Efficiency of the Breslow estimator in semiparametric transformation models.

Semiparametric transformation models for failure time data consist of a parametric regression component and an unspecified cumulative baseline hazard. The nonparametric maximum likelihood estimator (NPMLE) of the cumulative baseline hazard can be summarized in terms of weights introduced into a Breslow-type estimator (Weighted Breslow). At any given time point, the weights invoke an integral over the future of the cumulative baseline hazard, which presents theoretical and computational challenges. A simpler non-MLE Breslow-type estimator (Breslow) was derived earlier from a martingale estimating equation (MEE) setting observed and expected counts of failures equal, conditional on the past history. Despite much successful theoretical and computational development, the simpler Breslow estimator continues to be commonly used as a compromise between simplicity and perceived loss of full efficiency. In this paper we derive the relative efficiency of the Breslow estimator and consider the properties of the two estimators using simulations and real data on prostate cancer survival.

National Long-term Survival Estimates After Radical Prostatectomy for Prostate Cancer.

OBJECTIVE: To examine survival and disease control outcomes, including metastasis-related survival outcomes, in a large contemporary cohort of patients undergoing radical prostatectomy for localized prostate cancer. METHODS: We conducted a retrospective study of men with localized prostate cancer treated with radical prostatectomy from 2005 to 2015 with follow-up through 2019 in the Veterans Health Administration. We defined biochemical recurrence (BCR) as a prostate-specific antigen ≥0.2 ng/mL. We used a validated natural language processing encoded dataset to identify incident metastatic prostate cancer. We estimated overall survival from time of surgery, time of BCR, and time of first metastasis using the Kaplan-Meier method. We then estimated time from surgery to BCR, BCR to metastatic disease, and prostate-cancer-specific survival from various time points using cumulative incidence considering competing risk of death. RESULTS: Of 21,992 men undergoing radical prostatectomy, we identified 5951 (27%) who developed BCR. Of men with BCR, 677 (11%) developed metastases. We estimated the 10-year cumulative incidence of BCR and metastases after BCR were 28% and 20%, respectively. Median overall survival after BCR was 14years, with 10-year survival of 70%. From the time of metastasis, median overall survival approached 7years, with 10-year overall survival of 34%. Prostate cancer-specific survival for the entire cohort at 10years was 94%. CONCLUSION: In this large contemporary national cohort, survival for men with biochemically recurrent prostate cancer is longer than historical cohorts. When counseling patients and designing clinical studies, these updated estimates may serve as more reliable reflections of current outcomes.

Outcomes after definitive radiation therapy for localized prostate cancer in a national health care delivery system.

PURPOSE: Accurate information regarding real-world outcomes after contemporary radiation therapy for localized prostate cancer is important for shared decision-making. Clinically relevant end points at 10 years among men treated within a national health care delivery system were examined. METHODS: National administrative, cancer registry, and electronic health record data were used for patients undergoing definitive radiation therapy with or without concurrent androgen deprivation therapy within the Veterans Health Administration from 2005 to 2015. National Death Index data were used through 2019 for overall and prostate cancer-specific survival and identified date of incident metastatic prostate cancer using a validated natural language processing algorithm. Metastasis-free, prostate cancer-specific, and overall survival using Kaplan-Meier methods were estimated. RESULTS: Among 41,735 men treated with definitive radiation therapy, the median age at diagnosis was 65 years and median follow-up was 8.7 years. Most had intermediate (42%) and high-risk (33%) disease, with 40% receiving androgen deprivation therapy as part of initial therapy. Unadjusted 10-year metastasis-free survival was 96%, 92%, and 80% for low-, intermediate-, and high-risk disease. Similarly, unadjusted 10-year prostate cancer-specific survival was 98%, 97%, and 90% for low-, intermediate-, and high-risk disease. The unadjusted overall survival was lower across increasing disease risk categories at 77%, 71%, and 62% for low-, intermediate-, and high-risk disease (p < .001). CONCLUSIONS: These data provide population-based 10-year benchmarks for clinically relevant end points, including metastasis-free survival, among patients with localized prostate cancer undergoing radiation therapy using contemporary techniques. The survival rates for high-risk disease in particular suggest that outcomes have recently improved.

