Sequential modeling for a class of reference-based imputation methods in clinical trials with quantitative or binary outcomes.

We consider treatment effect estimation in a randomized clinical trial with longitudinally measured quantitative or categorical outcomes. To handle missing data, we usually assume missing at random and then conduct sensitivity analysis for missing not at random. In the literature, several reference-based imputation methods, including "jump to reference" (J2R) and "copy reference" (CR), have been commonly used for conducting sensitivity analysis. J2R assumes the mean effect profile of patients who discontinue the investigative treatment jumps to that of the patients in the reference group after discontinuation, while CR assumes the conditional mean effect profile given the status prior to the time of discontinuation copies that of the patients in the reference group after discontinuation. In this article, we propose a novel, wide class of reference-based imputation methods for conducting sensitivity analysis, which includes J2R and CR as two extreme ends. The framework is motivated by the thought that the investigative treatment may have no, partially, or fully carried-over effect after deviation from the assigned treatment (eg, discontinue the assigned treatment or change to a different treatment). Further, we show that the proposed reference-based imputation methods can be implemented through sequential modeling. This property ensures that the methods can be applied to clinical trials with either quantitative or categorical outcomes. We use both causal-inference arguments and numerical examples to demonstrate the performance of the proposed methods.

Value of variation of end-tidal carbon dioxide for predicting fluid responsiveness during the passive leg raising test in patients with mechanical ventilation: a systematic review and meta-analysis.

BACKGROUND: The ability of end-tidal carbon dioxide (ΔEtCO2) for predicting fluid responsiveness has been extensively studied with conflicting results. This meta-analysis aimed to explore the value of ΔEtCO2 for predicting fluid responsiveness during the passive leg raising (PLR) test in patients with mechanical ventilation. METHODS: PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched up to November 2021. The diagnostic odds ratio (DOR), sensitivity, and specificity were calculated. The summary receiver operating characteristic curve was estimated, and the area under the curve (AUROC) was calculated. Q test and I2 statistics were used for study heterogeneity and publication bias was assessed by Deeks' funnel plot asymmetry test. We performed meta-regression analysis for heterogeneity exploration and sensitivity analysis for the publication bias. RESULTS: Overall, six studies including 298 patients were included in this review, of whom 149 (50%) were fluid responsive. The cutoff values of ΔEtCO2 in four studies was 5%, one was 5.8% and the other one was an absolute increase 2 mmHg. Heterogeneity between studies was assessed with an overall Q = 4.098, I2 = 51%, and P = 0.064. The pooled sensitivity and specificity for the overall population were 0.79 (95% CI 0.72-0.85) and 0.90 (95% CI 0.77-0.96), respectively. The DOR was 35 (95% CI 12-107). The pooled AUROC was 0.81 (95% CI 0.77-0.84). On meta-regression analysis, the number of patients was sources of heterogeneity. The sensitivity analysis showed that the pooled DOR ranged from 21 to 140 and the pooled AUC ranged from 0.92 to 0.96 when one study was omitted. CONCLUSIONS: Though the limited number of studies included and study heterogeneity, our meta-analysis confirmed that the ΔEtCO2 performed moderately in predicting fluid responsiveness during the PLR test in patients with mechanical ventilation.

Practical considerations in utilizing cluster randomized controlled trials conducted in biopharmaceutical industry.

Cluster randomized controlled trials (cluster RCTs), also known as parallel-arm group-randomized trials, are trials in which the randomized units are groups of participants, as opposed to individual participants. These trials have largely been implemented to address broad public health issues, but with the growing interest in use of real-world data in the regulatory setting, this design may be increasingly considered for industry trials. The key difference between cluster RCTs and traditional RCTs is the intraclass correlation coefficient (ICC) that needs to be considered in cluster RCTs. In this article, we discuss some key practical considerations that are related to ICC in the design, conduct, analysis, and report stages of a cluster RCT. These key considerations related to ICC can lead to improvement in how we translate research findings from cluster RCTs into practices in the biopharmaceutical industry.

On Reference-based Imputation for Analysis of Incomplete Repeated Binary Endpoints.

