Indeterminate Outcomes Research Articles

Using Serial Trichotomization to Determine Fitness to Drive in Medically At-Risk Drivers.

Clinical tests that identify fit and unfit drivers with 100% sensitivity and specificity would reduce uncertainty and improve efficiency of occupational therapists performing comprehensive driving evaluations (CDEs). To examine whether serial trichotomization of clinical tests predicts pass-fail outcomes with 100% sensitivity and specificity in a sample of medically at-risk drivers and in drivers with and without cognitive impairment (CI) referred for a CDE. Retrospective data collection and analysis of scores on the Montreal Cognitive Assessment; Trail Making Test, Part A and Part B; and the Useful Field of View® Subtests 1 to 3 and outcomes on the CDE (pass-fail or indeterminate requiring lessons and retesting). Receiver operating characteristic curves of clinical tests were performed to determine 100% sensitivity and specificity cut points in predicting CDE outcomes. Clinical tests were arranged in order from most to least predictive to identify pass-fail and indeterminate outcomes. A driving assessment clinic. Among 142 medically at-risk drivers (M age = 69.2 yr, SD = 14.1), 66 with CI, 46 passed and 39 failed the CDE; 57 were indeterminate. On-road pass-fail outcomes. Together, the six clinical tests predicted 62 pass and 49 fail outcomes in the total sample; 21 pass and 34 fail outcomes in participants with CI; and 58 pass and 14 fail outcomes in participants without CI. Serial trichotomization of clinical tests increases the accuracy of making informed decisions and reduces the number of drivers undergoing unnecessary on-road assessments. Plain-Language Summary: Clinical tests and their cut points that identify fit and unfit drivers vary substantially across settings and research studies. Serial trichotomization is one method that could help control for this variation by combining clinical test scores showing 100% sensitivity and specificity to identify pass (fit drivers) and fail outcomes (unfit drivers) and to reduce the number of drivers undergoing unnecessary on-road assessments.

Binary subclassification scheme (AUS-Nuclear versus AUS-Other) adequately risk-stratifies thyroid fine needle aspiration specimens classified as Atypia of Undetermined Significance

The Bethesda System for Reporting Thyroid Cytopathology previously described 4subclassesof atypia within the Atypia of Undetermined Significance (AUS) category: nuclear (AUS-Nuc), architectural (AUS-A), oncocytic (AUS-Onc), and atypia not otherwise specified (AUS-NOS). Accumulating evidence supports a binary AUS subclassification scheme based primarily on the presence of nuclear atypia only. The purpose of this study is to compare the risk stratification of binary versus 4-tier AUS subclassification systems among AUS nodules with molecular and/or histologic follow-up. Thyroid aspirates classified as AUS and tested using Afirma (Veracyte, Inc.) between 6/2013 and 7/2021 were included. For resected nodules, histological classification was considered as the final outcome. For unresected nodules, benign Afirma results were considered low-risk outcomes, similar to histologically benign nodules. Suspicious or nondiagnostic Afirma results were considered indeterminate outcomes. The prevalence of outcomes warranting surgery (noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP] or cancer) was calculated for each AUS subclass. A total of 559 AUS nodules with Afirma testing were identified. Excluding nodules with indeterminate molecular outcomes, NIFTP/cancer prevalence for AUS-Nuc was 21% (57/266), which was higher than that for AUS-A (6%, 11/188), AUS-Onc (8%, 4/53), and AUS-NOS (0%, 0/9). A binary AUS subclassification scheme based on nuclear atypia showed a significant difference in NIFTP/cancer prevalence (21% versus 6%, P < 0.0001). Binary reporting of AUS subclasses based on nuclear atypia distinguishes cases with a higher risk of NIFTP/cancer. There is a low but non-negligible prevalence of NIFTP/cancer in cases without nuclear atypia.

Patients' Knowledge About the Endoscopic UltrasoundGuided Fine Needle Aspiration of Pancreas Is Not Enough.

