Measure Of Treatment Effect Research Articles

Unexpressed Wishes and Unmet Needs: a Mixed Methods Study of Youth Negative Experiences in Psychotherapy

Unlike best practice guidelines for detecting and addressing medication side effects, there are no widely adopted guidelines to help therapists identify and address the possible negative effects of psychotherapy. Psychotherapy is a first-line evidence-based intervention for youth depression and anxiety, but the literature contains few studies of psychotherapy’s potential negative effects, and even fewer direct youth reports of their negative psychotherapy experiences. A mixed-methods study design was used to study youth with self-reported depression and/or anxiety and measure negative experiences associated with psychotherapy treatment. Youth were recruited from a larger study. Qualitative and quantitative data were collected from 45 youth with psychotherapy experience. Study design was informed by feedback from youth with lived experience of mental health challenges. Youth completed standardized measures of psychopathology, treatment effects, and detailed qualitative interviews. All youth experienced at least one negative effect during psychotherapy, and 30 youth (66.7%) attributed a negative effect as ‘caused’ by psychotherapy. While this attribution did not significantly differ based on severity of underlying current psychopathology, effect size estimates suggest moderate to large group differences regarding internalizing issues and baseline coping skills. Four major qualitative themes were identified from the interviews, summarizing the negative experiences of psychotherapy: (1) Barriers Experienced in Psychotherapy; (2) Concerns about Therapist; (3) Concerns about Therapy Itself; (4) Negative Experiences as a part of the Therapeutic Process. No youth raised any of these concerns directly with their therapists. These data support the need for validated, systematic assessment of psychotherapy’s negative effects among youth, with the aim of improving engagement and treatment outcomes.

Generalized pairwise comparisons for censored data: An overview.

The method of generalized pairwise comparisons (GPC) is an extension of the well-known nonparametric Wilcoxon-Mann-Whitney test for comparing two groups of observations. Multiple generalizations of Wilcoxon-Mann-Whitney test and other GPC methods have been proposed over the years to handle censored data. These methods apply different approaches to handling loss of information due to censoring: ignoring noninformative pairwise comparisons due to censoring (Gehan, Harrell, and Buyse); imputation using estimates of the survival distribution (Efron, Péron, and Latta); or inverse probability of censoring weighting (IPCW, Datta and Dong). Based on the GPC statistic, a measure of treatment effect, the "net benefit," can be defined. It quantifies the difference between the probabilities that a randomly selected individual from one group is doing better than an individual from the other group. This paper aims at evaluating GPC methods for censored data, both in the context of hypothesis testing and estimation, and providing recommendations related to their choice in various situations. The methods that ignore uninformative pairs have comparable power to more complex and computationally demanding methods in situations of low censoring, and are slightly superior for high proportions (>40%) of censoring. If one is interested in estimation of the net benefit, Harrell's c index is an unbiased estimator if the proportional hazards assumption holds. Otherwise, the imputation (Efron or Peron) or IPCW (Datta, Dong) methods provide unbiased estimators in case of proportions of drop-out censoring up to 60%.

Patient-Reported Outcome Measures in Cardiovascular Disease: An Evidence Map of the Psychometric Properties of Health Status Instruments.

Patient-reported outcomes (PROs) are important measures of treatment effect and can be used to inform the approval of cardiovascular drugs and devices by the U.S. Food and Drug Administration (FDA). To catalogue the health status patient-reported outcome measures (PROMs) validated in cardiovascular diseases (CVDs), describe their psychometric properties, and assess adherence with both FDA recommendations and the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) framework. MEDLINE, EMBASE, CINAHL, and Allied and Complementary Medicine Database from inception to August 2022. Studies that developed and/or validated health status PROMs in CVD populations. Two study authors extracted data on CVD type, PROM psychometric properties, and adherence to FDA recommendations. The risk of bias informing the development or validation of PROMs was assessed using the COSMIN framework. Fifty health status PROMs (described in 83 studies) were identified, of which 45 were disease specific and 5 were generic. Eleven (22%) of the 50 PROMs validated in CVDs had minimally important differences (MIDs) established, and 8 (16%) reported on the validation of all psychometric properties recommended by the FDA. By COSMIN standards, only 2 PROMs (4%) had all of their psychometric properties rated as sufficient in quality, and 32 PROMs (64%) had less than 50% of psychometric properties rated as sufficient. The quality of reporting varied across included studies. Of 50 PROMs validated in CVDs, only a small minority reported on the validation of all FDA-recommended psychometric properties, had psychometric properties rated as sufficient by COSMIN, or had MIDs established. Given the use of PROMs to guide FDA approvals of drugs and devices in CVDs, there is a need for better adherence to quality standards in PROM validation. None.

