22Jun

The novel rabbit model of corneal reinnervation surgery in denervated eye

TITLE: The novel rabbit model of corneal reinnervation surgery in denervated eye

INVESTIGATORS:

Patcharaporn Chandraparnik (1,2)

Andrea Kossler (1)

Cigdem Yasar (1)

David Myung (1)

Ophthalmology Department, Byers Eye Institute, Stanford University, California, USA
Ophthalmology Department, Phramongkutklao Hospital/College of Medicine, Bangkok, Thailand

DATE: Wednesday, 8 February 2023

TIME: 1:30–3:00 PM

LOCATION: Conference Room X399, Medical School Office Building, 1265 Welch Road, Stanford, CA

WEBPAGE: https://dbds.stanford.edu/data-studio/

ABSTRACT

The Data Studio Workshop brings together a biomedical investigator with a group of experts for an in-depth session to solicit advice about statistical and study design issues that arise while planning or conducting a research project. This week, the investigator(s) will discuss the following project with the group.

INTRODUCTION

Neurotrophic keratopathy (NK) is a rare and underdiagnosed degenerative disease of the cornea that is caused by damage to the ophthalmic branch of the trigeminal nerve. Epithelial breakdown, corneal ulceration, corneal melting (thinning), perforation, and loss of vision may occur over time. Currently, corneal reinnervation surgery is the only method to regrow the sensory nerve in the cornea to treat NK.

STUDY DESIGN

We wish to create the rabbit model of corneal reinnervation. Corneal reinnervation rabbit models will be utilized in further studies to evaluate the efficacy of each vehicle that delivers growth factors to accelerate nerve regeneration after the surgery. We plan to conduct the study in 2 phases with all rabbits undergoing both phases.

Phase 1: Denervation surgery by using radio-frequency thermocoagulation to create lesion at trigeminal ganglion. Corneal wound will be created on the same side of trigeminal ganglion lesion.

Phase 2: Reinnervation surgery by using infraorbital nerve graft connect to limbus of cornea. Corneal wound will be created on the same side.

HYPOTHESIS & AIM

Our aim is to assess the rate of corneal abrasion wound closure in reinnervated eye in rabbit. We hypothesize that the rate of corneal abrasion wound closure will be increased in reinnervated eye compared to denervated eye.

DATASET

We will collect the following data from each rabbit: size of corneal wound, blink rate, tear meniscus, and survival of rabbit. The primary outcome will be the rate of corneal wound healing in each group. The secondary outcomes are corneal sensation, blink rate, blink reflex, tear meniscus, and survival of rabbit.

STATISTICAL ISSUES

Sample size calculation for number of rabbits needed to show statistical significance in denervation group?
How many treatment groups (i.e., number of vehicles that deliver growth factors to accelerate nerve regeneration after the surgery) can we accommodate?
Should we have a single control group or one for each treatment group?
Given the general constraint of minimizing the number of study animals, how should we deal with missing data (e.g., death of the rabbit, failure to collect data from a rabbit, etc.)?
What is the appropriate design for this experimental study?
Do we need to control for multiple comparisons?
Should we use parametric or nonparametric methods for the hypothesis tests in this study?

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Password: 571460TITLE: Transversus abdominis plane blocks in autologous breast reconstruction

22Jun

Clinical Implementation Study of Feasibility and Effectiveness of Pharmacogenomically-Guided Treatment in Gastrointestinal Cancer Patients

TITLE: Clinical Implementation Study of Feasibility and Effectiveness of Pharmacogenomically-Guided Treatment in Gastrointestinal Cancer Patients

DATE: Wednesday, 15 February 2023

TIME: 1:30–3:00 PM

LOCATION: Conference Room X399, Medical School Office Building, 1265 Welch Road, Stanford, CA

INVESTIGATORS:

Tinashe A. Mazhindu (1, 2, 3, 4)

Collen Masimirembwa (2, 4)

Ntokozo Ndlovu (3)

Margaret Borok (3)

(1) Chemical & Systems Biology Department, Stanford University School of Medicine

(2) African Institute of Biomedical Sciences & Technology (AiBST)

(3) Department of Oncology, University of Zimbabwe

(4) Consortium for Genomics & Therapeutics in Africa (CTGA) – iPROTECTA PROJECT

WEBPAGE: https://dbds.stanford.edu/data-studio/

ABSTRACT

Pharmacogenomics (PGx) is the study of how genetic variations determine drug response and efficacy. The goal of PGx is to have molecular, genetic, and external phenotypic characteristics jointly guide prescribing the right drug, at the right dose, to the right patient, and have favourable outcomes with minimal toxicity. The clinical response rates to medicines for some cancers range from 25–80% which means a significant proportion of the cancer patient population may experience drug adverse drug reaction (ADR) with no clinical benefit whatsoever. These ADRs result in resource utilization in patient care through blood transfusion, use of colony-stimulating factors, hospitalizations, additional tests, and further treatment delays, a situation that is best kept to a minimum especially in resource-limited developing countries like Zimbabwe.