Reference-based imputation (RBI) is a popular method for missing data. The methodology is well established for continuous end points but less well developed for repeated binary end points due to the lack of natural multivariate conditional distributions for such end points. In this paper, we propose RBI methods for repeated binary end points based on a multivariate probit model and a logistic model, including jump-to-reference (J2R), copy-reference (CR) and copy-increment-in-reference (CIR). We explore the distribution of the missing binary end points under RBI and propose efficient algorithms to implement the proposed RBI methods. We evaluate the proposed methods by simulations and a data set from a clinical trial.

The effect of early vasopressin use on patients with septic shock: A systematic review and meta-analysis.

BACKGROUND: The effect of early vasopressin initiation on clinical outcomes in patients with septic shock is uncertain. A systematic review and meta-analysis was performed to evaluate the impact of early start of vasopressin support within 6 h after the diagnosis on clinical outcomes in septic shock patients. METHODS: We searched the PubMed, Cochrane, and Embase databases for randomized controlled trials (RCTs) and cohort studies from inception to the 1st of February 2021. We included studies involving adult patients (> 16 years)with septic shock. All authors reported our primary outcome of short-term mortality and in the experimental group patients in the studies receiving vasopressin infusion within 6 h after diagnosis of septic shock and in the control group patients in the studies receiving no vasopressin infusion or vasopressin infusion 6 h after diagnosis of septic shock, clearly comparing with clinically relevant secondary outcomes(use of renal replacement therapy(RRT),new onset arrhythmias, ICU length of stay and length of hospitalization). Results were expressed as odds ratio (OR) and mean difference (MD) with accompanying 95% confidence interval (CI). RESULTS: Five studies including 788 patients were included. The primary outcome of this meta-analysis showed that short-term mortality between the two groups was no difference (odds ratio [OR] = 1.09; 95% CI, 0.8 to 1.48; P = 0.6; χ2 = 0.83; I2 = 0%). Secondary outcomes demonstrated that the use of RRT was less in the experimental group than that of the control group (OR = 0.63; 95% CI, 0.44 to 0.88; P = 0.007; χ2 = 3.15; I2 = 36%).The new onset arrhythmias between the two groups was no statistically significant difference (OR = 0.59; 95% CI, 0.31 to 1.1; P = 0.10; χ2 = 4.7; I2 = 36%). There was no statistically significant difference in the ICU length of stay(mean difference = 0.16; 95% CI, - 0.91 to 1.22; P = 0.77; χ2 = 6.08; I2 = 34%) and length of hospitalization (mean difference = -2.41; 95% CI, -6.61 to 1.78; P = 0.26; χ2 = 8.57; I2 = 53%) between the two groups. CONCLUSIONS: Early initiation of vasopressin in patients within 6 h of septic shock onset was not associated with decreased short-term mortality, new onset arrhythmias, shorter ICU length of stay and length of hospitalization, but can reduce the use of RRT. Further large-scale RCTs are still needed to evaluate the benefit of starting vasopressin in the early phase of septic shock.

A method for sample size calculation via E-value in the planning of observational studies.

Confounding adjustment plays a key role in designing observational studies such as cross-sectional studies, case-control studies, and cohort studies. In this article, we propose a simple method for sample size calculation in observational research in the presence of confounding. The method is motivated by the notion of E-value, using some bounding factor to quantify the impact of confounders on the effect size. The method can be applied to calculate the needed sample size in observational research when the outcome variable is binary, continuous, or time-to-event. The method can be implemented straightforwardly using existing commercial software such as the PASS software. We demonstrate the performance of the proposed method through numerical examples, simulation studies, and a real application, which show that the proposed method is conservative in providing a slightly bigger sample size than what it needs to achieve a given power.

Predicting adults likely to develop heart failure using readily available clinical information: An analysis of heart failure incidence using the NHEFS.