Intermittent Tiotropium for Episodic Wheezing.

Approximately one third of children experience an episode of wheezing during the first 3 years of life, and nearly half of these children have recurrent wheezing episodes.1–3In spite of the substantial morbidity associated with this common condition, the optimal approach to management of acute wheezing episodes in young children is not known. Although short-acting β agonists and corticosteroids are frequently used, the effects of these medications in children younger than 3 years of age are less predictable than in school-aged children and adolescents.4 In addition, inhaled and systemic corticosteroids can be associated with harms, so effective corticosteroid-sparing therapies may be preferable.5,6Tiotropium, a selective long-acting anticholinergic agent, has been studied in older children and adults, mostly as adjunctive therapy in patients with moderate-to-severe asthma.7–12 Although not rigorously studied in young children, its anticholinergic mechanism of action offers potential benefits over—or in addition to—β agonists and corticosteroids by simultaneously promoting bronchodilation and preventing mucous secretion.In this issue of Pediatrics, Kotaniemi-Syrjänen et al report results from a randomized, open-label, controlled study of intermittent tiotropium for recurrent acute wheezing episodes in 80 children ages 6 to 35 months.13 Participants with 2 to 4 prior episodes of wheezing were randomized to receive either (1) tiotropium 5 µg once daily for 7 to 14 days, (2) fluticasone 125 µg twice daily for 7 to 14 days, or (3) albuterol 0.2 mg as needed 4 to 6 times daily, each at the onset of an acute respiratory tract infection. Participants in the tiotropium and fluticasone groups also used albuterol as needed. The primary outcome was the proportion of symptom-free days during the 48-week follow-up period, and secondary outcomes were the number of albuterol doses used and the number of adverse events requiring medical attention.Although recruitment was terminated early because of financial, logistical, and ethical reasons, the investigators found that treatment with tiotropium was associated with a greater proportion of symptom-free days (97%) compared with fluticasone (87%) or as-needed albuterol (88%). The differences in the primary outcome between the tiotropium group and the fluticasone and albuterol groups remained statistically significant after a 2-way factorial analysis of variance, accounting for baseline differences across groups. Because the distribution of the number of illness episodes was similar across study groups, the measured effect of tiotropium was attributed to less severe symptoms during illness episodes rather than to less frequent occurrence of illness. Patients in the tiotropium group used albuterol less frequently during illness episodes than those in fluticasone or albuterol groups, and all treatments were found to be safe.The investigators acknowledge important limitations of the study, including the small sample size, which—although not sufficiently small to obscure a difference in the main outcome measure across study groups—limited the study’s power to detect differences in rarer outcomes and may have contributed to imbalances in important baseline characteristics across groups. In addition, the lack of blinding may have led to biased measurement of treatment effects, particularly since the primary outcome was a parent-reported symptom score rather than an objective measure of lung function. Finally, some of the included patients who were less than 24 months of age may have had viral bronchiolitis, for which routine pharmacologic treatment has not been shown to be effective.14Despite these limitations, the investigators deserve praise for conducting an important exploratory study. Their results support prior findings that tiotropium is likely safe in young children15 and provide preliminary evidence that its intermittent use during respiratory tract infections could improve symptoms. If replicated in larger blinded studies, these results suggest that intermittent tiotropium use could prevent, on average, approximately 5 weeks of symptoms per year in young children with recurrent wheezing.This study also highlights the importance of ongoing work to define clinically useful phenotypes in young children with recurrent wheezing episodes. Existing classification systems define wheezing phenotypes according to epidemiologic characteristics, symptoms over time, genetics, and environmental factors.3,4,16–23 Although some of these tools have proven helpful to predict a future diagnosis of asthma, young children may express different phenotypes over time, and whether specific treatments are more effective among patients with different phenotypes is uncertain. In this way, studying the problem through the lens of precision medicine may help to better define which patients with wheezing are most likely to benefit from specific therapies.

Use of copula to model within-study association in bivariate meta-analysis of binomial data at the aggregate level: ABayesian approach and application to surrogate endpoint evaluation.