The aim of the study is to evaluate the extent to which patients acquired necessary knowledge about pancreatic endoscopic ultrasound-guided fine needle aspiration and assess what should be more focused on in the informed consent process. Adult patients enrolled in this study had pancreatic lesions confirmed by regular imaging and planned to undergo the first pancreatic endoscopic ultrasound-guided fine needle aspiration. These patients were asked to complete a questionnaire, including indications, possible results, downstream events, the risk for false-negative and malignant lesions, and so on. Then we conducted a longterm follow-up of these patients to obtain the final results. Most people (94.25%) correctly recognized that the indication of pancreatic endoscopic ultrasound-guided fine needle aspiration was to exclude malignant lesions. Almost all patients knew that the results could be benign or malignant, while the number of people who were aware of non-diagnostic (22%), indeterminate (18%) outcomes, and the possibility of further testing (20%) after the endoscopic ultrasound-guided fine needle aspiration has decreased significantly. Finally, we got that the false-negative rate and percentages of malignancy were 17.81% and 83.91%, while 98% of participants did not recognize that there is a false-negative risk of endoscopic ultrasound-guided fine needle aspiration and more than 2/3 of participants did not know how much risk they might have for malignant lesions. A high proportion of patients who received endoscopic ultrasound-guided fine needle aspiration could identify the indication for this procedure but remained unaware of possible outcomes, downstream events, especially the risk for false-negative and malignant lesions. It is necessary to improve the quality of dialogue between clinicians and patients, and the information about the risk of false-negative and malignancy may need to be emphasized in the informed consent process.

Clonal hematopoiesis of indeterminate potential and outcomes after heart transplantation: A multicenter study

Cardiac allograft vasculopathy (CAV) is a leading cause of late graft failure and mortality after heart transplantation (HT). Sharing some features with atherosclerosis, CAV results in diffuse narrowing of the epicardial coronaries and microvasculature, with consequent graft ischemia. Recently, clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for cardiovascular disease and mortality. We aimed to investigate the relationship between CHIP and posttransplant outcomes, including CAV. We analyzed 479 HT recipients with stored DNA samples at 2 high-volume transplant centers, Vanderbilt University Medical Center and Columbia University Irving Medical Center. We explored the association between the presence of CHIP mutations with CAV and mortality after HT. In this case-control analysis, carriers of CHIP mutations were not at increased risk of CAV or mortality after HT. In a large multicenter genomics study of the heart transplant population, the presence of CHIP mutations was not associated with an increased risk of CAV or posttransplant mortality.

Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease

BackgroundClonal hematopoiesis of indeterminate potential (CHIP)—the age-related clonal expansion of blood stem cells with leukemia-associated mutations—is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear. ObjectivesThis study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD. MethodsIndividuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage repair genes], and SF3B1/SRSF2/U2AF1 [spliceosome genes]) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression. ResultsOf 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P <0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P < 0.001). ConclusionsCHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.

Navigating the Labyrith of De-sign

Navigating the multicursal pattern of labyrinths is at the core of De-sign (the fusion of design and signs). Due to the ephemerality of de-sign situations and the infinite possibility of outcomes, the navigational trajectory, while intentional, is ambiguous and labyrinthine. Intentionality entices us to engage in the process of creating that which-is-yet-to-become—not deliberately looking for those that are already existent as ontic things but engaging in a process that allows qualities to emerge unexpectedly. Considering the immateriality of intentionality and its indeterminate outcomes, the process of navigating through the labyrinth of De-sign should not be perceived as a set of predetermined activities aiming at an expected result or thing. Navigating through unknown territories for the purpose of seeking qualitatively desired outcomes is the effective, nonlinear, reiterative de-sign process, which is constantly adjusted pragmatically by feedback and feedforward loops in order for the emergent outcome to become compatible with intentionality.