BACKGROUND: Heart failure is a heavy burden on the health care system in the United States. Once heart failure develops, the quality of life and longevity are dramatically affected. As such, its prevention is critical for the well-being of at risk patients. We evaluated the predictive ability of readily available clinical information to identify those likely to develop heart failure. METHODS: We used a classification and regression tree (CART) model to determine the top predictors for heart failure incidence using the NHANES Epidemiologic Follow-up Study (NHEFS). The identified predictors were hypertension, diabetes, obesity, and myocardial infarction (MI). We evaluated the relationship between these variables and incident heart failure by the product-limit method and Cox models. All analyses incorporated the complex sample design to provide population estimates. RESULTS: We analyzed data from 14,407 adults in the NHEFS. Participants with diabetes, MI, hypertension, or obesity had a higher incidence of heart failure than those without risk factors, with diabetes and MI being the most potent predictors. Individuals with multiple risk factors had a higher incidence of heart failure as well as a higher hazard ratio than those with just one risk factor. Combinations that included diabetes and MI had the highest incidence rates of heart failure per 1000 person years and the highest hazard ratios for incident heart failure. CONCLUSIONS: Having diabetes, MI, hypertension or obesity significantly increased the risk for incident heart failure, especially combinations including diabetes and MI. This suggests that individuals with these conditions, singly or in combination, should be prioritized in efforts to predict and prevent heart failure incidence.

Value of variation index of inferior vena cava diameter in predicting fluid responsiveness in patients with circulatory shock receiving mechanical ventilation: a systematic review and meta-analysis.

BACKGROUND: Respiratory variations in the inferior vena cava diameter (ΔIVCD) have been studied extensively with respect to their value in predicting fluid responsiveness, but the results are conflicting. The aim of this meta-analysis was to explore the value of ΔIVCD for predicting fluid responsiveness in patients with circulatory shock receiving mechanical ventilation. METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched up to June 2017. The diagnostic OR (DOR), sensitivity, and specificity were calculated. The summary ROC curve was estimated, and the area under the ROC curve (AUROC) was calculated. RESULTS: Overall, 603 patients were included in this review, 324 (53.7%) of whom were fluid-responsive. The cutoff values of ΔIVCD varied across studies, ranging from 8% to 21%. Heterogeneity between studies was assessed with an overall Q = 0.069, I2 = 0%, and P = 0.483. The pooled sensitivity and specificity for the overall population were 0.69 (95% CI, 0.51-0.83) and 0.80 (95% CI, 0.66-0.89), respectively. The DOR was 9.28 (95% CI, 2.33-36.98). AUROCs were reported in five studies. Overall, the pooled AUROC was 0.82 (95% CI, 0.79-0.85). CONCLUSIONS: The findings of this study suggest that the ΔIVCD performed moderately well in predicting fluid responsiveness in patients with circulatory shock receiving mechanical ventilation.

Protocol for the CHORD project (community health outreach to reduce diabetes): a cluster-randomized community health worker trial to prevent diabetes.

BACKGROUND: Type 2 diabetes mellitus (DM) affects 9.4% of US adults and children, while another 33.9% of Americans are at risk of DM. Health care institutions face many barriers to systematically delivering the preventive care needed to decrease DM incidence. Community health workers (CHWs) may, as frontline public health workers bridging clinic and community, help overcome these challenges. This paper presents the protocol for a pragmatic, cluster-randomized trial integrating CHWs into two primary care clinics to support DM prevention for at-risk patients. METHODS: The trial will randomize 15 care teams, stratified by practice site (Bellevue Hospital and Manhattan VA), totaling 56 primary care physicians. The study cohort will consist of ~ 2000 patients who are 18-75 years of age, actively enrolled in a primary care team, able to speak English or Spanish, and have at least one glycosylated hemoglobin (HbA1c) result in the prediabetic range (5.7-6.4%) since 2012. Those with a current DM diagnosis or DM medication prescription (other than metformin) are ineligible. The intervention consists of four core activities - setting health goals, health education, activation for doctor's appointments, and referrals to DM prevention programs - adjustable according to the patient's needs and readiness. The primary outcome is DM incidence. Secondary outcomes include weight loss, HbA1C, and self-reported health behaviors. Clinical variables and health behaviors will be obtained through electronic medical records and surveys, respectively. Implementation outcomes, namely implementation fidelity and physicians' perspectives about CHW integration into the clinic, will be assessed using interviews and CHW activity logs and analyzed for the influence of moderating organizational factors. DISCUSSION: This is the first rigorous, pragmatic trial to test the effectiveness of integrating CHWs into primary care for DM prevention reaching a population-based sample. Our study's limitations include language-based eligibility and the use of HbA1c as a measure of DM risk. It will measure both clinical and implementation outcomes and potentially broaden the evidence base for CHWs and patient-centered medical home implementation. Further, the intervention's unique features, notably patient-level personalization and referral to existing programs, may offer a scalable model to benefit patients at-risk of DM. TRIAL REGISTRATION: Clinicaltrials.gov NCT03006666 (Received 12/27/2016).