Bivariate meta-analysis provides a useful framework for combining information across related studies and has been utilized to combine evidence from clinical studies to evaluate treatment efficacy on two outcomes. It has also been used to investigate surrogacy patterns between treatment effects on the surrogate endpoint and the final outcome. Surrogate endpoints play an important role in drug development when they can be used to measure treatment effect early compared to the final outcome and to predict clinical benefit or harm. The standard bivariate meta-analytic approach models the observed treatment effects on the surrogate and the final outcome outcomes jointly, at both the within-study and between-studies levels, using a bivariate normal distribution. For binomial data, a normal approximation on log odds ratio scale can be used. However, this method may lead to biased results when the proportions of events are close to one or zero, affecting the validation of surrogate endpoints. In this article, we explore modeling the two outcomes on the original binomial scale. First, we present a method that uses independent binomial likelihoods to model the within-study variability avoiding to approximate the observed treatment effects. However, the method ignores the within-study association. To overcome this issue, we propose a method using a bivariate copula with binomial marginals, which allows the model to account for the within-study association. We applied the methods to an illustrative example in chronic myeloid leukemia to investigate the surrogate relationship between complete cytogenetic response and event-free-survival.

Pharmacological Interventions to Prevent Clotting in Extracorporeal Circuits During Continuous Renal Replacement Therapy

What are the risks and benefits of pharmacological interventions to prevent clotting in extracorporeal circuits during continuous renal replacement therapy (CRRT)?Patients who are critically ill in an intensive care unit often develop kidney complications related to multiple factors such as infection, hypotension, and necessary medications. Acute kidney injury occurs in approximately 11% to 18% of hospitalized patients and contributes to an estimated 1.7 million deaths every year.1 Because these patients are hemodynamically unstable, they cannot tolerate standard dialysis, which is typically a 3- to 4-hour procedure. Instead, continuous dialysis is the treatment of choice, and critically ill patients often tolerate it better. This continuous treatment, known as CRRT, provides opportunities for the health care team to introduce treatment modalities that would otherwise cause waste products and fluid to accumulate within the injured kidneys.2Standard practice is to run CRRT continuously for 24 hours; however, the therapy is often inadvertently stopped for periods of time because of clotting in the circuits. When such clotting occurs, the circuits must be changed immediately. The need to change the circuits not only delays treatment but also takes staff time and adds costs. To maintain the full therapeutic effect of CRRT, reducing any interruptions to therapy is essential.2During CRRT, blood contacts the circuit system, which can activate the coagulation pathway. Pharmacological approaches to avoid clotting in CRRT circuits involve several medications including intravenous anticoagulants (eg, unfractionated heparin [UFH], low-molecular-weight heparin, argatroban, citrate), oral anticoagulants (warfarin), and antiplatelet agents.3 The purpose of this systematic review was to assess the benefits and harms of pharmacological interventions for preventing clotting in extracorporeal circuits during CRRT.This systematic review, conducted by Tsujimoto et al,4 included 34 randomized controlled trials (and some quasi-experimental trials) comprising 1960 adult participants. The main primary outcomes investigated included major bleeding, successful prevention of clotting (defined as not needing a circuit change during the first 24 hours), and death from any cause at day 28. The included studies evaluated many different pharmacological comparisons; the most common were heparin derivatives and citrate. Because citrate and UFH are the most commonly used medications to prevent clotting during CRRT,2 this summary describes only the comparison of these 2 interventions.Tsujimoto et al4 independently assessed the risk of bias for each study, including selection, performance, detection, attrition, reporting, and publication biases. They resolved any disagreements by reviewing the data together and through discussion. For dichotomous outcomes, risk ratios (RRs) with 95% CIs were used as measures of treatment effect between various comparisons and outcomes. The authors also used the internationally approved Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to determine the certainty of evidence—high, moderate, low, or very low—for each outcome5: This review showed that, when comparing citrate with UFH to prevent clotting during CRRT, moderate-certainty evidence supports citrate resulting in less major bleeding and having slightly more success at the prevention of clotting.4 The findings from this systematic review align with those of other studies showing that citrate, when compared with UFH, more effectively prolongs the duration of CRRT circuits and reduces the risk of bleeding.6 Currently, several ongoing studies could, once completed or published, be included in similar assessments in future systematic reviews.4The evidence from this systematic review can affect clinical care teams’ decisions when they are creating treatment plans for patients in this population. As nurses caring for critically ill patients, advocating for the best evidence-based treatment remains an important piece of our role. We must always consider the best available evidence and understand the feasibility, appropriateness, meaningfulness, and effectiveness of any intervention to determine whether it is most appropriate to implement in our individual context.

The benefits of covariate adjustment for adaptive multi-arm designs.