STUDY BASIS

Gastrointestinal (GIT) cancer accounts for approximately 20% of all new cancer cases in Zimbabwe and hence represents a significant disease burden. PGx recommendations are ranked according to strength of the evidence; 5-fluorouracil (5-FU), irinotecan, and analgesic have strong rankings. These drugs form the backbone of most first- and second-line therapies used in GIT cancers. In a newly published Pan-European study by Swen et al (2023), implementation of PGx guidelines by the Dutch Pharmacogenetics Working Group (DPWG) reduced the occurrence of adverse drug effects by 30%. Additionally, the study showed that the effect size of PGx guidelines differed among countries and different drug-gene pairs. However, only 1% of the participants in this study were Africans. Resource limitations call in to question the ability of African cancer treatment sites to implement PGx biomarker-guided therapy. Furthermore, such guidelines have limitations in an African setting because the populations possess distinct PGx biomarkers not found in Europeans.

STUDY DESIGN

This study is a single centre, PGx biomarker-guided implementation study to investigate feasibility and clinical effectiveness in gastrointestinal cancer patients. We will use reactive pharmacogenomic testing for DPYD, UGT1A1, CYP2D6, and CYP2C9 to guide therapy. Genotyping will be done using locally available next generation sequencing (NGS) capacity provided by the study sponsor. Patients will be enrolled into the study if they have an indication to receive chemotherapy inclusive of irinotecan and 5-FU (or its oral prodrug capecitabine) based on National Comprehensive Cancer Network (NCCN) guideline recommendations. Dosing will be based on the DPWG guidelines for their specific variants. Patients will be monitored through therapeutic drug measurements, NCI CTAE for toxicity, and disease response using RECIST criteria for up to 12 months with clinical reviews that include routine CT scans.

PROPOSED ENDPOINTS

Primary

Dose deviation rate due to pharmacogenomics biomarker guidance and resultant drug/drug metabolite concentration at T_max
Turnover time for pharmacogenomics results availability to clinicians to guide intervention decision making

Secondary

Numbers and proportion of patients with ≥ grade 3 toxicity (NCI CTAE v5)
Turnover time therapeutic drug monitoring results availability to clinicians to guide intervention decision
Disease-free and overall survival of study participants at one year
Tumour objective response rate (for neoadjuvant therapy or metastatic stage patients) using the RECIST criteria.
Measure quality of life (QoL) scores among study participants using QoL questionnaires
Number of samples bio-banked out of the total planned per patient.
Cost-effectiveness of implementing PGx guided therapy

Exploratory

PGx polymorphism impact of cancer supportive therapy outcomes- (analgesia and emesis)
Cancer care biomarker and genomic mutation assessment for GI cancer patients including mapping the mutation trends

STATISTICAL ISSUES

What is the best study design for this implementation question and are these endpoints suited for such a study?
Retrospective data on adverse drug effects (ADR) before PGx usage is obtainable. Would this be a valid control for ADR and cost-effectiveness evaluation?
How do you calculate a sample size for such an implementation study?
How do you evaluate safety and dose deviation in such a study?

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22Jun

Data Studio Office Hour

TITLE: Data Studio Office Hour

DATE: Wednesday, 22 February 2023

TIME: 1:30–3:00 PM

LOCATION: Conference Room X399, Medical School Office Building, 1265 Welch Road, Stanford, CA

REGISTRATION FORM: https://redcap.stanford.edu/surveys/?s=WMH74XCX33

DESCRIPTION

The Data Studio Office Hour brings together a series of biomedical investigators with a group of experts for brief individualized sessions to solicit advice about a statistical and study design issue that arises while planning or conducting a research project.

This week, Data Studio holds office hours for your data science needs. Biomedical Data Science faculty are available to provide assistance with your research questions. If you need help with bioinformatics software and pipelines, check out the Computational Services and Bioinformatics Facility (http://cmgm-new.stanford.edu/) and the Genetics Bioinformatics Service Center (http://med.stanford.edu/gbsc.html).

Reserve a Data Studio Office Hour session by completing the Registration Form. Sessions are about 30 minutes long but might be extended at the discretion of the coordinator. If you register for a session, please be present at the start time on Wednesday.

