scholarly journals Analysis of patient derived xenograft studies in Oncology drug development: impact on design and interpretation of future studies

2019 ◽  
Author(s):  
Jake Dickinson ◽  
Marcel de Matas ◽  
Paul A Dickinson ◽  
Hitesh Mistry
Keyword(s):  
Time Series ◽  
Drug Development ◽  
Simulation Study ◽  
Statistical Power ◽  
T Test ◽  
Model Based ◽  
Patient Derived Xenograft ◽  
Oncology Drug Development ◽  
Paired T Test ◽  
Model Based Analysis

AbstractBackgroundPreclinical Oncology drug development is heavily reliant on xenograft studies to assess the anti-tumour effect of new compounds. Patient derived xenograft (PDX) have become popular as they may better represent the clinical disease, however variability is greater than in cell-line derived xenografts. The typical approach of analysing these studies involves performing an un-paired t-test on the mean tumour volumes between the treated and control group at the end of the study. This approach ignores the time-series and may result in false conclusions, especially when considering the increased variability of PDX studies.AimTo test the hypothesis that a model-based analysis provides increased power than analysis of final day volumes and to provide insights into more efficient PDX study designs.MethodsData was extracted from tumour xenograft time-series data from a large publicly available PDX drug treatment database released by Novartis. For all 2-arm studies the percent tumour growth inhibition (TGI) at two time-points, day 10 and day 14 was calculated. For each study, the effect of treatment was calculated using an un-paired t-test and also a model-based analysis using the likelihood ratio-test. In addition a simulation study was also performed to assess the difference in power between the two data-analysis approaches for different levels of TGI for PDX or standard cell-line derived xenografts (CDX).ResultsThe model-based analysis had greater statistical power than the un-paired t-test approach within the PDX data-set. The model-based approach was able to detect TGI values as low as 25 percent whereas the un-paired t-test approach required at least 50 percent TGI. These findings were confirmed within the simulation study performed which also highlighted that CDX studies require less animals than PDX studies which show the equivalent level of TGI.ConclusionThe analysis of 59 2-arm PDX studies highlighted that taking a model-based approach gave increased statistical power over simply performing an un-paired t-test on the final study day. Importantly the model-based approach was able to detect smaller size of effect compared to the un-paired t-test approach is which maybe common of such studies. These findings were confirmed within simulated studies which also highlighted the same sample size used for CDX studies would lead to inadequately powered PDX studies. Application of a model-based analysis should allow studies to use less animals and run experiments for a shorter period thus providing effective insight into compound anti-tumour activity

scholarly journals Exploring a model-based analysis of patient derived xenograft studies in oncology drug development

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10681
Author(s):  
Jake Dickinson ◽  
Marcel de Matas ◽  
Paul A. Dickinson ◽  
Hitesh B. Mistry
Keyword(s):  
Simulation Study ◽  
Statistical Power ◽  
Tumour Growth ◽  
Empirical Approach ◽  
Series Data ◽  
Ratio Test ◽  
Data Set ◽  
Model Based ◽  
Patient Derived Xenograft ◽  
Model Based Analysis

Purpose To assess whether a model-based analysis increased statistical power over an analysis of final day volumes and provide insights into more efficient patient derived xenograft (PDX) study designs. Methods Tumour xenograft time-series data was extracted from a public PDX drug treatment database. For all 2-arm studies the percent tumour growth inhibition (TGI) at day 14, 21 and 28 was calculated. Treatment effect was analysed using an un-paired, two-tailed t-test (empirical) and a model-based analysis, likelihood ratio-test (LRT). In addition, a simulation study was performed to assess the difference in power between the two data-analysis approaches for PDX or standard cell-line derived xenografts (CDX). Results The model-based analysis had greater statistical power than the empirical approach within the PDX data-set. The model-based approach was able to detect TGI values as low as 25% whereas the empirical approach required at least 50% TGI. The simulation study confirmed the findings and highlighted that CDX studies require fewer animals than PDX studies which show the equivalent level of TGI. Conclusions The study conducted adds to the growing literature which has shown that a model-based analysis of xenograft data improves statistical power over the common empirical approach. The analysis conducted showed that a model-based approach, based on the first mathematical model of tumour growth, was able to detect smaller size of effect compared to the empirical approach which is common of such studies. A model-based analysis should allow studies to reduce animal use and experiment length providing effective insights into compound anti-tumour activity.