An Interventional Response Phenotyping Study in Chronic Low Back Pain: Protocol for a Mechanistic Randomized Controlled Trial.

Evidence-based treatments for chronic low back pain (cLBP) typically work well in only a fraction of patients, and at present there is little guidance regarding what treatment should be used in which patients. Our central hypothesis is that an interventional response phenotyping study can identify individuals with different underlying mechanisms for their pain who thus respond differentially to evidence-based treatments for cLBP. Thus, we will conduct a randomized controlled Sequential, Multiple Assessment, Randomized Trial (SMART) design study in cLBP with the following three aims. Aim 1: Perform an interventional response phenotyping study in a cohort of cLBP patients (n = 400), who will receive a sequence of interventions known to be effective in cLBP. For 4 weeks, all cLBP participants will receive a web-based pain self-management program as part of a run-in period, then individuals who report no or minimal improvement will be randomized to: a) mindfulness-based stress reduction, b) physical therapy and exercise, c) acupressure self-management, and d) duloxetine. After 8 weeks, individuals who remain symptomatic will be re-randomized to a different treatment for an additional 8 weeks. Using those data, we will identify the subsets of participants that respond to each treatment. In Aim 2, we will show that currently available, clinically derived measures, can predict differential responsiveness to the treatments. In Aim 3, a subset of participants will receive deeper phenotyping (n = 160), to identify new experimental measures that predict differential responsiveness to the treatments, as well as to infer mechanisms of action. Deep phenotyping will include functional neuroimaging, quantitative sensory testing, measures of inflammation, and measures of autonomic tone.

The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma.

Multiple myeloma is the second most common hematological malignancy. Despite significant advances in treatment, relapse is common and carries a poor prognosis. Thus, it is critical to elucidate the genetic factors contributing to disease progression and drug resistance. Here, we carry out integrative clinical sequencing of 511 relapsed, refractory multiple myeloma (RRMM) patients to define the disease's molecular alterations landscape. The NF-κB and RAS/MAPK pathways are more commonly altered than previously reported, with a prevalence of 45-65% each. In the RAS/MAPK pathway, there is a long tail of variants associated with the RASopathies. By comparing our RRMM cases with untreated patients, we identify a diverse set of alterations conferring resistance to three main classes of targeted therapy in 22% of our cohort. Activating mutations in IL6ST are also enriched in RRMM. Taken together, our study serves as a resource for future investigations of RRMM biology and potentially informs clinical management.

Better Understanding the Timing Of Androgen Deprivation Trial Outcomes: Impacts of Prior Androgen Deprivation Therapy.

BACKGROUND: The Timing Of Androgen Deprivation (TOAD) trial found an overall survival benefit for immediate vs delayed androgen deprivation therapy (ADT) for prostate-specific antigen (PSA)-relapsed or noncurable prostate cancer. However, broad eligibility criteria allowed entry of a heterogeneous participant group, including those with prior ADT exposure, raising concerns about subsequent androgen sensitivity. For these reasons, we completed previously specified subgroup analyses to assess if prior ADT was associated with ADT timing efficacy after PSA relapse. METHODS: We examined TOAD trial patient-level data for participants with PSA relapse after local therapy. We performed Kaplan-Meier analyses for overall survival stratified by prior ADT and randomized treatment arm (immediate or delayed ADT). We compared group characteristics using Mann-Whitney U and Fisher exact tests. All hypothesis tests were 2-sided. RESULTS: We identified 261 patients with PSA relapse, 125 of whom received prior ADT. Patients with prior ADT had higher PSA at presentation (12.1 vs 9.0 ng/mL; P < .001), more cT3 disease (38.4% vs 25.0%; P = .007), and more likely received radiotherapy as local treatment (80.0% vs 47.8%; P < .001) but were otherwise similar to patients without prior ADT exposure. Within this prior ADT group, those who received immediate ADT (n = 56) had improved overall survival compared with those who received delayed ADT (n = 69; P = .02). This benefit was not observed in the group with no prior ADT (P = .98). CONCLUSIONS: The survival benefit demonstrated in the TOAD trial may be driven by patients who received ADT prior to trial entry. We provide possible explanations for this finding with implications for treatment of PSA-relapsed prostate cancer and future study planning.

A copula-based approach for dynamic prediction of survival with a binary time-dependent covariate.