If you are not able to register for a session, you are welcome to complete our Data Studio Consultation services form for a free one-hour meeting with one of our statisticians. You will find a link to the Consultation services form on our Data Studio web page (https://dbds.stanford.edu/data-studio/).

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22Jun

Capillary Adaptation in Right Heart Failure

TITLE: Capillary Adaptation in Right Heart Failure

DATE: Wednesday, 1 March 2023

TIME: 1:30–3:00 PM

INVESTIGATORS:

Kenzo Ichimura (1, 2, 3)

Ross Metzger (3)

Edda Spiekerkoetter (1, 2, 3)

(1) Pulmonary, Allergy and Critical Care Medicine

(2) Cardiovascular Institute

(3) Vera Moulton Wall Center for Pulmonary Vascular Disease

LOCATION: Conference Room X399, Medical School Office Building, 1265 Welch Road, Stanford, CA

WEBPAGE: https://dbds.stanford.edu/data-studio/

ABSTRACT

INTRODUCTION

Right ventricular (RV) function is the primary determinant of functional status and survival in various cardiovascular diseases characterized by an increased RV afterload. Despite the importance of the RV function in diseases such as pulmonary hypertension (PH), the mechanism of RV failure is not well understood which limits the development of RV-targeted therapies.

Capillary rarefaction due to vessel loss or insufficient growth of the capillaries is one of the proposed structural hallmarks of RV failure. Multiple studies using rodent models of PH have shown that capillary numbers and density decrease at the stage of decompensated RV failure. Furthermore, some human studies corroborated these findings and reported that the capillary density was decreased in PH patients with end-stage RV failure. However, most of the studies documenting capillary rarefaction in the RV were performed on thin sections using conventional two-dimensional (2D) imaging which limits the evaluation of the architectural changes of the three-dimensional (3D) microvascular network of the heart.

Developments in 3D deep tissue imaging have added significant depth to our knowledge of complex microstructures such as the central nervous system and blood vessels of the heart. Deep tissue imaging can be used not only to visualize 3D tubular networks such as the vasculature, but allows for quantification of network properties such as length, diameter, orientation angle, straightness, number of branching points, number of segments, and capillary volume.

By using a mouse model of pressure overload-induced RV failure (i.e., pulmonary artery banding, PAB), we developed a 3D deep-tissue imaging and analysis method to visualize and quantify the capillary network in the RV and its relation with the cardiomyocytes (capillary-cardiomyocyte contact area). We also applied this method to human heart tissue which was obtained either from patients undergoing heart transplantation or from control cases without RV failure.

HYPOTHESES

In PAB model, the capillary architecture changes over the disease time course.
In PAB model, the capillary-cardiomyocyte contact area is preserved throughout the disease time course, except for the areas of fibrosis.
In PAB, males and females have different capillary properties at baseline and in response to RV pressure overload.
In patients with end-stage RV failure, capillary architectural change is associated with etiology and disease duration.
) cases have a different capillary architecture compared to other PAH cases.

DATASET

This study has two parts, an analysis of a mouse model of RV failure (i.e., PAB), and an analysis of samples obtained from patients with end-stage RV failure due to PH.

For the PAB mouse model, parameters of the capillary structure (length, diameter, orientation angle, straightness, number of branching points, number of segments, capillary volume), fibrosis (fibrotic tissue volume), RV tissue volume, as well as cardiomyocytes (cardiomyocyte size, capillary-cardiomyocyte contact area) were obtained from several timepoints after PAB (week 1, week 4, week 7) from male and female mice, and compared to Sham animals. N=5–7 each.

For the patient samples, parameters of the capillary structure (length, diameter, orientation angle, straightness, number of branching points, number of segments, capillary volume), fibrosis (fibrotic tissue volume), RV tissue volume, as well as clinical information (etiology, hemodynamic parameters, disease duration) were obtained. N=7 PAH cases (all female), N=4 control cases (3 males and 1 female).

For the capillary parameters, each sample has 10,000–15,000 observations, as all capillary segments have their own measurements (i.e., length, diameter, orientation angle, and straightness). Likewise, all cardiomyocytes have their own measurements (cardiomyocyte size, capillary-cardiomyocyte contact area) of around 30 observations/sample. Other parameters are unique to each sample (i.e., only one observation for “numbers of branching points” as it is the number of branches/sample).

STATISTICAL ISSUES

(1) How to do a power calculation for multiple endpoints (length, diameter, etc.) that have different SD.

(2) What is the best statistical method to compare the parameters of the capillary structures and cardiomyocytes in PAB mice? Two-way ANOVA? Mixed-effect model?

(3) How can we associate the changes in the capillary structure with etiology, hemodynamic parameters, and disease duration in patient samples? Principal component analysis? tSNE?

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