scholarly journals The design, analysis and application of mouse clinical trials in oncology drug development

2018 ◽  
Author(s):  
Sheng Guo ◽  
Xiaoqian Jiang ◽  
Binchen Mao ◽  
Qi-Xiang Li
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Statistical Power ◽  
Objective Response ◽  
Drug Efficacy ◽  
Design Analysis ◽  
Frailty Models ◽  
Oncology Drug ◽  
Power Curves ◽  
Oncology Drug Development

AbstractMouse clinical trials (MCTs) are becoming widely used in pre-clinical oncology drug development. In this study, we provide some general guidelines on the design, analysis and application of MCTs. We first established empirical quantitative relationships between mouse number and measurement accuracy for both categorical and continuous efficacy endpoints, and showed that more mice are needed to achieve given accuracy for syngeneic models than for PDXs and CDXs. There is considerable disagreement between categorical methods on calling drug responses as objective response, indicating limitations of such approaches. We then introduced linear mixed models, or LMMs, to describe MCTs as clustered longitudinal studies, which explicitly model growth and drug response heterogeneities across mouse models and among mice within a mouse model. Several case studies were used to demonstrate the advantages of LMMs in discovering biomarkers and exploring a drug’s mechanism of action. We also introduced the additive frailty models to perform survival analysis on MCTs, which more accurately estimate hazard ratios by modeling the clustered population structures in MCTs. We performed computational simulations for LMMs and frailty models to generate statistical power curves, and showed that statistical power is close for designs with similar total number of mice at given drug efficacy. Finally, we explained how MCTs can explain discrepant results in clinical trials, hence, MCTs are more than preclinical versions of clinical trials but possess their unique values. Results in the report will make MCTs a better tool for oncology drug development.

scholarly journals Penurunanan Tekanan Darah pada Lansia Hipertensi dengan Senam Ergonomik

2020 ◽  
Vol 5 (1) ◽  
pp. 71
Author(s):  
Sri Muharni ◽  
Utari Christya Wardhani
Keyword(s):  
Blood Pressure ◽  
Time Series ◽  
Pharmacological Therapy ◽  
T Test ◽  
The Body ◽  
Control Group ◽  
P Value ◽  
Purposive Sampling ◽  
Group Time ◽  
Paired T Test

<div class="Section1"><p><em><em>Hypertension is one of the most common cardiovascular problem in elderly.  Prolonged high blood pressure canlead to destructionof the blood vessels throughout the body. However it can be controlled with pharmacology and non-pharmacology technique, one of the non-pharmacological therapy is ergonomic exercise. Ergonomic exercise is the gymnastic motion which is combined with breathing techniques. This study aimed was to know about the effect of ergonomic exercise to decreasing blood pressure in elderly with hypertensions in Community Health Center Sei Pancur region. The design was One Group Time Series, intervention given to one group only, without control group. Ergonomic exercise efectivity rated by comparing blood pressure pre and post exercise, during first, second, and third week. Sampling technique was used purposive sampling with 50 respondents. The respondents were given interventions four times. The data analysis used Paired T-Test and Annova Test. The results were shown that the blood pressure significantly decreased during fourth week, with p value: 0.00 for both systolic and diastolic blood pressure. As conclusions, ergonomic exercise had effect to decreasing blood pressure in elderly with hypertensions</em></em></p><p><em><br /></em></p><p><em>Hipertensi adalah salah satu masalah kardiovaskular yang sering terjadi pada lansia. Tekanan darah yang tinggi akan mengakibatkan kerusakan pembuluh darah di seluruh tubuh, kerusakan  tersebut dapat kita  kendalikan dengan terapi farmakologi maupun non farmakologi, salah satunya adalah senam ergonomik. Senam ergonomik adalah  suatu gerakan senam yang dikombinasikan dengan teknik pernapasan. Penelitian ini bertujuan untuk mengetahui pengaruh senam ergonomik terhadap penurunan tekanan darah  pada lansia  hipertensi di wilayah kerja Puskemas Sei Pancur. Desain dalam penelitian ini adalah One Group Time Series Design dengan mengintervensi satu kelompok saja tanpa kelompok pembanding. Efektifitas perlakukan senam ergonomik dinilai dengan cara membandingkan tekanan darah sebelum diberikan senam ergonomik dengan hasil tekanan darah setelah senam ergonomik minggu pertama,kedua dan ketiga. Dimana Teknik sampling yang digunakan adalah Purposive Sampling dengan jumlah sampel 50 responden. Pemberian sebanyak 4  kali intervensi. Analisa data menggunakan uji Paired T-Test dan Annova Test. Hasil penelitian menunjukkan bahwa tekanan darah mulai turun signifikan pada minggu ke-4, dengan nilai p = 0,00 untuk tekanan darah sistole dan 0,00 untuk tekanan darah diastol. Kesimpulan dalam penelitian ini adalah senam ergonomik berpengaruh terhadap penurunan tekanan darah pada lansia dengan hipertensi</em></p></div>