Covariate adjustment via a regression approach is known to increase the precision of statistical inference when fixed trial designs are employed in randomized controlled studies. When an adaptive multi-arm design is employed with the ability to select treatments, it is unclear how covariate adjustment affects various aspects of the study. Consider the design framework that relies on pre-specified treatment selection rule(s) and a combination test approach for hypothesis testing. It is our primary goal to evaluate the impact of covariate adjustment on adaptive multi-arm designs with treatment selection. Our secondary goal is to show how the Uniformly Minimum Variance Conditionally Unbiased Estimator can be extended to account for covariate adjustment analytically. We find that adjustment with different sets of covariates can lead to different treatment selection outcomes and hence probabilities of rejecting hypotheses. Nevertheless, we do not see any negative impact on the control of the familywise error rate when covariates are included in the analysis model. When adjusting for covariates that are moderately or highly correlated with the outcome, we see various benefits to the analysis of the design. Conversely, there is negligible impact when including covariates that are uncorrelated with the outcome. Overall, pre-specification of covariate adjustment is recommended for the analysis of adaptive multi-arm design with treatment selection. Having the statistical analysis plan in place prior to the interim and final analyses is crucial, especially when a non-collapsible measure of treatment effect is considered in the trial.

Quantification of hematoma and perihematomal edema volumes in intracerebral hemorrhage study: Design considerations in an artificial intelligence validation (QUANTUM) study.

Hematoma and perihematomal edema volumes are important radiographic markers in spontaneous intracerebral hemorrhage. Accurate, reliable, and efficient quantification of these volumes will be paramount to their utility as measures of treatment effect in future clinical studies. Both manual and semi-automated quantification methods of hematoma and perihematomal edema volumetry are time-consuming and susceptible to inter-rater variability. Efforts are now underway to develop a fully automated algorithm that can replace them. A (QUANTUM) study to establish inter-quantification method measurement equivalency, which deviates from the traditional use of measures of agreement and a comparison hypothesis testing paradigm to indirectly infer quantification method measurement equivalence, is described in this article. The Quantification of Hematoma and Perihematomal Edema Volumes in Intracerebral Hemorrhage study aims to determine whether a fully automated quantification method and a semi-automated quantification method for quantification of hematoma and perihematomal edema volumes are equivalent to the hematoma and perihematomal edema volumes of the manual quantification method. Hematoma and perihematomal edema volumes of supratentorial intracerebral hemorrhage on 252 computed tomography scans will be prospectively quantified in random order by six raters using the fully automated, semi-automated, and manual quantification methods. Primary outcome measures for hematoma and perihematomal edema volumes will be quantified via computed tomography scan on admission (<24 h from symptom onset) and on day 3 (72 ± 12 h from symptom onset), respectively. Equivalence hypothesis testing will be conducted to determine if the hematoma and perihematomal edema volume measurements of the fully automated and semi-automated quantification methods are within 7.5% of the hematoma and perihematomal edema volume measurements of the manual quantification reference method. By allowing direct equivalence hypothesis testing, the Quantification of Hematoma and Perihematomal Edema Volumes in Intracerebral Hemorrhage study offers advantages over radiology validation studies which utilize measures of agreement to indirectly infer measurement equivalence and studies which mistakenly try to infer measurement equivalence based on the failure of a comparison two-sided null hypothesis test to reach the significance level for rejection. The equivalence hypothesis testing paradigm applied to artificial intelligence application validation is relatively uncharted and warrants further investigation. The challenges encountered in the design of this study may influence future studies seeking to translate artificial intelligence medical technology into clinical practice.

ID:16261 Number Needed to Treat Concept for Pain Relief Outcomes in Patients Treated With SCS

In the rapidly evolving field of spinal cord stimulation (SCS), measures of treatment effect are needed to help understand the benefits of new therapies. The present article elaborates the number needed to treat (NNT) concept and applies it to the SCS field.

Intravitreal Delivery of rAAV2tYF-CB-hRS1 Vector for Gene Augmentation Therapy in Patients with X-Linked Retinoschisis: 1-Year Clinical Results

To evaluate the safety and efficacy of rAAV2tYF-CB-hRS1, a recombinant adeno-associated virus vector expressing retinoschisin (RS1), in individuals with retinal disease caused by mutations in the RS1 gene. Open-label, phase I/II dose-escalation clinical trial. Twenty-two adults and 5 children with X-linked retinoschisis (XLRS), aged 10 to 79 years, were enrolled. The participants received an intravitreal (IVT) injection of rAAV2tYF-CB-hRS1, at 1 of 3 dose levels, in the poorer-seeing eye and were followed up for a minimum of 1 year after treatment. The primary safety measures were local (ocular) or systemic (nonocular) adverse events (AEs) during the 12-month period after study agent administration. Efficacy was assessed based on measures of best-corrected visual acuity (BCVA), schisis cavity volume, static perimetry visual field testing, and electroretinography (ERG). The IVT administration of rAAV2tYF-CB-hRS1 was generally safe at each of the dose levels. There were no AEs resulting in early termination, and no dose-limiting toxicities were reported. The most common ocular AEs observed were related to ocular inflammation (blurred vision, visual impairment, and the presence of vitreous cells, keratic precipitates, vitreous floaters, anterior chamber cells, and vitreous haze). Ocular inflammation was generally either mild or moderate in severity and responsive to standard immunosuppressive therapy, except in 3 participants (all in the highest-dose group) who developed chronic uveitis, which required prolonged therapy. Two patients experienced retinal detachments. There was no overall improvement in BCVA, visual fields, or ERG in the study eye compared with that in the fellow eye for any dose group. Variable changes in the cystic cavity volume over time were similar in the study and fellow eyes. Gene augmentation therapy with rAAV2tYF-CB-hRS1 for XLRS was generally safe and well tolerated but failed to demonstrate a measurable treatment effect. The clinical trial is ongoing through 5 years of follow-up to assess its long-term safety.