Backbone Degradable N-(2-Hydroxypropyl)methacrylamide Copolymer Conjugates with Gemcitabine and Paclitaxel: Impact of Molecular Weight on Activity toward Human Ovarian Carcinoma Xenografts.

Degradable diblock and multiblock (tetrablock and hexablock) N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-gemcitabine (GEM) and -paclitaxel (PTX) conjugates were synthesized by reversible addition-fragmentation chain-transter (RAFT) copolymerization followed by click reaction for preclinical investigation. The aim was to validate the hypothesis that long-circulating conjugates are needed to generate a sustained concentration gradient between vasculature and a solid tumor and result in significant anticancer effect. To evaluate the impact of molecular weight of the conjugates on treatment efficacy, diblock, tetrablock, and hexablock GEM and PTX conjugates were administered intravenously to nude mice bearing A2780 human ovarian xenografts. For GEM conjugates, triple doses with dosage 5 mg/kg were given on days 0, 7, and 14 (q7dx3), whereas a single dose regime with 20 mg/kg was applied on day 0 for PTX conjugates treatment. The most effective conjugates for each monotherapy were the diblock ones, 2P-GEM and 2P-PTX (Mw ≈ 100 kDa). Increasing the Mw to 200 or 300 kDa resulted in decrease of activity most probably due to changes in the conformation of the macromolecule because of interaction of hydrophobic residues at side chain termini and formation of "unimer micelles". In addition to monotherapy, a sequential combination treatment of diblock PTX conjugate followed by GEM conjugate (2P-PTX/2P-GEM) was also performed, which showed the best tumor growth inhibition due to synergistic effect: complete remission was achieved after the first treatment cycle. However, because of low dose applied, tumor recurrence was observed 2 weeks after cease of treatment. To assess optimal route of administration, intraperitoneal (i.p.) application of 2P-GEM, 2P-PTX, and their combination was examined. The fact that the highest anticancer efficiency was achieved with diblock conjugates that can be synthesized in one scalable step bodes well for the translation into clinics.

What are the Patterns Between Depression, Smoking, Unhealthy Alcohol Use, and Other Substance Use Among Individuals Receiving Medical Care? A Longitudinal Study of 5479 Participants.

To evaluate and characterize the structure of temporal patterns of depression, smoking, unhealthy alcohol use, and other substance use among individuals receiving medical care, and to inform discussion about whether integrated screening and treatment strategies for these conditions are warranted. Using the Veterans Aging Cohort Study (VACS) we measured depression, smoking, unhealthy alcohol use and other substance use (stimulants, marijuana, heroin, opioids) and evaluated which conditions tended to co-occur within individuals, and how this co-occurrence was temporally structured (i.e. concurrently, sequentially, or discordantly). Current depression was associated with current use of every substance examined with the exception of unhealthy alcohol use. Current unhealthy alcohol use and marijuana use were also consistently associated. Current status was strongly predicted by prior status (p < 0.0001; OR = 2.99-22.34) however, there were few other sequential relationships. Associations in the HIV infected and uninfected subgroups were largely the same with the following exceptions. Smoking preceded unhealthy alcohol use and current smoking was associated with current depression in the HIV infected subgroup only (p < 0.001; OR = 1.33-1.41 and p < 0.001; OR = 1.25-1.43). Opioid use and current unhealthy alcohol use were negatively associated only in the HIV negative subgroup (p = 0.01; OR = 0.75). Patterns of depression, smoking, unhealthy alcohol use, and other substance use were temporally concordant, particularly with regard to depression and substance use. These patterns may inform future development of more integrated screening and treatment strategies.

Do Alcohol Misuse, Smoking, and Depression Vary Concordantly or Sequentially? A Longitudinal Study of HIV-Infected and Matched Uninfected Veterans in Care.

