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Browsing by Author "Qiu, Yingjie"
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Item Adaptive phase I-II clinical trial designs identifying optimal biological doses for targeted agents and immunotherapies(Sage, 2024) Zang, Yong; Guo, Beibei; Qiu, Yingjie; Liu, Hao; Opyrchal, Mateusz; Lu, Xiongbin; Biostatistics and Health Data Science, School of MedicineTargeted agents and immunotherapies have revolutionized cancer treatment, offering promising options for various cancer types. Unlike traditional therapies the principle of "more is better" is not always applicable to these new therapies due to their unique biomedical mechanisms. As a result, various phase I-II clinical trial designs have been proposed to identify the optimal biological dose that maximizes the therapeutic effect of targeted therapies and immunotherapies by jointly monitoring both efficacy and toxicity outcomes. This review article examines several innovative phase I-II clinical trial designs that utilize accumulated efficacy and toxicity outcomes to adaptively determine doses for subsequent patients and identify the optimal biological dose, maximizing the overall therapeutic effect. Specifically, we highlight three categories of phase I-II designs: efficacy-driven, utility-based, and designs incorporating multiple efficacy endpoints. For each design, we review the dose-outcome model, the definition of the optimal biological dose, the dose-finding algorithm, and the software for trial implementation. To illustrate the concepts, we also present two real phase I-II trial examples utilizing the EffTox and ISO designs. Finally, we provide a classification tree to summarize the designs discussed in this article.Item Impact of Skin Biopsy and Clinical-Pathologic Correlation in Dermatology Inpatient Consults(Springer Nature, 2022-08-29) Wells, Amy; Harmel, Allison; Smith, Kristin N.; Beers, Paula; Qiu, Yingjie; Datta, Susmita; Schoch, Jennifer J.; De Benedetto, Anna; Longo, Isabel; Motaparthi, Kiran; Biostatistics and Health Data Science, School of MedicineBackground: While studies of hospital dermatology have demonstrated diagnostic discordance between primary teams and dermatology consultants, little is known about the impact of biopsy and clinical-pathologic correlation (CPC) in consultation. This study compares biopsy performance based on diagnostic discordance and evaluates the impact of CPC on the diagnosis. Methods: This was a retrospective review of 376 dermatologic consultations at a single academic medical center between July 1, 2017, and June 27, 2018. Results: Biopsy was significantly less likely to be performed when the diagnosis by the referring primary team was unspecified (p < 0.001). In 24 percent of cases, the diagnosis based on histopathology alone differed from the diagnosis reached by formal CPC consensus review with either potential or significant impact on management. Conclusion: Dermatologists who perform inpatient consultations and rely on hospital-based pathology services may consider a consensus review for CPC. Requests to perform a biopsy may be interpreted as a request for diagnostic assistance rather than pressure to perform a procedure.Item Medication burden and anticholinergic use are associated with overt HE in individuals with cirrhosis(Wolters Kluwer, 2024-07-22) Montrose, Jonathan A.; Desai, Archita; Nephew, Lauren; Patidar, Kavish R.; Ghabril, Marwan S.; Campbell, Noll L.; Chalasani, Naga; Qiu, Yingjie; Hays, Matthew E.; Orman, Eric S.; Medicine, School of MedicineBackground: Polypharmacy and anticholinergic medications are associated with cognitive decline in elderly populations. Although several medications have been associated with HE, associations between medication burden, anticholinergics, and HE have not been explored. We examined medication burden and anticholinergics in patients with cirrhosis and their associations with HE-related hospitalization. Methods: We conducted a retrospective cohort study of patients aged 18-80 with cirrhosis seen in hepatology clinics during 2019. The number of chronic medications (medication burden) and anticholinergic use were recorded. The primary outcome was HE-related hospitalization. Results: A total of 1039 patients were followed for a median of 840 days. Thirty-seven percent had a history of HE, and 9.8% had an HE-related hospitalization during follow-up. The mean number of chronic medications was 6.1 ± 4.3. Increasing medication burden was associated with HE-related hospitalizations in univariable (HR: 1.09, 95% CI: 1.05-1.12) and multivariable (HR: 1.07, 95% CI: 1.03-1.11) models. This relationship was maintained in those with baseline HE but not in those without baseline HE. Twenty-one percent were taking an anticholinergic medication. Anticholinergic exposure was associated with increased HE-related hospitalizations in both univariable (HR: 1.68, 95% CI: 1.09-2.57) and multivariable (HR: 1.71, 95% CI: 1.11-2.63) models. This relationship was maintained in those with baseline HE but not in those without baseline HE. Conclusions: Anticholinergic use and medication burden are both associated with HE-related hospitalizations, particularly in those with a history of HE. Special considerations to limit anticholinergics and minimize overall medication burden should be tested for potential benefit