Dynamic prediction methods incorporate longitudinal biomarker information to produce updated, more accurate predictions of conditional survival probability. There are two approaches for obtaining dynamic predictions: (1) a joint model of the longitudinal marker and survival process, and (2) an approximate approach that specifies a model for a specific component of the joint distribution. In the case of a binary marker, an illness-death model is an example of a joint modeling approach that is unified and produces consistent predictions. However, previous literature has shown that approximate approaches, such as landmarking, with additional flexibility can have good predictive performance. One such approach proposes using a Gaussian copula to model the joint distribution of conditional continuous marker and survival distributions. It has the advantage of specifying established, flexible models for the marginals for which goodness-of-fit can be assessed, and has easy estimation that can be implemented in standard software. In this article, we provide a Gaussian copula approach for dynamic prediction to accommodate a binary marker using a continuous latent variable formulation. We compare the predictive performance of this approach to joint modeling and landmarking using simulations and demonstrate its use for obtaining dynamic predictions in an application to a prostate cancer study.

The Effects of Intraoperative Caffeine on Postoperative Opioid Consumption and Related Outcomes After Laparoscopic Surgery: A Randomized Controlled Trial.

BACKGROUND: Surgical patients are vulnerable to opioid dependency and related risks. Clinical-translational data suggest that caffeine may enhance postoperative analgesia. This trial tested the hypothesis that intraoperative caffeine would reduce postoperative opioid consumption. The secondary objective was to assess whether caffeine improves neuropsychological recovery postoperatively. METHODS: This was a single-center, randomized, placebo-controlled trial. Participants, clinicians, research teams, and data analysts were all blinded to the intervention. Adult (≥18 years old) surgical patients (n = 65) presenting for laparoscopic colorectal and gastrointestinal surgery were randomized to an intravenous caffeine citrate infusion (200 mg) or dextrose 5% in water (40 mL) during surgical closure. The primary outcome was cumulative opioid consumption through postoperative day 3. Secondary outcomes included subjective pain reporting, observer-reported pain, delirium, Trail Making Test performance, depression and anxiety screens, and affect scores. Adverse events were reported, and hemodynamic profiles were also compared between the groups. RESULTS: Sixty patients were included in the final analysis, with 30 randomized to each group. The median (interquartile range) cumulative opioid consumption (oral morphine equivalents, milligrams) was 77 mg (33-182 mg) for caffeine and 51 mg (15-117 mg) for placebo (estimated difference, 55 mg; 95% confidence interval [CI], -9 to 118; P = .092). After post hoc adjustment for baseline imbalances, caffeine was associated with increased opioid consumption (87 mg; 95% CI, 26-148; P = .005). There were otherwise no differences in prespecified pain or neuropsychological outcomes between the groups. No major adverse events were reported in relation to caffeine, and no major hemodynamic perturbations were observed with caffeine administration. CONCLUSIONS: Caffeine appears unlikely to reduce early postoperative opioid consumption. Caffeine otherwise appears well tolerated during anesthetic emergence.

A Gaussian copula approach for dynamic prediction of survival with a longitudinal biomarker.

Dynamic prediction uses patient information collected during follow-up to produce individualized survival predictions at given time points beyond treatment or diagnosis. This allows clinicians to obtain updated predictions of a patient's prognosis that can be used in making personalized treatment decisions. Two commonly used approaches for dynamic prediction are landmarking and joint modeling. Landmarking does not constitute a comprehensive probability model, and joint modeling often requires strong distributional assumptions and computationally intensive methods for estimation. We introduce an alternative approximate approach for dynamic prediction that aims to overcome the limitations of both methods while achieving good predictive performance. We separately specify the marker and failure time distributions conditional on surviving up to a prediction time of interest and use standard variable selection and goodness-of-fit techniques to identify the best-fitting models. Taking advantage of its analytic tractability and easy two-stage estimation, we use a Gaussian copula to link the marginal distributions smoothly at each prediction time with an association function. With simulation studies, we examine the proposed method's performance. We illustrate its use for dynamic prediction in an application to predicting death for heart valve transplant patients using longitudinal left ventricular mass index information.

Top down or bottom up? An observational investigation of improvement in fibromyalgia symptoms following hip and knee replacement.