1016. Real-World Use of Omadacycline in Physician Office Infusion Centers (POICs)

Abstract Background Omadacycline (OMC) is approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. Real-world data on the use of OMC are limited. We present a multicenter observational review of OMC outpatient use in Infectious Disease POICs. Methods Medical records of patients (pts) receiving intravenous OMC from May 2019 to April 2022 from 5 POICs were included in this ongoing study. Data included demographics, diagnosis, medical history, microbiology, OMC regimen, adverse events (AEs), health care utilization and clinical outcomes. Clinical success was defined as complete or partial symptom resolution at completion of OMC with oral antibiotics as needed. Persistent or recurrent infection and premature discontinuation of OMC were deemed non-success. Indeterminate outcomes were excluded in outcome assessment. Chi Square, Fisher’s exact, and t-test were used to identify characteristics associated with clinical outcome. Results Overall, 37 pts (mean age: 61±13 yrs, 65% male) were identified. Infections treated were 62% bone and joint (BJI), 24% complicated skin and skin structure infections (CSSSI), 11% pulmonary nontuberculous mycobacterial (NTM) and 3% diverticulitis. A total of 61 pathogens were identified in 30 pts of which 83% had ≥1 Gram-positive isolate. Polymicrobial pathogens were reported in 13/30 pts (43%). Ten pts (27%) received concomitant IV antibiotics. Median duration of OMC therapy was 38 days (IQR, 21-47). OMC was initiated in the POIC without prior hospitalization in 62% of pts. Overall clinical success was 75% (24/31). Non-success due to persistent infection was reported in 5 pts (3 BJI, 2 CSSSI), of which 4 were hospitalized. Three additional pts were deemed non-successful due to early discontinuations (2 difficulty with administration, 1 AE) (Fig 1). Six pts were non-evaluable for outcome. Ten pts reported 14 AEs, most commonly nausea (4 pts) and elevated liver function tests (3 pts). Figure 1.Clinical outcome of omadacycline by infection type Conclusion These real-world results support the outpatient use of omadacycline in additional, difficult to treat, complicated infections, including bone and joint infections. Disclosures Lucinda J. Van Anglen, PharmD, Merck &amp; Co.: Grant/Research Support|Paratek: Grant/Research Support.

Postsecular Pilgrimage in Malek Bennabi’s Lebbeik: pèlerinage de pauvres and Abdelkébir Khatibi’s Pèlerinage d’un artiste amoureux

Abstract This paper explores representations of the Islamic pilgrimage to Mecca in two North African literary texts, Malek Bennabi’s Lebbeik (1947) and Abdelkébir Khatibi’s Pèlerinage d’un artiste amoureux (2003). It considers the divergent ways in which pilgrimage is used to explore the place of both literature and religion, as well as their interrelation, when it comes to working out ethics and values on individual and collective levels in Bennabi’s late-colonial Algeria, and Khatibi’s postcolonial Morocco. Drawing on Alain Badiou’s notion of the event as an occurrence that is retrospectively determined to have disrupted the status quo, and contrasting this with Derek Attridge’s idea of literature as a disruptive event with indeterminate outcomes, I consider the different ways in which both the pilgrimage and the narratives representing it can be seen as events, implicitly imparting reflections and even teachings on life and how to approach it in both texts.

Using Serial Trichotomization to Determine Fitness to Drive in Medically At-Risk Drivers

<h3>Research Objectives</h3> To determine if serial trichotomization of cognitive tests predicts passing or failing a comprehensive driving evaluation (CDE) with 100% sensitivity and 100% specificity in medically at-risk drivers. <h3>Design</h3> Retrospective cohort of CDE data. <h3>Setting</h3> CDE's assessed by occupational therapists at two driving assessment centers in Canada. <h3>Participants</h3> Participants included 143 drivers (72% male; mean age = 69.3 ± 14.1 years, range 24-94) referred by physicians for suspicion of being unfit to drive, and who had complete data on all cognitive tests and the CDE outcome. <h3>Interventions</h3> Not applicable. <h3>Main Outcome Measures</h3> Cognitive tests included the Montreal Cognitive Assessment (MoCA), Trail Making Test Part A (Trails A) and Part B (Trails B), and Useful Field of View® subtests 1-3 (UFOV1-3). The CDE outcome, based on clinical and on-road driving performance, included a pass (considered fit to continue driving), fail (considered unfit to continue driving), or indeterminate outcome (requires lessons and retesting). Serial trichotomization involved performing a receiver operating characteristics curve for each cognitive test to determine cut points with 100% sensitivity and 100% specificity in predicting pass (i.e., pass and indeterminate) or fail outcomes on the CDE. A funnel was created by arranging the cognitive tests in order from most to least predictive and using the cut points to identify pass, fail, and indeterminate outcomes. <h3>Results</h3> Approximately 33% passed, 27% failed, and 40% had indeterminate outcomes on the CDE. Through serial trichotomization, the UFOV3, UFOV2, UFOV1, Trails B, MoCA, and Trails A (from most to least predictive) predicted more pass (44.1%) and fail outcomes (34.3%) with fewer indeterminate outcomes (21.6%). <h3>Conclusions</h3> Serial trichotomization of cognitive tests is more accurate in identifying fit and unfit drivers, reducing the number of unnecessary on-road assessments by approximately twofold (indeterminate outcomes from 40% to 21.6%). Further research using larger samples and more clinical tests will identify the best combination and most accuracy in predicting fit and unfit drivers via serial trichotomization. <h3>Author(s) Disclosures</h3> This work was supported by the University of Waterloo CIHR Research Incentive Fund (PI Crizzle).