Growth response of Garcinia kola (Heckel) plant to natural shade in a rainforest environment of Nigeria

Sustainable production of Garcinia kola can be achieved through the establishment of its plantation with the right silvicultural requirements. The growth response of Garcinia kola (Heckel) plant under a Tectona grandis L. plantation and open field was studied for three years. The experiment was laid out in a Randomized Complete Block Design (RCBD) involving three replicates per treatment. The treatments were shade from Tectona grandis (Teak) and control (open field without shade where fresh clear-felling/harvesting of Tectona grandis (Teak) has just been carried out). Measurement of treatment effects on growth of Garcinia kola commenced six months after planting and was repeated at six-month intervals, while soil temperature was measured at two week intervals. Significantly (P ≤ 0.05) higher differences were observed after the first year in height, collar diameter, and crown width on the shaded plant. The soil temperature for the shaded field was significantly (P ≤ 0.05) lower than the control field. Hence it is recommended that sustainable production of Garcinia kola through plantation establishment should be done under the shade of older trees.

Information extraction from free text for aiding transdiagnostic psychiatry: constructing NLP pipelines tailored to clinicians’ needs

BackgroundDeveloping predictive models for precision psychiatry is challenging because of unavailability of the necessary data: extracting useful information from existing electronic health record (EHR) data is not straightforward, and available clinical trial datasets are often not representative for heterogeneous patient groups. The aim of this study was constructing a natural language processing (NLP) pipeline that extracts variables for building predictive models from EHRs. We specifically tailor the pipeline for extracting information on outcomes of psychiatry treatment trajectories, applicable throughout the entire spectrum of mental health disorders (“transdiagnostic”).MethodsA qualitative study into beliefs of clinical staff on measuring treatment outcomes was conducted to construct a candidate list of variables to extract from the EHR. To investigate if the proposed variables are suitable for measuring treatment effects, resulting themes were compared to transdiagnostic outcome measures currently used in psychiatry research and compared to the HDRS (as a gold standard) through systematic review, resulting in an ideal set of variables. To extract these from EHR data, a semi-rule based NLP pipeline was constructed and tailored to the candidate variables using Prodigy. Classification accuracy and F1-scores were calculated and pipeline output was compared to HDRS scores using clinical notes from patients admitted in 2019 and 2020.ResultsAnalysis of 34 questionnaires answered by clinical staff resulted in four themes defining treatment outcomes: symptom reduction, general well-being, social functioning and personalization. Systematic review revealed 242 different transdiagnostic outcome measures, with the 36-item Short-Form Survey for quality of life (SF36) being used most consistently, showing substantial overlap with the themes from the qualitative study. Comparing SF36 to HDRS scores in 26 studies revealed moderate to good correlations (0.62—0.79) and good positive predictive values (0.75—0.88). The NLP pipeline developed with notes from 22,170 patients reached an accuracy of 95 to 99 percent (F1 scores: 0.38 – 0.86) on detecting these themes, evaluated on data from 361 patients.ConclusionsThe NLP pipeline developed in this study extracts outcome measures from the EHR that cater specifically to the needs of clinical staff and align with outcome measures used to detect treatment effects in clinical trials.

Robust and Heterogenous Odds Ratio: Estimating Price Sensitivity for Unbought Items

Problem definition: Mining for heterogeneous responses to an intervention is a crucial step for data-driven operations, for instance, to personalize treatment or pricing. We investigate how to estimate price sensitivity from transaction-level data. In causal inference terms, we estimate heterogeneous treatment effects when (a) the response to treatment (here, whether a customer buys a product) is binary, and (b) treatment assignments are partially observed (here, full information is only available for purchased items). Methodology/Results: We propose a recursive partitioning procedure to estimate heterogeneous odds ratio, a widely used measure of treatment effect in medicine and social sciences. We integrate an adversarial imputation step to allow for robust estimation even in presence of partially observed treatment assignments. We validate our methodology on synthetic data and apply it to three case studies from political science, medicine, and revenue management. Managerial implications: Our robust heterogeneous odds ratio estimation method is a simple and intuitive tool to quantify heterogeneity in patients or customers and personalize interventions, while lifting a central limitation in many revenue management data. History: This paper has been accepted as part of the 2020 MSOM Data Driven Research Challenge. Supplemental Material: The online appendix is available at https://doi.org/10.1287/msom.2022.1118 .