We analyzed temporal patterns of alcohol misuse, smoking, and depression among veterans in care to determine whether these conditions vary concordantly or sequentially. Using the Veterans Aging Cohort Study, harmful alcohol use (AUDIT-C ≥ 4), current smoking, and depression (PHQ-9 ≥ 8), were measured. In regression analyses, predictors included each outcome condition at baseline, the other two conditions in the same survey, the other two conditions in the immediately preceding survey, number of years since enrollment, and HIV status. We found that current smoking and depression were more common among HIV infected individuals. Harmful alcohol use was more common among uninfected individuals. Temporal analyses suggested a concurrent pattern: each condition was associated with the other two conditions (p < 0.03, OR 1.12-1.66) as well as with the prior presence of the same condition (p < 0.0001; OR 6.38-22.02). Smoking was associated with prior depression after controlling for current depression (OR 1.16; p = 0.003). In conclusion, alcohol misuse, smoking, and depression were temporally concordant and persistent, raising the question of whether they constitute a common syndrome in HIV infected patients and others with chronic diseases.

Preoperative Renal Insufficiency: Underreporting and Association With Readmission and Major Postoperative Morbidity in an Academic Medical Center.

BACKGROUND: Making a formal diagnosis of chronic kidney disease (CKD) in the preoperative setting may be challenging because of lack of longitudinal data. We explored the predictive value of a single reduced preoperative estimated glomerular filtration rate (eGFR) value on adverse patient outcomes in the first 30 days after elective surgery. We compared the rate of major postoperative adverse events, including 30-day readmission rate, hospital length of stay, infection, acute kidney injury (AKI), and myocardial infarction across patients with declining preoperative eGFR values. We hypothesized that there is an association between decreasing preoperative eGFR values and major postoperative morbidity including readmission within 30 days of discharge and that the reasons for unplanned readmissions may be associated with poor preoperative renal function. METHODS: This was a retrospective analysis of the electronic health record of 39 989 adult patients who underwent elective surgery between June 2011 and July 2013 at our institution. Patients with reduced eGFR (<60 mL/min/1.73 m) were identified and categorized by the stages of CKD that correlated with the preoperative eGFR value. Odds of readmission to our hospital within 30 days, as well as new diagnosis of AKI, myocardial infarction, and infection, were determined with multivariate logistic regression. The subset of patients who were readmitted within 30 days also were subdivided further into patients who had an eGFR <60 mL/min/1.73 m and those with an eGFR ≥60 mL/min/1.73 m, as well as whether the readmission was planned or unplanned. RESULTS: Of the 4053 patients with eGFR <60 mL/min/1.73 m, 3290 (81.2%) did not carry a preoperative diagnosis of CKD. Adjusted odds ratios of being readmitted were 1.48 (99% confidence interval [CI], 1.18-1.87; P < .001) for eGFR 30 to 44 mL/min/1.73 m to 2.06 (99% CI, 1.32-3.23; P < .001) for eGFR <15 mL/min/1.73 m compared with patients with a preoperative eGFR value ≥60 mL/min/1.73 m. Patients with a lower eGFR also demonstrated increasing odds of AKI from 2.78 (99% CI, 1.86-4.17; P < .001) for eGFR 45 to 59 mL/min/1.73 m to 3.81 (99% CI, 1.68-8.16; P < .001) for eGFR <15 mL/min/1.73 m. CONCLUSIONS: This study highlights that preoperative renal insufficiency may be underreported and appears to be significantly associated with postoperative complications. It extends the association between a single low preoperative eGFR and postoperative morbidity to a broader range of surgical populations than previously described. Our results suggest that preoperative calculation of eGFR may be a relatively low-cost, readily available tool to identify patients who are at an increased risk of readmission within 30 days of surgery and postoperative morbidity in patients presenting for elective surgery.

End Tidal Carbon Dioxide as a Screening Tool for Computed Tomography Angiogram in Postoperative Orthopaedic Patients Suspected of Pulmonary Embolism.