scholarly journals Pharmacometrics-Based Considerations for the Design of a Pharmacogenomic Clinical Trial Assessing Irinotecan Safety

2021 ◽  
Author(s):  
Iris K. Minichmayr ◽  
Mats O. Karlsson ◽  
Siv Jönsson
Keyword(s):  
Statistical Power ◽  
Rational Design ◽  
Total Sample ◽  
Individual Variability ◽  
Statistical Testing ◽  
Poor Metabolizers ◽  
Model Based ◽  
Exposure Response ◽  
Study Power ◽  
Model Based Analysis

Abstract Purpose Pharmacometric models provide useful tools to aid the rational design of clinical trials. This study evaluates study design-, drug-, and patient-related features as well as analysis methods for their influence on the power to demonstrate a benefit of pharmacogenomics (PGx)-based dosing regarding myelotoxicity. Methods Two pharmacokinetic and one myelosuppression model were assembled to predict concentrations of irinotecan and its metabolite SN-38 given different UGT1A1 genotypes (poor metabolizers: CLSN-38: -36%) and neutropenia following conventional versus PGx-based dosing (350 versus 245 mg/m2 (-30%)). Study power was assessed given diverse scenarios (n = 50–400 patients/arm, parallel/crossover, varying magnitude of CLSN-38, exposure-response relationship, inter-individual variability) and using model-based data analysis versus conventional statistical testing. Results The magnitude of CLSN-38 reduction in poor metabolizers and the myelosuppressive potency of SN-38 markedly influenced the power to show a difference in grade 4 neutropenia (<0.5·109 cells/L) after PGx-based versus standard dosing. To achieve >80% power with traditional statistical analysis (χ2/McNemar’s test, α = 0.05), 220/100 patients per treatment arm/sequence (parallel/crossover study) were required. The model-based analysis resulted in considerably smaller total sample sizes (n = 100/15 given parallel/crossover design) to obtain the same statistical power. Conclusions The presented findings may help to avoid unfeasible trials and to rationalize the design of pharmacogenetic studies.

scholarly journals Model-Based Meta-Analysis for Multiple Myeloma: A Quantitative Drug-Independent Framework for Efficient Decisions in Oncology Drug Development

2017 ◽  
Vol 11 (2) ◽  
pp. 218-225 ◽  
Author(s):  
Zhaoyang Teng ◽  
Neeraj Gupta ◽  
Zhaowei Hua ◽  
Guohui Liu ◽  
Vivek Samnotra ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Development ◽  
Meta Analysis ◽  
Model Based ◽  
Oncology Drug ◽  
Oncology Drug Development

scholarly journals Pengaruh Edukasi Diet Diabetes Dan Senam Kaki Terhadap Kadar Gula Darah Pada Penderita Diabetes Melitus Di Puskesmas Padurenan RT 002 / RW 10 Bekasi 2019

2020 ◽  
Vol 2 (1) ◽  
pp. 8-15
Author(s):  
Ernauli Meliyana
Keyword(s):  
Time Series ◽  
T Test ◽  
P Value ◽  
Series Design ◽  
Time Series Design ◽  
Paired T Test ◽  
Diabetes Melitus

