes. Replication studies are warranted and should include a control group, prolonged time period, additional validated outcome measures, and measurement of costs and professional impact.

Neurodevelopment in Young Children Born to HIV-Infected Mothers: A Meta-analysis.

CONTEXT: HIV-infected (HIV+) children have worse neurodevelopmental outcomes compared with HIV-uninfected children. However, little is known regarding the differences in neurodevelopment between young HIV+ children, HIV-exposed but uninfected (HEU) children, and HIV-unexposed and uninfected (HUU) children. OBJECTIVE: To systematically review and meta-analyze data on neurodevelopmental performance between young HIV+, HEU, and HUU children. DATA SOURCES: We systematically searched the following electronic bibliographic databases: Ovid Medline, Embase, PsycINFO, Education Resources Information Center, and the Cochrane Database of Systematic Reviews. STUDY SELECTION: Studies were selected on the basis of defined inclusion criteria. Titles, abstracts, and full texts were assessed by 2 independent reviewers. DATA EXTRACTION: Data were extracted by 2 independent reviewers and cross-checked by 2 additional reviewers. RESULTS: Forty-five studies were identified for inclusion in the systematic review, and of these, 11 were included in the meta-analysis on the basis of availability of Bayley Scales of Infant and Toddler Development scores. Within the meta-analysis, when compared with their HUU peers, HIV+ and HEU children had lower cognitive and motor scores. HIV+ and HEU children with antiretroviral (ARV) exposure had lower cognitive and motor scores compared with those without ARV exposure. LIMITATIONS: We were unable to control adequately for intravenous drug use, geographic location, or quality of the assessment independently. CONCLUSIONS: Both HIV+ and HEU children had worse developmental outcomes compared with HUU children. HIV+ and HEU children with ARV exposure also had worse developmental outcomes compared with those without exposure; however, these results should be interpreted with caution. More research is needed to identify the impact of ARV exposure on young children.

Trends in typologies of concurrent alcohol, marijuana, and cigarette use among US adolescents: An ecological examination by sex and race/ethnicity.

Substance use during adolescence is a public health concern due to associated physical and behavioral health consequences. Such consequences are amplified among concurrent substance users. Although sex and racial/ethnic differences in single-substance use have been observed, the current literature is inconclusive as to whether differences exist in the prevalence of concurrent use. The current study used data from the 2011-2014 National Survey on Drug Use and Health to examine typologies (single and concurrent patterns) of alcohol, marijuana, and cigarette use among current adolescent users age 12-18 by sex and race/ethnicity. Participants were 14,667 White, Hispanic, African American, Asian, and Native American adolescents. The most common typology was alcohol only, followed by concurrent use of alcohol and marijuana. Weighted prevalence estimates indicated that adolescent females were more likely to be current users of alcohol only, whereas male adolescents were more likely to belong to all other typologies. Compared to Whites, racial/ethnic minorities had larger proportions of marijuana only users and were generally less likely than or equally likely to be concurrent users. One exception was for African American adolescents, who were more likely to be alcohol and marijuana users than their White counterparts. Results suggest that concurrent substance use is common among U.S. adolescents, making up over 40% of past-month use, but typologies of use vary by sex and race/ethnicity. Preventive interventions should consider all typologies of use rather than only single substance exposures and address patterns of use that are most pertinent to adolescents based on sex and race/ethnicity.

Implementation and Operational Research: Declining Tuberculosis Incidence Among People Receiving HIV Care and Treatment Services in East Africa, 2007-2012.

BACKGROUND: Antiretroviral therapy (ART) reduces the risk of Tuberculosis (TB) among people living with HIV (PLWH). With ART scale-up in sub-Saharan Africa over the past decade, incidence of TB among PLWH engaged in HIV care is predicted to decline. METHODS: We conducted a retrospective analysis of routine clinical data from 168,330 PLWH receiving care at 35 facilities in Kenya, Tanzania, and Uganda during 2003-2012, participating in the East African region of the International Epidemiologic Databases to Evaluate AIDS. Temporal trends in facility-based annual TB incidence rates (per 100,000 person years) among PLWH and country-specific standardized TB incidence ratios using annual population-level TB incidence data from the World Health Organization were computed between 2007 and 2012. We examined patient-level and facility-level factors associated with incident TB using multivariable Cox models. RESULTS: Overall, TB incidence rates among PLWH in care declined 5-fold between 2007 and 2012 from 5960 to 985 per 100,000 person years [P = 0.0003] (Kenya: 7552 to 1115 [P = 0.0007]; Tanzania: 7153 to 635 [P = 0.0025]; Uganda: 3204 to 242 [P = 0.018]). Standardized TB incidence ratios significantly decreased in the 3 countries, indicating a narrowing gap between incidence rates among PLWH and the general population. We observed lower hazards of incident TB among PLWH on ART and/or isoniazid preventive therapy and receiving care in facilities offering TB treatment onsite. CONCLUSIONS: Annual TB incidence rates among PLWH significantly declined during ART scale-up but remained higher than the general population. Increasing access to ART and isoniazid preventive therapy and co-location of HIV and TB treatment may further reduce TB incidence among PLWH.