BACKGROUND: Computed tomography pulmonary angiography (CTA) is the gold standard for diagnosing pulmonary embolism (PE) but involves radiation and iodinated contrast exposure. Of orthopedic patients evaluated for PE, a minority have a positive CTA study. Herein, we evaluate end tidal carbon dioxide (ETCO2) as a method to identify patients at low risk for PE and may not require a CTA. We hypothesize that ETCO2 will be useful for predicting the absence of PE in postoperative orthopedic patients. METHODS: In this prospective study, all patients older than 18 years who were admitted for orthopedic surgery and who had a CTA performed for PE were eligible. These patients underwent an ETCO2 measurement. Patients were determined to have PE if they had a positive PE-protocol CT. RESULTS: Between May 2014 and April 2015, 121 patients met the inclusion criteria for the study. Of these patients, 84 had a negative CTA examination, 25 had a positive examination, and 12 had a nondiagnostic examination. We found a statistically significant difference (P = .03) when comparing the average ETCO2 values for the positive and negative CTA groups. An ETCO2 cutoff value of 43 mm Hg was 100% sensitive with a negative predictive value of 100% for absence of PE on CTA. CONCLUSION: This study demonstrates a significant difference in ETCO2 measurements between postoperative orthopedic patients with and without CTA-detected PE. A cutoff value of >43 mm Hg may be useful in excluding patients from undergoing CTA.

Association Between End-of-Rotation Resident Transition in Care and Mortality Among Hospitalized Patients.

IMPORTANCE: Shift-to-shift transitions in care among house staff are associated with adverse events. However, the association between end-of-rotation transition (in which care of the patient is transferred) and adverse events is uncertain. OBJECTIVE: To examine the association of end-of-rotation house staff transitions with mortality among hospitalized patients. DESIGN, SETTING, AND PARTICIPANTS: Retrospective multicenter cohort study of patients admitted to internal medicine services (N = 230 701) at 10 university-affiliated US Veterans Health Administration hospitals (2008-2014). EXPOSURES: Transition patients (defined as those admitted prior to an end-of-rotation transition who died or were discharged within 7 days following transition) were stratified by type of transition (intern only, resident only, or intern + resident) and compared with all other discharges (control). An alternative analysis comparing admissions within 2 days before transition with admissions on the same 2 days 2 weeks later was also conducted. MAIN OUTCOMES AND MEASURES: The primary outcome was in-hospital mortality. Secondary outcomes included 30-day and 90-day mortality and readmission rates. A difference-in-difference analysis assessed whether outcomes changed after the 2011 Accreditation Council for Graduate Medical Education (ACGME) duty hour regulations. Adjustments included age, sex, race/ethnicity, month, year, length of stay, comorbidities, and hospital. RESULTS: Among 230 701 patient discharges (mean age, 65.6 years; men, 95.8%; median length of stay, 3.0 days), 25 938 intern-only, 26 456 resident-only, and 11 517 intern + resident end-of-rotation transitions occurred. Overall mortality was 2.18% in-hospital, 9.45% at 30 days, and 14.43% at 90 days. Adjusted hospital mortality was significantly greater in transition vs control patients for the intern-only group (3.5% vs 2.0%; odds ratio [OR], 1.12 [95% CI, 1.03-1.21]) and the intern + resident group (4.0% vs 2.1%; OR, 1.18 [95% CI, 1.06-1.33]), but not for the resident-only group (3.3% vs 2.0%; OR, 1.07 [95% CI, 0.99-1.16]). Adjusted 30-day and 90-day mortality rates were greater in all transition vs control comparisons (30-day mortality: intern-only group, 14.5% vs 8.8%, OR, 1.17 [95% CI, 1.13-1.22]; resident-only group, 13.8% vs 8.9%, OR, 1.11 [95% CI, 1.04-1.18]; intern + resident group, 15.5% vs 9.1%, OR, 1.21 [95% CI, 1.12-1.31]; 90-day mortality: intern-only group, 21.5% vs 13.5%, OR, 1.14 [95% CI, 1.10-1.19]; resident-only group, 20.9% vs 13.6%, OR, 1.10 [95% CI, 1.05-1.16]; intern + resident group, 22.8% vs 14.0%, OR, 1.17 [95% CI, 1.11-1.23]). Duty hour changes were associated with greater adjusted hospital mortality for transition patients in the intern-only group and intern + resident group than for controls (intern-only: OR, 1.11 [95% CI, 1.02-1.21]; intern + resident: OR, 1.17 [95% CI, 1.02-1.34]). The alternative analyses did not demonstrate any significant differences in mortality between transition and control groups. CONCLUSIONS AND RELEVANCE: Among patients admitted to internal medicine services in 10 Veterans Affairs hospitals, end-of-rotation transition in care was associated with significantly higher in-hospital mortality in an unrestricted analysis that included most patients, but not in an alternative restricted analysis. The association was stronger following institution of ACGME duty hour regulations.

