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A prospective multicenter study on genome wide associations to ranibizumab treatment outcome for age-related macular degeneration.

ABSTRACT: We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naïve AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatment, the requirement for an additional treatment, and visual acuity changes during the 12-month observation period. In addition, we evaluated 9 single-nucleotide polymorphisms (SNPs) in 8 previously reported AMD-related genes for their associations with treatment outcome. The discovery stage with 256 patients evaluated 8,480,849 SNPs, but no SNPs showed genome-wide level significance in association with treatment outcomes. Although SNPs with P-values of?<5?×?10-6 were evaluated in replication samples of 205 patients, no SNP was significantly associated with treatment outcomes. Among AMD-susceptibility genes, rs10490924 in ARMS2/HTRA1 was significantly associated with additional treatment requirement in the discovery stage (P?=?0.0023), and pooled analysis with the replication stage further confirmed this association (P?=?0.0013). ARMS2/HTRA1 polymorphism might be able to predict the frequency of injection after initial ranibizumab treatment.

SUBMITTER: Yamashiro K

PROVIDER: S-EPMC5569099 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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A prospective multicenter study on genome wide associations to ranibizumab treatment outcome for age-related macular degeneration.

Yamashiro Kenji K Mori Keisuke K Honda Shigeru S Kano Mariko M Yanagi Yasuo Y Obana Akira A Sakurada Yoichi Y Sato Taku T Nagai Yoshimi Y Hikichi Taiichi T Kataoka Yasushi Y Hara Chikako C Koyama Yasurou Y Koizumi Hideki H Yoshikawa Munemitsu M Miyake Masahiro M Nakata Isao I Tsuchihashi Takashi T Horie-Inoue Kuniko K Matsumiya Wataru W Ogasawara Masashi M Obata Ryo R Yoneyama Seigo S Matsumoto Hidetaka H Ohnaka Masayuki M Kitamei Hirokuni H Sayanagi Kaori K Ooto Sotaro S Tamura Hiroshi H Oishi Akio A Kabasawa Sho S Ueyama Kazuhiro K Miki Akiko A Kondo Naoshi N Bessho Hiroaki H Saito Masaaki M Takahashi Hidenori H Tan Xue X Azuma Keiko K Kikushima Wataru W Mukai Ryo R Ohira Akihiro A Gomi Fumi F Miyata Kazunori K Takahashi Kanji K Kishi Shoji S Iijima Hiroyuki H Sekiryu Tetsuju T Iida Tomohiro T Awata Takuya T Inoue Satoshi S Yamada Ryo R Matsuda Fumihiko F Tsujikawa Akitaka A Negi Akira A Yoneya Shin S Iwata Takeshi T Yoshimura Nagahisa N

Scientific reports 20170823 1

We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naïve AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatm ...[more]

PMID: 28835685

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Project description:BackgroundClinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data.MethodsIn a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart.ResultsBevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.ConclusionsAt 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.).

Project description:PurposeNeovascular age-related macular degeneration (nAMD) shows variable treatment response to intravitreal anti-VEGF. This analysis compared the potential of different artificial intelligence (AI)-based machine learning models using OCT and clinical variables to accurately predict at baseline the best-corrected visual acuity (BCVA) at 9 months in response to ranibizumab in patients with nAMD.DesignRetrospective analysis.ParticipantsBaseline and imaging data from patients with subfoveal choroidal neovascularization secondary to age-related macular dengeration.MethodsBaseline data from 502 study eyes from the HARBOR (NCT00891735) prospective clinical trial (monthly ranibizumab 0.5 and 2.0 mg arms) were pooled; 432 baseline OCT volume scans were included in the analysis. Seven models, based on baseline quantitative OCT features (Least absolute shrinkage and selection operator [Lasso] OCT minimum [min], Lasso OCT 1 standard error [SE]); on quantitative OCT features and clinical variables at baseline (Lasso min, Lasso 1SE, CatBoost, RF [random forest]); or on baseline OCT images only (deep learning [DL] model), were systematically compared with a benchmark linear model of baseline age and BCVA. Quantitative OCT features were derived by a DL segmentation model on the volume images, including retinal layer volumes and thicknesses, and retinal fluid biomarkers, including statistics on fluid volume and distribution.Main outcome measuresPrognostic ability of the models was evaluated using coefficient of determination (R2) and median absolute error (MAE; letters).ResultsIn the first cross-validation split, mean R2 (MAE) of the Lasso min, Lasso 1SE, CatBoost, and RF models was 0.46 (7.87), 0.42 (8.43), 0.45 (7.75), and 0.43 (7.60), respectively. These models ranked higher than or similar to the benchmark model (mean R2, 0.41; mean MAE, 8.20 letters) and better than OCT-only models (mean R2: Lasso OCT min, 0.20; Lasso OCT 1SE, 0.16; DL, 0.34). The Lasso min model was selected for detailed analysis; mean R2 (MAE) of the Lasso min and benchmark models for 1000 repeated cross-validation splits were 0.46 (7.7) and 0.42 (8.0), respectively.ConclusionsMachine learning models based on AI-segmented OCT features and clinical variables at baseline may predict future response to ranibizumab treatment in patients with nAMD. However, further developments will be needed to realize the clinical utility of such AI-based tools.Financial disclosuresProprietary or commercial disclosure may be found after the references.

Dataset Information

A prospective multicenter study on genome wide associations to ranibizumab treatment outcome for age-related macular degeneration.

Publications

A prospective multicenter study on genome wide associations to ranibizumab treatment outcome for age-related macular degeneration.

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