Freedom of Discussion versus Predetermined Futures in Deliberation Processes

Methods of deliberative consultations usually propose expert information materials to increase knowledge among lay citizens about the considered subject. These materials sometimes also include alternative scenarios for action presented with pros and cons. In our study, we pose the following research questions: (1) Do the participants tend to use predetermined scenarios or diverge from them and generate their reference structures for the deliberation’s indeterminate outcomes? (2) How do the scenarios intervene in the “loping to-and-fro form of movement” in the interactions? (3) How is the knowledge about the preexisting scenarios reflected in the “as if” ontology of thought and action? We introduce play and game as two ideal types of deliberation processes emphasizing the opposition of freedom and pre-determination of outcomes. The analysis used empirical material from online group discussions about various aspects of studying at Warsaw universities. The results showed that regardless of the situation in groups, predefined scenarios are the focus of discussions and anchoring points for the “loping to-and-fro form of movement.” However, participants demonstrated some selectivity, and they did not consider all alternatives. Moreover, they introduced some modifications and new proposals. At the same time, participants tended to diverge more from briefing materials in argumentation. Experiential arguments prevailed, and the pros and cons of each scenario appeared rarely across groups. Interestingly, stricter moderation did not necessarily intervene here, and the group with the highest level of own proposals in some instances followed the game rules more accordingly than other groups. Finally, the language of listening and understanding is frequent, regardless of the number of predefined scenarios discussed by groups, which strengthened the “as if” ontology of thought and action.

Treatments of Peyronie's disease with Scutellaria baicalensis and surgery according to the disease course: a single-center retrospective study of 261 patients.

Oral medication therapies are more conventional than other non-surgical therapies in the acute phase of Peyronie's disease (PD). Although the commonly used oral drugs for PD have shown poor or indeterminate outcomes, most patients prefer oral medications. The aim of this study was to evaluate the efficacy and safety of Scutellaria baicalensis extract for treating acute-phase PD patients and examine the practicality of treatment strategies for PD according to the disease course. This retrospective study was performed at our institution from 2005 to 2015 and analyzed the data of 261 patients with PD. The acute-phase PD patients received Scutellaria baicalensis extract for 6 months. After oral treatment, the patients with persistent curvature underwent surgical correction during the stable phase. During this study period, 183 patients received oral treatment with Scutellaria baicalensis, and 78 patients did not. Compared to the untreated patients, treatment with Scutellaria baicalensis had a significant effect in improving the symptoms of acute-phase PD. The mean time required for stabilization also showed a significant statistical difference. Treatment with Scutellaria baicalensis was safe and well-tolerated. After the disease stabilized, 70 and 31 patients with significant penile curvature underwent surgical correction by 16- dot plication and great saphenous vein grafting procedures, respectively. At the one-year follow-up, complete penile straightening and penile length shortening were observed in 92.86% and 41.43% of the patients after 16-dot plication and in 87.10% and 25.81% of the patients after grafting procedures, respectively. The postoperative Erectile Function domain of the International Index of Erectile Function scales were maintained in all patients after the 16-dot plication procedure and decreased in 54.84% of the patients after the grafting procedure. Overall, 92.86% and 83.87% of the patients who received 16-dot plication and grafting procedures, respectively, were satisfied with the final surgical results. Treatment with extract of Scutellaria baicalensis seems to be beneficial for improvements in symptoms of acute phase PD and acceleration of the disease stabilization. The 16-dot plication and great saphenous vein grafting procedure seem effective options in the surgical management of the stable phase after Scutellaria baicalensis administration in the acute phase of PD.