Abstract 3090: Patient derived cancer organoids predict clinical response for patients with locally advanced rectal cancer

Abstract Background: Locally advanced rectal cancer (LARC) is a common disease in the US, with a growing incidence in younger patients. These patients undergo multimodality treatments including chemotherapy, radiation, and surgery. For some patients this is likely over-treatment, while other patients require further treatment escalation. To date there is no clinical tool to know the potential benefit of these individual therapies. Patient-derived cancer organoids (PDCOs) are beginning to be evaluated for use as a means to predict individual patient response to clinical therapies. Here we use PDCOs from patients with LARC to compare the PDCO response to the individual clinical response. Methods: Fresh LARC tissues from patients undergoing an endoscopy and tattooing procedure were obtained following consent on an IRB-approved protocol. PDCOs were cultured in using Matrigel and our previously published CRC organoids media. Following culture maturation, PDCOs were treated with control media, 5uM 5FU, 10uM Oxaliplatin, Combination (FOLFOX), XRT (2Gy) or 5FU and XRT. Brightfield imaging was performed at baseline and following 96 hours of treatment. Glass’s delta is used as a measure of the organoid treatment effect. A Glass’s delta of 1.25 was used as a threshold of treatment response based on prior studies. Clinical imaging was evaluated using standard RECIST v1.1 criteria of the objective response. Results: Endoscopic LARC biopsy samples were obtained from 22 patients. 11 of the 22 samples were able to be grown as PDCOs. To date 9 cultures have been treated with FOLFOX and 9 have been treated with 5FU and XRT. For those treated with FOLFOX, 3/9 had a Glass’s delta greater than 1.25 and all of these patients has a clinical partial response (PR). None of those patients’ whose PDCOs did not achieve a Glass’s delta of at least 1.25 had a PR to FOLFOX clinically. No PDCO’s treated with 5FU and XRT achieved a Glass’s delta of &amp;gt;1.25. 3/9 PDCOs had a Glass’s delta &amp;gt;1.0. All of these patients had a PR. Of the 7 patients whose PDCOs did not achieve a Glass’s delta of 1 in response to 5FU and XRT, none had a clinical PR (Glass’s delta range 0.6-0.93). Conclusion: PDCOs hold great promise as a tool to predict clinical outcomes for patients with LARC. Further evaluations need to establish improved methods of PDCO generation from biopsy samples and confirm the optimum response thresholds for prediction of treatment response. Citation Format: Shirsa Udgata, Aishwarya Sunil, Rebecca L. Schmitz, Barsha Pantha, Amani Gillette, Jeremy Kratz, Patrick Grogan, Rebecca DeStefanis, Katherine Johnson, Sean Kraus, Evie Carchman, Elise Lawson, Christina Sanger, Charles Heise, Michael Bassetti, Randall Kimple, Kayla Lemmon, Morgan Larson, Cheri Pasch, Melissa Skala, Dustin Deming. Patient derived cancer organoids predict clinical response for patients with locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3090.

Causal inference for observational longitudinal studies using deep survival models

ObjectiveCausal inference for observational longitudinal studies often requires the accurate estimation of treatment effects on time-to-event outcomes in the presence of time-dependent patient history and time-dependent covariates. Materials and MethodsTo tackle this longitudinal treatment effect estimation problem, we have developed a time-variant causal survival (TCS) model that uses the potential outcomes framework with an ensemble of recurrent subnetworks to estimate the difference in survival probabilities and its confidence interval over time as a function of time-dependent covariates and treatments. ResultsUsing simulated survival datasets, the TCS model showed good causal effect estimation performance across scenarios of varying sample dimensions, event rates, confounding and overlapping. However, increasing the sample size was not effective in alleviating the adverse impact of a high level of confounding. In a large clinical cohort study, TCS identified the expected conditional average treatment effect and detected individual treatment effect heterogeneity over time. TCS provides an efficient way to estimate and update individualized treatment effects over time, in order to improve clinical decisions. DiscussionThe use of a propensity score layer and potential outcome subnetworks helps correcting for selection bias. However, the proposed model is limited in its ability to correct the bias from unmeasured confounding, and more extensive testing of TCS under extreme scenarios such as low overlapping and the presence of unmeasured confounders is desired and left for future work. ConclusionTCS fills the gap in causal inference using deep learning techniques in survival analysis. It considers time-varying confounders and treatment options. Its treatment effect estimation can be easily compared with the conventional literature, which uses relative measures of treatment effect. We expect TCS will be particularly useful for identifying and quantifying treatment effect heterogeneity over time under the ever complex observational health care environment.