OBJECTIVES: Many patients with osteoarthritis have comorbid symptoms of FM, but it is unknown how these symptoms respond to surgical procedures that address nociceptive input in the periphery, such as total joint replacement. Here we explore differences in clinical characteristics between patients whose FM symptoms do and do not improve following total hip or knee replacement. METHODS: Participants were 150 patients undergoing knee or hip replacement who had a minimum FM survey score of 4 or greater prior to surgery. The top tertile of patients experiencing the most improvement in FM symptoms at month 6 were categorized as 'Improve' (n = 48) while the bottom two tertiles were categorized as 'Worsen/Same' (n = 102). Baseline symptom characteristics were compared between groups, as well as improvement in overall pain severity, surgical pain severity and physical function at 6 months. RESULTS: The Worsen/Same group had higher levels of fatigue, depression and surgical site pain at baseline (all P < 0.05). Additionally, they improved less on overall pain severity and physical functioning 6 months after surgery (both P < 0.05). CONCLUSION: Most patients derive significant benefit in improvement of comorbid FM symptoms following total joint replacement, but a substantial proportion do not. Understanding the neurobiological basis for these different trajectories may help inform clinical judgment and improve patient care.

Heritability of the Fibromyalgia Phenotype Varies by Age.

OBJECTIVE: Many studies suggest a strong familial component to fibromyalgia (FM). However, those studies have nearly all been confined to individuals with primary FM, i.e., FM without any other accompanying disorder. The current 2011 and 2016 criteria for diagnosing FM construct a score using a combination of the number of painful body sites and the severity of somatic symptoms (FM score). This study was undertaken to estimate the genetic heritability of the FM score across sex and age groups to identify subgroups of individuals with greater heritability, which may help in the design of future genetic studies. METHODS: We collected data on 26,749 individuals of European ancestry undergoing elective surgery at the University of Michigan (Michigan Genomics Initiative study). We estimated the single-nucleotide polymorphism-based heritability of FM score by age and sex categories using genome-wide association study data and a linear mixed-effects model. RESULTS: Overall, the FM score had an estimated heritability of 13.9% (SE 2.9%) (P = 1.6 × 10-7 ). Estimated FM score heritability was highest in individuals ≤50 years of age (23.5%; SE 7.9%) (P = 3.0 ×10-4 ) and lowest in individuals >60 years of age (7.5%; SE 8.1%) (P = 0.41). These patterns remained the same when we analyzed FM as a case-control phenotype. Even though women had an ~30% higher average FM score than men across age categories, FM score heritability did not differ significantly by sex. CONCLUSION: Younger individuals appear to have a much stronger genetic component to the FM score than older individuals. Older individuals may be more likely to have what was previously called "secondary FM." Regardless of the cause, these results have implications for future genetic studies of FM and associated conditions.

Implementation of Evidence-Based Practice for Benign Paroxysmal Positional Vertigo in the Emergency Department: A Stepped-Wedge Randomized Trial.

STUDY OBJECTIVE: We evaluated a strategy to increase use of the test (Dix-Hallpike's test [DHT]) and treatment (canalith repositioning maneuver [CRM]) for benign paroxysmal positional vertigo in emergency department (ED) dizziness visits. METHODS: We conducted a stepped-wedge randomized trial in 6 EDs. The population was visits with dizziness as a principal reason for the visit. The intervention included educational sessions and decision aid materials. Outcomes were DHT or CRM documentation (primary), head computed tomography (CT) use, length of stay, admission, and 90-day stroke events. The analysis was multilevel logistic regression with intervention, month, and hospital as fixed effects and provider as a random effect. We assessed fidelity with monitoring intervention use and semistructured interviews. RESULTS: We identified 7,635 dizziness visits during 18 months. The DHT or CRM was documented in 1.5% of control visits (45/3,077; 95% confidence interval 1% to 1.9%) and 3.5% of intervention visits (159/4,558; 95% confidence interval 3% to 4%; difference 2%, 95% confidence interval 1.3% to 2.7%). Head CT use was lower in intervention visits compared with control visits (44.0% [1,352/3,077] versus 36.9% [1,682/4,558]). No differences were observed in admission or 90-day subsequent stroke risk. In fidelity evaluations, providers who used the materials typically reported positive clinical experiences but provider engagement was low at facilities without an emergency medicine residency program. CONCLUSION: These findings provide evidence that an implementation strategy of a benign paroxysmal positional vertigo-focused approach to ED dizziness visits can be successful and safe in promoting evidence-based care. Absolute rates of DHT and CRM use, however, were still low, which relates in part to our broad inclusion criteria for dizziness visits.