Foramen oval permeable. Una actualización para atención primaria

Patent foramen ovale (FOP) is the most prevalent cause of cryptogenic strokes in people under 60 years old. Although it is usually asymptomatic, it has a high risk of producing paradoxical embolism and, therefore, stroke with indeterminate outcomes. The study should be started based on clinical suspicion, and includes a multidisciplinary assessment and a determination of the type of treatment to be performed. The therapeutic possibilities range from conservative treatment (indefinite antithrombotic treatment), to its percutaneous closure (currently the most widely used). The first objective is to decrease the number of stroke recurrences. Conservative treatment should be reserved for those cases of low embolic risk. The risk assessment must be individualised, fundamentally based on the anatomical characteristics of the FOP and the patient clinic picture. The use of the RoPE risk scale (The Risk of Paradoxical Embolism) should be a tool to consider.

Temporal Anchoring as a Tool for Initial Organizational Structuring

I inductively examine organizational search for initially indeterminate outcomes (i.e., based on novel ideas). Here, how actors search is central to establish organizational structures—instead of being determined by them. I build theory from longitudinal case data that I collected by closely following the emergence of 35 new entrepreneurial ventures over a core period of 2.5 years. I find two contrasting modes of how founders search and development of distinct organizational structures. Both modes originate from how founders mentally anchor to either, future or the past reference points: when anchoring to future reference points, founders searching backwardly to identify related strategies, and create less hierarchical organizational structures, which develop more linearly. Contrary, when anchoring to past reference points, founders search forwardly, pursue opportunistic decisions to meet short-term performance goals, and create more hierarchical organizational structures, which develop more multi-directionally. I provide first insights into the emergence of organizational structure and the role of cognition for organizational search. I highlight the power of founders’ unique mental representations (i.e., new beliefs) to search more specifically in highly uncertain environments, and to achieve more novel outcomes. I contribute by answering central questions about effective strategies in new venture development.

EROS AND LOGOS

For the ancient Greeks, the world was both Eros, the god of chaos and creativity, and Logos, the regularity of the heavens as law. From chaos the world came forth. The world was home to ultimate creativity. Two thousand years later Kepler, Galileo, and then mighty Newton created deterministic classical physics in which all that happens in the universe is determined by the laws of motion, initial and boundary conditions. The Theistic God who worked miracles became the Deistic God who set up the universe and let Newton’s laws take over. Eros, raw creativity, is dead, all is Logos.Quantum mechanics replaced the determinism of classical physics with fundamental indeterminism. This was a major crisis in physics, but remained entirely within the Newtonian paradigm of laws, here the Schrödinger equation, initial and boundary conditions. The Schrödinger equation entails the deterministic propagation of a probability distribution. The probabilities concern the indeterminate outcomes of quantum measurement events.The central issue of this article is to show that no laws at all determine or entail the becoming of our biosphere or any other among the 1022 solar systems in the universe. This claim is radical. If no laws determine or entail the becoming of biospheres, and biospheres are part of the universe, the Pythagorean dream that All is Number, All is Logos, is dead. There is no Final Theory that entails all that become in the universe. Eros is again, and always was, rambunctiously alive in the raw creativity of the becoming of life anywhere in the universe. The becoming of life is based on physics, on Logos, but beyond it, emerging from Eros.The reasons Eros is at play in the evolution of biospheres are fourfold.First, the universe will not make all possible complex things. That is, the universe is vastly non-ergodic. Yet complex things such as the human heart exist.Second, the reason human hearts exist is that organisms are Kantian Wholes in which the parts exist for and by means of the whole. Hearts exist because they fulfill the function of pumping the blood that keeps the whole organism alive. Such organisms propagate progeny that carry with them the hearts that keep them alive.Third, adaptations like hearts, the flagellar motor, the loop of Henle in kidneys that concentrates urine, and flight feathers, are tinkered-together contraptions stumbled upon in evolution. Parts and processes that arise in evolution are jury-rigged for unprestatable new functions that help keep the entire Kantian Whole organism alive and propagating in the evolving biosphere. There is no deductive theory of jury rigging. We cannot deduce the emergence of such novel functions.Fourth, the functions of parts of organisms emerge in unprestatable ways and form the unprestatable and ever-changing phase space of evolution. Since we cannot prestate the ever-changing phase space of evolution, we can write no laws of motion in differential equation form, so cannot integrate the equations we do not have. Thus, no laws entail the becoming of any biosphere.Evolving biospheres are everywhere creative. This is Eros, the chaos from which the world emerges. This profound creative emergence is the stuff of story, of narrative. Evolving biospheres always were and always will be both Eros and Logos, the stuff of story and the stuff of law. We always live in a world of Art and Science.