Benefits of treadmill training for patients with Down Syndrome

IntroductionDown syndrome (DS) is a complex condition that causes various health problems and it is accepted that treadmill training is a therapy method for some of them.ObjectivesThe objective was to evaluate the effectiveness of various results of treadmill training in children and adults with DS.MethodsWe included studies in which participants with DS from every age group received treadmill training, alone or combined with physiotherapy and could optionally be compared to a control group with patients with DS who did not use treadmill training. The search was conducted in medical databases: PubMed, PEDro, Science Direct, Scopus and Web of Science and involved trials published until July 2021. Following PRISMA criteria, the Risk of Bias assessment was conducted using a tool developed by the Cochrane Collaboration for RCT. The included studies presented multiple outcomes and various methodologies therefore we were not able to conduct any sort of data synthesis, we presented measures of treatment effect as mean differences and corresponding 95% confidence intervals.Results5 studies with a total number of 687 participants were included. 10 trials reported on walking onset, 8 on gait parameters or cardiovascular functions, 4 on anti-inflammatory effect and 3 on executive or cognitive functions. We came across 25 different outcomes in different age groups which are presented in a narrative manner. In all outcomes we have observed a positive result favouring the treadmill training.ConclusionsIntroducing treadmill exercise into typical physiotherapy generates improvements of mental and physical health of people with DS of all ages.DisclosureNo significant relationships.

Can Neurocognitive Outcomes Assist Measurement-Based Care for Children with Attention-Deficit/Hyperactivity Disorder? A Systematic Review and Meta-Analyses of the Relationships Among the Changes in Neurocognitive Functions and Clinical Outcomes of Attention-Deficit/Hyperactivity Disorder in Pharmacological and Cognitive Training Interventions.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental conditions among school-age children. Early intervention and ongoing evaluation of treatment effectiveness are essential to minimize the life-long negative impact of ADHD. Neurocognitive functions have been reported to improve with pharmacological and cognitive training interventions for children with ADHD. We evaluated the value of measuring change in neurocognitive functions following ADHD interventions as a treatment outcome. We systematically reviewed randomized control trials of two distinctive types of ADHD interventions-pharmacological treatments and cognitive training-and summarized the changes in neurocognitive and clinical outcomes using a series of meta-analyses. Both pharmacological and cognitive training interventions showed positive effects on some aspects of neurocognitive functions. However, there were no significant correlations between changes in neurocognitive function (e.g., inhibition) and changes in ADHD behavioral symptoms (e.g., impulsive behavior). Although the associations between changes in neurocognitive function and clinical outcomes are not well studied, based on current findings, it is not suitable to use change in neurocognitive outcomes as a proxy for change in ADHD clinical symptom-based outcomes. There is, however, notable value in monitoring changes in neurocognitive function associated with ADHD interventions to achieve the following aims: (1) understanding full treatment effect on children with ADHD, (2) identifying ancillary indicators of subclinical changes, and (3) provision of objective and less biased measures of treatment effects. These findings are important evidence that changes in neurocognitive function could be a co-occurring objective indication that parallels the clinical effects of ADHD treatments.

Incidence and impact of proportional hazards violations in phase 3 cancer clinical trials.