Flexible combination of multiple diagnostic biomarkers to improve diagnostic accuracy.

BACKGROUND: In medical research, it is common to collect information of multiple continuous biomarkers to improve the accuracy of diagnostic tests. Combining the measurements of these biomarkers into one single score is a popular practice to integrate the collected information, where the accuracy of the resultant diagnostic test is usually improved. To measure the accuracy of a diagnostic test, the Youden index has been widely used in literature. Various parametric and nonparametric methods have been proposed to linearly combine biomarkers so that the corresponding Youden index can be optimized. Yet there seems to be little justification of enforcing such a linear combination. METHODS: This paper proposes a flexible approach that allows both linear and nonlinear combinations of biomarkers. The proposed approach formulates the problem in a large margin classification framework, where the combination function is embedded in a flexible reproducing kernel Hilbert space. RESULTS: Advantages of the proposed approach are demonstrated in a variety of simulated experiments as well as a real application to a liver disorder study. CONCLUSION: Linear combination of multiple diagnostic biomarkers are widely used without proper justification. Additional research on flexible framework allowing both linear and nonlinear combinations is in need.

The Mobile Insulin Titration Intervention (MITI) for Insulin Adjustment in an Urban, Low-Income Population: Randomized Controlled Trial.

BACKGROUND: Diabetes patients are usually started on a low dose of insulin and their dose is adjusted or "titrated" according to their blood glucose levels. Insulin titration administered through face-to-face visits with a clinician can be time consuming and logistically burdensome for patients, especially those of low socioeconomic status (SES). Given the wide use of mobile phones among this population, there is the potential to use short message service (SMS) text messaging and phone calls to perform insulin titration remotely. OBJECTIVE: The goals of this pilot study were to (1) evaluate if our Mobile Insulin Titration Intervention (MITI) intervention using text messaging and phone calls was effective in helping patients reach their optimal insulin glargine dose within 12 weeks, (2) assess the feasibility of the intervention within our clinic setting and patient population, (3) collect data on the cost savings associated with the intervention, and (4) measure patient satisfaction with the intervention. METHODS: This was a pilot study evaluating an intervention for patients requiring insulin glargine titration in the outpatient medical clinic of Bellevue Hospital Center in New York City. Patients in the intervention arm received weekday SMS text messages from a health management platform requesting their fasting blood glucose values. The clinic's diabetes nurse educator monitored the texted responses on the platform website each weekday for alarm values. Once a week, the nurse reviewed the glucose values, consulted the MITI titration algorithm, and called patients to adjust their insulin dose. Patients in the usual care arm continued to receive their standard clinic care for insulin titration. The primary outcome was whether a patient reached his/her optimal insulin glargine dose within 12 weeks. RESULTS: A total of 61 patients consented and were randomized into the study. A significantly greater proportion of patients in the intervention arm reached their optimal insulin glargine dose than patients in the usual care arm (88%, 29/33 vs 37%, 10/27; P<.001). Patients responded to 84.3% (420/498) of the SMS text messages requesting their blood glucose values. The nurse reached patients within 2 attempts or by voicemail 91% of the time (90/99 assigned calls). When patients traveled to the clinic, they spent a median of 45 minutes (IQR 30-60) on travel and 39 minutes (IQR 30-64) waiting prior to appointments. A total of 61% (37/61) of patients had appointment copays. After participating in the study, patients in the intervention arm reported higher treatment satisfaction than those in the usual care arm. CONCLUSIONS: MITI is an effective way to help low-SES patients reach their optimal insulin glargine dose using basic SMS text messaging and phone calls. The intervention was feasible and patients were highly satisfied with their treatment. The intervention was cost saving in terms of time for patients, who were able to have their insulin titrated without multiple clinic appointments. Similar interventions should be explored to improve care for low-SES patients managing chronic disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT01879579; https://clinicaltrials.gov/ct2/show/NCT01879579 (Archived by WebCite at http://www.webcitation.org/6YZik33L3).

A model-free estimation for the covariate-adjusted Youden index and its associated cut-point.