Comprehensive Analysis of Steroid Biomarkers for Guiding Primary Aldosteronism Subtyping.

Adrenal vein sampling (AVS) is required to distinguish unilateral from bilateral aldosterone sources in primary aldosteronism (PA), and cortisol is used for AVS data interpretation, but cortisol has several pitfalls. In this study, we present the utility of several other steroids in PA subtyping, both during AVS, as well as in peripheral serum. We included patients with PA who underwent AVS at University of Michigan between 2012 and 2018. We used mass spectrometry to simultaneously quantify 17 steroids in adrenal veins (AV) and periphery, both at baseline and after cosyntropin administration. PA was classified as unilateral or bilateral based on a lateralization index ≥ or <4, respectively, separately for baseline and post-cosyntropin administration. Of 131 participants, AV catheterizations was deemed failed in 28 (21 %) patients (36 AVs) at baseline. Eight steroids demonstrated higher AV/periphery ratios than cortisol (P<0.01 for all); 11ß-hydroxyandrostenedione, 11-deoxycortisol, and corticosterone rescued most failed baseline catheterizations. Lateralization was generally consistent when using these alternative steroids. Based on pre- and post-cosyntropin data, the remaining 103 patients were classified as: U/U, 37; B/B, 32; U/B, 20; B/U, 14. Discriminant analysis of multi-steroid panels from peripheral serum showed distinct profiles across the 4 groups, with highest aldosterone, 18-oxocortisol and 11-deoxycorticosterone in U/U patients. In conclusion, 11ß-hydroxyandrostenedione and 11-deoxycortisol are superior to cortisol for AVS data interpretation. Single assay multi-steroid panels measured in peripheral serum are helpful in stratified PA subtyping and have the potential to circumvent AVS in a subset of patients with PA.

Association between PSA values and surveillance quality after prostate cancer surgery.

BACKGROUND: Although prostate-specific antigen (PSA) testing is used for prostate cancer detection and posttreatment surveillance, thresholds in these settings differ. The screening cutoff of 4.0 ng/mL may be inappropriately used during postsurgery surveillance, where 0.2 ng/mL is typically used, creating missed opportunities for effective salvage radiation treatment. We performed a study to determine whether guideline concordance with annual postoperative PSA surveillance increases when PSA values exceed 4 ng/mL, which represents a screening threshold that is not relevant after surgery. METHODS: We used US Veterans Health Administration data to perform a retrospective longitudinal cohort study of men diagnosed with nonmetastatic prostate cancer from 2005 to 2008 who underwent radical prostatectomy. We used logistic regression to examine the association between postoperative PSA levels and receipt of an annual PSA test. RESULTS: Among 10 400 men and 38 901 person-years of follow-up, annual guideline concordance decreased from 95% in year 1 to 79% in year 7. After adjustment, guideline concordance was lower for the youngest and oldest men, Black, and unmarried men. Guideline concordance significantly increased as PSA exceeded 4 ng/mL (adjusted odds ratio 2.20 PSA > 4-6 ng/mL vs PSA > 1-4 ng/mL, 95% confidence interval 1.20-4.03; P = .01). CONCLUSIONS: Guideline concordance with prostate cancer surveillance increased when PSA values exceeded 4 ng/mL, suggesting a screening threshold not relevant after prostate cancer surgery, where 0.2 ng/mL is considered treatment failure, is impacting cancer surveillance quality. Clarification of PSA thresholds for early detection vs cancer surveillance, as well as emphasizing adherence for younger and Black men, appears warranted.

An Educational Intervention for Acute Dizziness Care: A Randomized, Vignette-based Study.