1561 Background: Hazard ratio (HR)-based analyses used in oncology trials rely on the assumption of proportional hazards, i.e. a HR that is constant over time. Proportional hazards violations (PHVs) may lead to misinterpretation of trial results. Restricted mean survival time (RMST) is valid with non-proportional hazards and has received recent attention specifically for immunotherapy (IO) trials but has not been routinely adopted in oncology trial design as a whole. We aimed to comprehensively characterize the incidence and factors associated with PHVs among phase 3 oncology trials and assess RMST as an alternate measure of treatment effect in survival analysis. Methods: We used Clinicaltrials.gov to identify all superiority-design, 2-arm phase 3 cancer trials with time-dependent endpoints with published results through February 2020. We manually reconstructed patient-level data from published Kaplan-Meier (KM) curves, assessed PHVs with the Schoenfeld residual test (p &lt;.05) and analyzed the RMST. To assess reconstruction accuracy, reported and reconstructed HRs were compared. Univariable logistic regression was used to assess the likelihood of PHVs by trial characteristic, with statistically significant factors (p &lt;.05) included in a multivariable analysis. Concordance of RMST-based and HR-based analysis was established when both tests agreed as to the statistical significance of the comparison. Results: Of 342 KM comparisons eligible for reconstruction, 318 comparisons across 315 trials, enrolling 347,538 patients from 1989-2017, were accurately reconstructed and analyzed. PHVs were identified in 76/318 (23.9%) trials. There was no difference in likelihood of PHVs among IO vs non-IO trials (LR 2.31, 95% CI 0.30 – 17.85, P =.37), nor by disease site, year of trial initiation, or sample size. Few trials with PHVs (16/76) pre-specified a plan to account for non-proportional hazards in statistical design. Trials with an overall survival (OS) primary endpoint (PEP) were less likely to have PHVs than trials with a non-OS PEP (LR: 0.50, 95% CI 0.28 - 0.90, P =.02). Trials whose PEP was non-significant were more likely to have PHVs (LR 1.73, 95% CI 1.01 - 2.97, P =.047). No factor remained significantly associated with PHV in multivariable analysis. Overall, 291/318 (91.5%) KM comparisons were concordant. Among trials with PHVs, 5/76 were significant by RMST but not HR, and 5/76 were significant by HR but not RMST. Of these, 1 led to FDA drug approval, and 2 others are cited in NCCN guidelines. Conclusions: PHVs are common across all phase 3 cancer clinical trials. Attempts to account for PHVs in trial design are lacking despite the potential for trial misinterpretation in the event of non-proportional hazards. RMST-based analysis is broadly concordant with HR-based analysis and may aid in interpretation of trials with PHVs. Hence, we recommend that prospective trials include a priori a statistical plan to account for PHVs.

An Exploratory Factor Analysis of the National Institutes of Health Patient-Reported Outcomes Measurement Information System and the Single Assessment Numeric Evaluation in Knee Surgery Patients.

Patient-Reported Outcomes (PROs) have been suggested for use in measuring treatment effectiveness. To minimize patient burden, two approaches have been proposed: An orthopedic-specific Single Assessment Numeric Evaluation (SANE) or computer adaptive testing methods such as the National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS). The goal of this work was to examine the constructs measured by the SANE and PROMIS system in a military orthopedic population undergoing knee surgery. In 732 patients and 2,166 complete observations, the SANE-Knee PRO and PROMIS surveys for Depression, Anxiety, Pain Interference, Sleep Disturbance, and Physical Function were obtained. A correlation matrix between the PROs was calculated, the number of latent factors to extract was determined via parallel plot, and the final principal axis exploratory factor analysis was performed. The parallel plot analysis indicated that two latent factors existed. One latent factor corresponded to measures of psychological distress (PROMIS Sleep Disturbance, Depression, and Anxiety) and the second latent factor corresponded to physical capability (SANE, PROMIS Physical Function, Pain Interference, and Sleep Disturbance). Both PROMIS Physical Function (0.83) and Pain Interference (-0.80) more strongly weigh on the physical capability latent factor than SANE (0.69). In a knee surgical population, the SANE, PROMIS Physical Function, and PROMIS Pain Interference measure the same human dimension of physical capability; however, PROMIS Physical Function and Pain Interference may measure this construct more effectively in isolation. The SANE may be a more viable option to gauge physical capability when computer adaptive testing is not possible.

Role of implant loading time in the prevention of marginal bone loss after implant-supported restorations: A targeted review.

The implant-supported restoration of missing teeth is a recognized method of treatment that ensures a functional, esthetic and durable effect, along with patient satisfaction. However, the preferable time of dental implant loading is under debate. Currently, 3 protocols are used: immediate loading; early loading; and conventional (late) loading. Immediate loading provides benefits such as short treatment time, the elimination of the second surgery required for later loading protocols, the protection of the gingival papilla, an immediate esthetic effect, and high patient satisfaction. This review aimed to summarize the evidence on the impact of loading time on marginal bone loss (MBL) around dental implants, which is considered a useful measure of implantological treatment effects. A literature search was conducted based on the PubMed/MEDLINE database. The search focused on studies providing the MBL values by protocol. Out of the 1,366 hits received in the initial search, 10 studies were included in the qualitative analysis. At 12 months, the MBL range was 0.17-1.86 mm in patients undergoing the immediate protocol, 0.14-1.22 mm in patients undergoing the early protocol, and 0.44-0.91 mm in patients undergoing the late protocol. The studies were heterogeneous, but no significant differences in the occurrence of MBL were reported between the immediately and early loaded implants as compared with the conventionally loaded ones. Further studies are needed to determine other factors that might be related to the type of protocol, important for optimal patient treatment.