Post-treatment FDG PET-CT in head and neck carcinoma: comparative analysis of 4 qualitative interpretative criteria in a large patient cohort

There is no consensus regarding optimal interpretative criteria (IC) for Fluorine-18 fluorodeoxyglucose (FDG) Positron Emission Tomography – Computed Tomography (PET-CT) response assessment following (chemo)radiotherapy (CRT) for head and neck squamous cell carcinoma (HNSCC). The aim was to compare accuracy of IC (NI-RADS, Porceddu, Hopkins, Deauville) for predicting loco-regional control and progression free survival (PFS). All patients with histologically confirmed HNSCC treated at a specialist cancer centre with curative-intent non-surgical treatment who underwent baseline and response assessment FDG PET-CT between August 2008 and May 2017 were included. Metabolic response was assessed using 4 different IC harmonised into 4-point scales (complete response, indeterminate, partial response, progressive disease). IC performance metrics (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy) were compared. Kaplan-Meier and Cox proportional hazards regression analyses were performed for survival analysis. 562 patients were included (397 oropharynx, 53 hypopharynx, 48 larynx, 64 other/unknown primary). 420 patients (75%) received CRT and 142 (25%) had radiotherapy alone. Median follow-up was 26 months (range 3–148). 156 patients (28%) progressed during follow-up. All IC were accurate for prediction of primary tumour (mean NPV 85.0% (84.6–85.3), PPV 85.0% (82.5–92.3), accuracy 84.9% (84.2–86.0)) and nodal outcome (mean NPV 85.6% (84.1–86.6), PPV 94.7% (93.8–95.1), accuracy 86.8% (85.6–88.0)). Number of indeterminate scores for NI-RADS, Porceddu, Deauville and Hopkins were 91, 25, 20, 13 and 55, 70, 18 and 3 for primary tumour and nodes respectively. PPV was significantly reduced for indeterminate uptake across all IC (mean PPV primary tumour 36%, nodes 48%). Survival analyses showed significant differences in PFS between response categories classified by each of the four IC (p <0.001). All four IC have similar diagnostic performance characteristics although Porceddu and Deauville scores offered the best trade off of minimising indeterminate outcomes whilst maintaining a high NPV.

Dealing with indeterminate outcomes in antimalarial drug efficacy trials: a comparison between complete case analysis, multiple imputation and inverse probability weighting

BackgroundAntimalarial clinical efficacy studies for uncomplicated Plasmodium falciparum malaria frequently encounter situations in which molecular genotyping is unable to discriminate between parasitic recurrence, either new infection or recrudescence. The current WHO guideline recommends excluding these individuals with indeterminate outcomes in a complete case (CC) analysis. Data from the four artemisinin-based combination (4ABC) trial was used to compare the performance of multiple imputation (MI) and inverse probability weighting (IPW) against the standard CC analysis for dealing with indeterminate recurrences.Methods3369 study participants from the multicentre study (4ABC trial) with molecularly defined parasitic recurrence treated with three artemisinin-based combination therapies were used to represent a complete dataset. A set proportion of recurrent infections (10, 30 and 45%) were reclassified as missing using two mechanisms: a completely random selection (mechanism 1); missingness weakly dependent (mechanism 2a) and strongly dependent (mechanism 2b) on treatment and transmission intensity. The performance of MI, IPW and CC approaches in estimating the Kaplan-Meier (K-M) probability of parasitic recrudescence at day 28 was then compared. In addition, the maximum likelihood estimate of the cured proportion was presented for further comparison (analytical solution). Performance measures (bias, relative bias, standard error and coverage) were reported as an average from 1000 simulation runs.ResultsThe CC analyses resulted in absolute underestimation of K-M probability of day 28 recrudescence by up to 1.7% and were associated with reduced precision and poor coverage across all the scenarios studied. Both MI and IPW method performed better (greater consistency and greater efficiency) compared to CC analysis. In the absence of censoring, the analytical solution provided the most consistent and accurate estimate of cured proportion compared to the CC analyses.ConclusionsThe widely used CC approach underestimates antimalarial failure; IPW and MI procedures provided efficient and consistent estimates and should be considered when reporting the results of antimalarial clinical trials, especially in areas of high transmission, where the proportion of indeterminate outcomes could be large. The analytical solution estimating the cured proportion could provide an alternative approach, in scenarios with minimal censoring due to loss to follow-up or new infections.