In medical research, continuous markers are widely employed in diagnostic tests to distinguish diseased and non-diseased subjects. The accuracy of such diagnostic tests is commonly assessed using the receiver operating characteristic (ROC) curve. To summarize an ROC curve and determine its optimal cut-point, the Youden index is popularly used. In literature, the estimation of the Youden index has been widely studied via various statistical modeling strategies on the conditional density. This paper proposes a new model-free estimation method, which directly estimates the covariate-adjusted cut-point without estimating the conditional density. Consequently, covariate-adjusted Youden index can be estimated based on the estimated cut-point. The proposed method formulates the estimation problem in a large margin classification framework, which allows flexible modeling of the covariate-adjusted Youden index through kernel machines. The advantage of the proposed method is demonstrated in a variety of simulated experiments as well as a real application to Pima Indians diabetes study.

Magnetic resonance imaging of the effortful swallow.

OBJECTIVE: The effortful swallow was designed to improve posterior mobility of the tongue base and increase intraoral pressures. We characterized the effects of this maneuver via dynamic magnetic resonance imaging (dMRI) in healthy patients. METHODS: A 3-T scanner was used to obtain dMRI images of patients swallowing pudding using normal as well as effortful swallows. Ninety sequential images were acquired at the level of the oropharynx in the axial plane for each swallow; 3 series were obtained for each swallow type for each patient. Images were acquired every 113 ms during swallowing. The images were analyzed with respect to oropharyngeal closure duration, anteroposterior and transverse distance between the oropharyngeal walls, and oropharyngeal area before and after closure. RESULTS: Preswallow reduced pharyngeal area was observed (P = .02; mean = 212.61 mm² for effortful, mean = 261.92 mm² for normal) as well as prolonged pharyngeal closure during the swallow (P < .0001; mean = 742.18 ms for effortful, mean = 437.31 ms for normal). No other differences were noted between swallow types. Interrater and intrarater reliability of all measurements was excellent. CONCLUSION: This preliminary investigation is the first to evaluate the effects of effortful swallows via dMRI. In our cohort, consistent physiologic changes were elicited, consistent with clinical dogma regarding this maneuver.

Longitudinal Molecular and Serological Evidence of SARS-CoV-2 Infections and Vaccination Status: Community-Based Surveillance Study (CONTACT).

INTRODUCTION: This prospective, longitudinal, community-based study, EpidemiologiCal POpulatioN STudy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Lake CounTy, Illinois (CONTACT), investigated coronavirus disease 2019 (COVID-19) immunity, occupational risks related to SARS-CoV-2 exposure, and long-term immunoglobulin G (IgG) seroconversion kinetics. METHODS: At baseline and follow up (3, 6, and 9 months), non-hospitalized adult participants provided nasal and blood serum specimens for molecular [reverse transcription polymerase chain reaction (RT-PCR)] and serological (IgG) testing (4 November 2020-30 October 2021). RESULTS: At baseline, 6.4% (65/1008) had evidence of current/prior SARS-CoV-2 infection. At 3, 6, and 9 months, positive PCR tests were obtained from 0.4% (3/781), 0.4% (3/733), and 0% (0/673) of participants, respectively. Positive IgG occurred at baseline and 3, 6, and 9 months in 4.5% (45/1008), 6.0% (48/799), 5.4% (39/733), and 2.8% (19/673) of participants, respectively. Of participants positive for IgG at baseline, 28 had a negative IgG test at a follow-up visit; of those 28, 21 had their first negative IgG test within 6 months. Participants were more likely to retain positive IgG if they were 18-29 years of age, were male, or had medium-high/high-risk occupations. A high vaccination rate (70% received ≥ 1 dose by 9 months) was observed. Influence of occupational status or characteristics on transmission and IgG, and COVID-19 vaccination trends, are shown. CONCLUSIONS: This study expands on prior studies assessing COVID-19 immunity and IgG seroconversion by including both RT-PCR and serologic testing and longitudinal follow-up of study participants. We observed decreased infection rates over the 9 month follow-up period as well as a decline in IgG persistency after 6 months. The findings from this community-based study regarding vaccinate rates, infection rates by PCR, and IgG persistency over time can help improve our understanding of COVID-19 immunity, occupational risks related to SARS-CoV-2 exposure, and the kinetics of long-term IgG seroconversion, which is important to help guide local and national mitigation strategies. CLINICAL TRIAL REGISTRATION: NCT04611230.