IMPORTANCE: Benign paroxysmal positional vertigo (BPPV) is a common cause of acute dizziness. Strong evidence exists for diagnosing BPPV using the Dix-Hallpike Test (DHT) and treating it with the canalith repositioning maneuver (CRM). Despite this, both are infrequently used in the emergency department (ED). OBJECTIVE: As an early method to evaluate a BPPV-focused educational intervention, we evaluated whether an educational intervention improved ED provider performance on hypothetical stroke and BPPV cases delivered by vignette. DESIGN: A randomized, controlled, educational intervention study in ED physicians. The intervention aimed to promote the appropriate use of the DHT and CRM. A BPPV vignette, a stroke-dizziness (safety) vignette, and vignette scoring schemes (higher scores indicating more optimal care) used previously established vignette methodology. SETTING: We recruited participants at the exhibitor hall of an emergency medicine annual meeting. PARTICIPANTS: We recruited 48 emergency physicians. All were board certified or residency trained and board eligible. All were engaged in the active practice of emergency medicine. None were trainees. INTERVENTIONS: Intervention group: a narrated, educational presentation by computer followed by the clinical vignettes. CONTROL GROUP: Received no educational intervention and completed the clinical vignettes-intended to mirror current clinician practice. MAIN OUTCOME MEASURE: Primary endpoint: total score (out of 200 points) on a vignette-based scoring instrument assessing the performance of history, physical, and diagnostic testing on hypothetical stroke and BPPV cases. RESULTS: The efficacy threshold was crossed at the interim analysis. The intervention group had higher performance scores compared with controls (113.2 versus 68.6, p < 0.00001). BPPV and safety subscores were both significantly higher in the intervention group. Sixty-two percent of the intervention group planned to use the DHT versus 29% of controls. After the vignette described characteristic BPPV nystagmus, 100% of the intervention group planned to use the CRM versus 17% of controls. CONCLUSIONS AND RELEVANCE: The educational intervention increased provider performance in dizziness vignettes, including more frequent appropriate use of the DHT/CRM. These findings indicate the intervention positively influenced planned behavior. Future work is needed to implement and evaluate this intervention in clinical practice.

Implementation of evidence-based practice for benign paroxysmal positional vertigo: DIZZTINCT- A study protocol for an exploratory stepped-wedge randomized trial.

BACKGROUND: Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular disorder, and accounts for 8% of individuals with moderate or severe dizziness. BPPV patients experience substantial inconveniences and disabilities during symptomatic periods. BPPV therapeutic processes - the Dix-Hallpike Test (DHT) and the Canalith Repositioning Maneuver (CRM) - have an evidence base that is at the clinical practice guideline level. The most commonly used CRM is the modified Epley maneuver. The DHT is the gold standard test for BPPV and the CRM is supported by numerous randomized controlled trials and systematic reviews. Despite this, BPPV care processes are underutilized. METHODS/DESIGN: This is a stepped-wedge, randomized clinical trial of a multi-faceted educational and care-process-based intervention designed to improve the guideline-concordant care of patients with BPPV presenting to the emergency department (ED) with dizziness. The unit of randomization and target of intervention is the hospital. After an initial observation period, the six hospitals will undergo the intervention in five waves (two closely integrated hospitals will be paired). The order will be randomized. The primary endpoint is measured at the individual patient level, and is the presence of documentation of either the Dix-Hallpike Test or CRM. The secondary endpoints are referral to a health care provider qualified to treat dizziness for CRM and 90-day stroke rates following an ED dizziness visit. Formative evaluations are also performed to monitor and identify potential and actual influences on the progress and effectiveness of the implementation efforts. DISCUSSION: If this study safely increases documentation of the DHT/CRM, this will be an important step in implementing the use of these evidenced-based processes of care. Positive results will support conducting larger-scale follow-up studies that assess patient outcomes. The data collection also enables evaluation of potential and actual influences on the progress and effectiveness of the implementation efforts. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02809599 . The record was first available to the public on 22 June 2016 prior to the enrollment of the first patients in October 2016.

Intrathoracic Fat Measurements Using Multidetector Computed Tomography (MDCT): Feasibility and Reproducibility.