Indeterminacy and Imperfect Information

We study equilibrium determination in an environment where two kinds of agents have different information sets: The fully informed agents know the structure of the model and observe histories of all exogenous and endogenous variables. The less in-formed agents observe only a strict subset of the full information set. All types of agents form expectations rationally, but agents with limited information need to solve a dynamic signal extraction problem to gather information about the variables they do not observe. We show that for parameters values that imply a unique equilibrium under full information, the limited information rational expectations equilibrium can be indeterminate. In a simple application of our framework to a monetary policy problem we show that limited information on part of the central bank implies indeterminate outcomes even when the Taylor Principle holds.

A SEMI-SUPERVISED MACHINE LEARNING PIPELINE FOR CARDIAC RISK STRATIFICATION USING ECHOCARDIOGRAPHIC VARIABLES

The current guidelines for echocardiographic assessment of left ventricular diastolic dysfunction (LVDD) utilize decision trees with rigid recursive dichotomizing rules, leading to overlapping and indeterminate outcomes. We investigated a novel machine-learning pipeline to integrate complex clinical

Three-valued modal logic for theory construction with contradictory data

This article refers to theory construction on the basis of binary data, where a configuration of several yes/no-variables is used in order to explain a binary outcome. The methodology proposed for this purpose has been developed by the political scientist Charles Ragin and is known under the name qualitative comparative analysis. It is frequently confronted with situations, where the same configuration of explanatory variables has contradictory yes/no-values for the outcome-variable of different related cases. Since the standard-solutions to this problem are not always satisfactory, the author proposes the use of three-valued modal logic, which was originally developed by the Polish philosopher Jan Lukasiewicz. In this logic there is a third truth-value indeterminate, which serves to code contradictory or missing data. Moreover, by the proposed use of modal operators it becomes possible to differentiate between strict and possible triggers and inhibitors of a given outcome. Since indeterminate outcomes do not really contribute to knowledge accumulation and theory building, the article discusses strategies for promoting scientific progress by minimizing this indeterminacy.

Patients' knowledge about the outcomes of thyroid biopsy: a patient survey.

Fine-needle aspiration biopsy of the thyroid is an increasingly common outpatient procedure. Patients are counseled about the indications and risks of this procedure and informed consent is obtained. We aimed to assess the extent to which patients acquired necessary knowledge during this process. Survey study conducted in a thyroid nodule clinic at a referral center. Adult patients who had just undergone a thyroid biopsy were asked to complete a survey, including eight questions regarding the indications and potential outcomes of thyroid biopsy. The main outcome of the study was to assess the patients' knowledge based on the response to each individual survey question. Two-hundred and ninety-seven patients were eligible, of which 196 (66%) completed the survey: most were women (76%), had adequate reading health literacy (95%) and a mean age of 58 years. Although 86% of patients correctly identified evaluation for thyroid cancer as the main indication for their biopsy, 56% were not aware of the likelihood of this diagnosis. Almost all (>90%) of respondents knew that results could be benign or malignant; fewer were aware of non-diagnostic (71%) or indeterminate (68%) outcomes, or of the need for additional diagnostic testing after the biopsy (33%). After undergoing thyroid biopsy, a high proportion of well-educated patients remained unaware of their risk for thyroid cancer, potential outcomes, and downstream consequences of their biopsy. This quality gap raises the possibility that informed consent procedures that meet legal standards may leave patients undergoing thyroid biopsy paradoxically uninformed.