in this population.Item Modified isotonic regression based phase I/II clinical trial design identifying optimal biological dose(Elsevier, 2023) Qiu, Yingjie; Zhao, Yi; Liu, Hao; Cao, Sha; Zhang, Chi; Zang, Yong; Biostatistics and Health Data Science, School of MedicineConventional phase I/II clinical trial designs often use complicated parametric models to characterize the dose-response relationships and conduct the trials. However, the parametric models are hard to justify in practice, and the misspecification of parametric models can lead to substantially undesirable performances in phase I/II trials. Moreover, it is difficult for the physicians conducting phase I/II trials to clinically interpret the parameters of these complicated models, and such significant learning costs impede the translation of novel statistical designs into practical trial implementation. To solve these issues, we propose a transparent and efficient phase I/II clinical trial design, referred to as the modified isotonic regression-based design (mISO), to identify the optimal biological doses for molecularly targeted agents and immunotherapy. The mISO design makes no parametric model assumptions on the dose-response relationship and yields desirable performances under any clinically meaningful dose-response curves. The concise, clinically interpretable dose-response models and dose-finding algorithm make the proposed designs highly translational from the statistical community to the clinical community. We further extend the mISO design and develop the mISO-B design to handle the delayed outcomes. Our comprehensive simulation studies show that the mISO and mISO-B designs are highly efficient in optimal biological dose selection and patients allocation and outperform many existing phase I/II clinical trial designs. We also provide a trial example to illustrate the practical implementation of the proposed designs. The software for simulation and trial implementation are available for free download.Item Refining colorectal cancer classification and clinical stratification through a single-cell atlas(Springer, 2022-05-11) Khaliq, Ateeq M.; Erdogan, Cihat; Kurt, Zeyneb; Turgut, Sultan Sevgi; Grunvald, Miles W.; Rand, Tim; Khare, Sonal; Borgia, Jeffrey A.; Hayden, Dana M.; Pappas, Sam G.; Govekar, Henry R.; Kam, Audrey E.; Reiser, Jochen; Turaga, Kiran; Radovich, Milan; Zang, Yong; Qiu, Yingjie; Liu, Yunlong; Fishel, Melissa L.; Turk, Anita; Gupta, Vineet; Al-Sabti, Ram; Subramanian, Janakiraman; Kuzel, Timothy M.; Sadanandam, Anguraj; Waldron, Levi; Hussain, Arif; Saleem, Mohammad; El-Rayes, Bassel; Salahudeen, Ameen A.; Masood, Ashiq; Medicine, School of MedicineBackground Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells. Results Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance. Conclusions Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patients.Item Transparent and Efficient Designs for Clinical Trials(2024-05) Qiu, Yingjie; Zhao, Yi; Zang, Yong; Perkins, Susan; Zhang, Pengyue; Yan, JingwenModern early phase clinical trials are integral in assessing the efficacy and safety of new treatments. Traditional methodologies heavily rely on complex parametric models to determine dose-response relationships. They come with inherent challenges: difficulty in practical validation, potential for poor performances if parametric assumptions are inaccurately defined, and a heavy learning burden for medical practitioners. The need for novel methods that bridge the gap between statistical robustness and clinical applicability is evident. To accommodate those issues, we proposed two transparent and efficient designs. The modified isotonic regression based phase I/II clinical trial design (mISO) and the utility-based model free phase I/II design (UFO) represent innovative strides in identifying optimal doses for clinical trials. The mISO design, eschewing traditional parametric assumptions, offers a transparent and efficient method, adaptable to various dose-response curves and enhanced by the mISO-B extension for delayed outcomes. In parallel, the UFO design, specifically tailored for immunotherapy trials, diverges from complex models to employ a dynamic, utility-based approach. This approach continuously updates with trial data, optimizing dose allocation for each patient cohort. Both designs have demonstrated superior performance in comprehensive simulation studies by comparing them with existing methods. Several sequential methods populate the statistical literature, but there remains a notable gap in addressing secondary objectives without altering the primary aim. Addressing this, a two-stage design for randomized controlled trials sequentially testing superiority and noninferiority introduces a novel two-stage group sequential strategy. This strategy primarily aims to establish the superiority of a treatment, assessed at both interim and final stages. Uniquely, it shifts to test noninferiority only if the superiority criterion is not met at the end of the second stage. This dual-focus approach is particularly appreciated in clinical settings for its practical application. Furthermore, it provides a valuable alternative in scenarios where achieving sufficient power for the superiority objective is hindered by limited participant recruitment, allowing the study to pivot towards demonstrating noninferiority.