Diabetes Melitus merupakan suatu penyakit kronis yang terjadi ketika pankreas tidak mampu menghasilkan insulin yang cukup. Penyakit Diabetes Melitus di Indonesia akan terus mengalami kenaikan seiring perubahan gaya hidup yang kurang sehat, terutama pola makan yang tidak sehat dan aktifitas fisik yang kurang. Edukasi diikuti dengan aktifitas fisik diperlukan untuk  memberikan manfaat bagi tubuh karena dengan cara berolahraga dapat menurunkan gula darah. Aktivitas fisik yang dianjurkan berupa senam, dimana salah satunya adalah senam kaki diabetes yang merupakan kegiatan atau latihan yang dilakukan oleh pasien diabetes melitus dalam rangka mencegah dan meminimalisir terjadinya luka, membantu memperlancar peredaran darah bagian kaki. Mengetahui Pengaruh edukasi diet diabetes dan aktivitas senam kaki diabetes terhadap kadar gula darah pada penderita Diabetes Melitus di Puskesmas Padurenan RT002/RW10 Bekasi 2019. Desain yang digunakan dalam penelitian ini adalah “Quasi Exsperiment Time Series Design” dengan intervensi edukasi diet diabetes dan senam kaki diabetes. Jumlah sampel penelitian ini 12 responden.Uji statistik menggunakan Paired T-Test. Ada pengaruh edukasi diet diabetes terhadap tingkat pengetahuan dengan nilai p value sebesar 0.000 (p value< 0.05), dan ada pengaruh senam kaki diabetes  terhadap kadar gula darah dengan nilai p value sebesar 0.002 (p value< 0.05). Edukasi diet diabetes dan senam kaki diabetes berpengaruh terhadap tingkat pengetahuan dan kadar gula darah pada penderita diabetes melitus di Puskesmas Padurenan RT 002 / RW 10 Bekasi.

scholarly journals The effect of sports massage with meditation on myalgia disorders

MEDIKORA ◽  
2021 ◽  
Vol 20 (2) ◽  
pp. 153-161
Author(s):  
Ali Satia Graha ◽  
Rina Yuniana
Keyword(s):  
Time Series ◽  
Design Research ◽  
Sampling Technique ◽  
T Test ◽  
Research Subjects ◽  
Sample Design ◽  
Purposive Sampling ◽  
Equivalent Time ◽  
Quasi Experimental ◽  
Paired T Test

Myalgia is pain that occurs in the muscles that can interfere with daily activities. Sports massage and meditation is an alternative to reduce the feeling. The purpose of this study was to determine the effect of sports massage on overcoming myalgia disorders. This study uses a quantitative quasi-experimental method with this type of design using the equivalent time series sample design. The population in this study was a total of 36 masseurs who worked in sports injury therapy massage centers on the 4th floor of UNY Plaza. The sample was determined using purposive sampling technique and obtained a number of 15 samples. This type of research is a quasi-experimental, using a pretest-posttest design. Research subjects were given 3 (three) repetitions of treatment, namely the first week, the second week and the third week. The data analysis technique in this study used a t-test (paired t-test), in test I, test II and test III, the overall significance was obtained with a value of 0.000 (sig. < 0.05). The conclusion in this research is sports massage with meditation can reduce myalgia disorders.Pengaruh sports massage dengan meditasi terhadap gangguan myalgiaAbstrakMyalgia merupakan nyeri yang terjadi pada otot yang dapat menganggu aktivitas sehari-hari. Sports massage dan meditasi merupakan salah satu alternatif untuk mengurangi rasa nyeri. Tujuan penelitian ini untuk mengetahui pengaruh sports massage dengan meditasi terhadap gangguan myalgia. Penelitian ini menggunakan metode quasi eksperimen kuantitatif dengan jenis rancangan menggunakan the equivalent time series sample design. Populasi dalam penelitian ini adalah masseur sejumlah total 36 yang bekerja di tempat masase terapi cedera olahraga di Plaza UNY lantai 4. Penentuan sampel menggunakan teknik purposive sampling dan diperoleh sejumlah 15 sampel. Subjek penelitian diberikan 3 (tiga) kali pengulangan perlakuan yaitu minggu ke- I, minggu ke-II dan minggu ke-III. Teknik analisis data dalam penelitian ini menggunakan uji-t (paired t-test). pada uji I diperoleh nilai 0,000 (sig. < 0,05), uji II diperoleh nilai 0,000 (sig. < 0,05) dan uji III diperoleh nilai 0,000 (sig. < 0,05). Kesimpulan dalam penelitan ini adalah sports massage dengan meditasi dapat mengurangi gangguan myalgia 

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