Intrathoracic fat volume, more specifically, epicardial fat volume, is an emerging imaging biomarker of adverse cardiovascular events. The purpose of this work is to show the feasibility and reproducibility of intrathoracic fat volume measurement applied to contrast-enhanced multidetector computed tomography images. A retrospective cohort study of 62 subjects free of cardiovascular disease (55% females, age = 49 ± 11 years) conducted from 2008 to 2011 formed the study group. Intrathoracic fat volume was defined as all fat voxels measuring -50 to -250 Hounsfield Unit within the intrathoracic cavity from the level of the pulmonary artery bifurcation to the heart apex. The intrathoracic fat was separated into epicardial and extrapericardial fat by tracing the pericardium. The measurements were obtained by 2 readers and compared for interrater reproducibility. The fat volume measurements for the study group were 141 ± 72 cm3 for intrathoracic fat, 58 ± 27 cm3 for epicardial fat, and 84 ± 50 cm3 for extrapericardial fat. There was no statistically significant difference in intrathoracic fat volume measurements between the 2 readers, with correlation coefficients of 0.88 (P = .55) for intrathoracic fat volume and -0.12 (P = .33) for epicardial fat volume. Voxel-based measurement of intrathoracic fat, including the separation into epicardial and extrapericardial fat, is feasible and highly reproducible from multidetector computed tomography scans.

11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency.

Context: Patients with 21-hydroxylase deficiency (21OHD) have long-term complications, resulting from poor disease control and/or glucocorticoid overtreatment. Lack of optimal biomarkers has made it challenging to tailor therapy and predict long-term outcomes. Objective: To identify biomarkers of disease control and long-term complications in 21OHD. Setting and Participants: Cross-sectional study of 114 patients (70 males), ages 2 to 67 years (median, 15 years), seen in a tertiary referral center. Methods: We correlated a mass-spectrometry panel of 23 steroids, obtained before first morning medication, with bone age advancement (children), adrenal volume (adults), testicular adrenal rest tumors (TART), hirsutism, menstrual disorders, and pituitary hormones. Results: Total adrenal volume correlated positively with 18 steroids, most prominently 21-deoxycortisol and four 11-oxygenated-C19 (11oxC19) steroids: 11ß-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11ketoA4), 11ß-hydroxytestosterone (11OHT), and 11-ketotestosterone (11ketoT) (r ≈ 0.7, P < 0.0001). Nine steroids were significantly higher (P ≤ 0.01) in males with TART compared with those without TART, including 11OHA4 (6.8-fold), 11OHT (4.9-fold), 11ketoT (3.6-fold), 11ketoA4 (3.3-fold), and pregnenolone sulfate (PregS; 4.8-fold). PregS (28.5-fold) and 17-hydroxypregnenolone sulfate (19-fold) levels were higher (P < 0.01) in postpubertal females with menstrual disorders. In males, testosterone levels correlated positively with all 11oxC19 steroids in Tanner stages 1 and 2 (r ≈ 0.7; P < 0.001) but negatively in Tanner stage 5 (r = -0.3 and P < 0.05 for 11ketoA4 and 11ketoT). In females, testosterone level correlated positively with all four 11oxC19 steroids across all Tanner stages (r ≈ 0.8; P < 0.0001). Conclusion: 11oxC19 steroids and PregS might serve as clinically useful biomarkers of disease control and long-term complications in 21OHD.

Comparison of joint modeling and landmarking for dynamic prediction under an illness-death model.

Dynamic prediction incorporates time-dependent marker information accrued during follow-up to improve personalized survival prediction probabilities. At any follow-up, or "landmark", time, the residual time distribution for an individual, conditional on their updated marker values, can be used to produce a dynamic prediction. To satisfy a consistency condition that links dynamic predictions at different time points, the residual time distribution must follow from a prediction function that models the joint distribution of the marker process and time to failure, such as a joint model. To circumvent the assumptions and computational burden associated with a joint model, approximate methods for dynamic prediction have been proposed. One such method is landmarking, which fits a Cox model at a sequence of landmark times, and thus is not a comprehensive probability model of the marker process and the event time. Considering an illness-death model, we derive the residual time distribution and demonstrate that the structure of the Cox model baseline hazard and covariate effects under the landmarking approach do not have simple form. We suggest some extensions of the landmark Cox model that should provide a better approximation. We compare the performance of the landmark models with joint models using simulation studies and cognitive aging data from the PAQUID study. We examine the predicted probabilities produced under both methods using data from a prostate cancer study, where metastatic clinical failure is a time-dependent covariate for predicting death following radiation therapy.