Machine Learning Methods Using Artificial Intelligence Deployed on Electronic Health Record Data for Identification and Referral of At-Risk Patients From Primary Care Physicians to Eye Care Specialists: Retrospective, Case-Controlled Study.

BACKGROUND: Identification and referral of at-risk patients from primary care practitioners (PCPs) to eye care professionals remain a challenge. Approximately 1.9 million Americans suffer from vision loss as a result of undiagnosed or untreated ophthalmic conditions. In ophthalmology, artificial intelligence (AI) is used to predict glaucoma progression, recognize diabetic retinopathy (DR), and classify ocular tumors; however, AI has not yet been used to triage primary care patients for ophthalmology referral. OBJECTIVE: This study aimed to build and compare machine learning (ML) methods, applicable to electronic health records (EHRs) of PCPs, capable of triaging patients for referral to eye care specialists. METHODS: Accessing the Optum deidentified EHR data set, 743,039 patients with 5 leading vision conditions (age-related macular degeneration [AMD], visually significant cataract, DR, glaucoma, or ocular surface disease [OSD]) were exact-matched on age and gender to 743,039 controls without eye conditions. Between 142 and 182 non-ophthalmic parameters per patient were input into 5 ML methods: generalized linear model, L1-regularized logistic regression, random forest, Extreme Gradient Boosting (XGBoost), and J48 decision tree. Model performance was compared for each pathology to select the most predictive algorithm. The area under the curve (AUC) was assessed for all algorithms for each outcome. RESULTS: XGBoost demonstrated the best performance, showing, respectively, a prediction accuracy and an AUC of 78.6% (95% CI 78.3%-78.9%) and 0.878 for visually significant cataract, 77.4% (95% CI 76.7%-78.1%) and 0.858 for exudative AMD, 79.2% (95% CI 78.8%-79.6%) and 0.879 for nonexudative AMD, 72.2% (95% CI 69.9%-74.5%) and 0.803 for OSD requiring medication, 70.8% (95% CI 70.5%-71.1%) and 0.785 for glaucoma, 85.0% (95% CI 84.2%-85.8%) and 0.924 for type 1 nonproliferative diabetic retinopathy (NPDR), 82.2% (95% CI 80.4%-84.0%) and 0.911 for type 1 proliferative diabetic retinopathy (PDR), 81.3% (95% CI 81.0%-81.6%) and 0.891 for type 2 NPDR, and 82.1% (95% CI 81.3%-82.9%) and 0.900 for type 2 PDR. CONCLUSIONS: The 5 ML methods deployed were able to successfully identify patients with elevated odds ratios (ORs), thus capable of patient triage, for ocular pathology ranging from 2.4 (95% CI 2.4-2.5) for glaucoma to 5.7 (95% CI 5.0-6.4) for type 1 NPDR, with an average OR of 3.9. The application of these models could enable PCPs to better identify and triage patients at risk for treatable ophthalmic pathology. Early identification of patients with unrecognized sight-threatening conditions may lead to earlier treatment and a reduced economic burden. More importantly, such triage may improve patients' lives.

Tuning corneal epithelial cell adhesive strength with varying crosslinker content in silicone hydrogel materials.

Purpose: To quantify the effect of silicone hydrogel crosslink density on the adhesion at corneal epithelial cells/silicone hydrogel contact lens interface. Methods: A custom-built rheometer, referred to as the live cell monolayer rheometer, was used to measure the adhesive strengths between corneal epithelial cell monolayers and silicone hydrogel lens surfaces. The resulting stress relaxations of senofilcon A-derived silicone hydrogel materials with varying crosslinking densities and delefilcon A were tested. Senofilcon A-like materials labeled L1, L2, L3, L4, and L5 contained crosslinker concentrations of 1.2, 1.35, 1.5, 1.65, and 1.8 wt%, respectively. The residual modulus measured from the live cell monolayer rheometer provided a direct indication of adhesive attachment. Results: Within the senofilcon-derived series, the adhesive strength shows a surprising minimum with respect to crosslink density. Specifically, L1 (1.20%) has the highest adhesive strength of 39.5 ± 11.2 Pa. The adhesive strength diminishes to a minimum of 11.2 ± 2.1 Pa for L3, whereafter it increases to 14.5 ± 2.5 Pa and 18.1 ± 5.1 Pa for L4 and L5, respectively. The delefilcon A lens exhibits a comparable adhesive strength of 27.8 ± 6.3 Pa to L1. Conclusions: These results demonstrated that increasing the crosslink density has a nonmonotonic influence on the adherence of lenses to mucin-expressing corneal epithelial cells, which suggests a competition mechanism at the cell/lens interface. Translational Relevance: Because the adhesiveness of contact lenses to ocular tissues may impact the comfort level for lens wearers and affect ease of removal, this study suggests that lens adhesion can be optimized through the control of crosslink density.

Carbon compositional analysis of hydrogel contact lenses by solid-state NMR spectroscopy.

Contact lenses are worn by over 140 million people each year and tremendous research and development efforts contribute to the identification and selection of hydrogel components and production protocols to yield lenses optimized for chemical and physiological properties, eye health and comfort. The final molecular composition and extent of incorporation of different components in contact lenses is routinely estimated after lens production through the analysis of the soluble components that were not included in the lens, i.e. remaining starting materials. Examination of composition in the actual intact materials is always valued and can reveal details that are missed by only examining the non-incorporated components, for example identifying chemical changes to components in lenses during the production process. Solid-state nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for the direct compositional analysis of insoluble and heterogeneous materials and is also uniquely suited to determining parameters of architecture in contact lenses. We utilized 13C cross-polarization magic angle spinning (CPMAS) NMR to examine and compare the carbon composition of soft contact lenses. 13C NMR spectra of individual polymer components enabled the determination of the approximate molecular carbon contributions of major lens components. Comparisons of the conventional etafilcon A hydrogel (1 Day Acuvue MOIST) lenses and silicone hydrogel lenses (Acuvue Oasys, Dailies Total 1, Clariti 1 Day, Biofinity, and Pure Vision) revealed major spectral differences, with considerable variation even among different silicone hydrogel lenses. The solid-state NMR approach provides a direct spectral reporting of carbon types in the hydrogel lens itself. This approach represents a valuable complementary analysis to benefit contact lens research and development and could be extended to isotopically labeled hydrogel lenses to map proximities and architecture between hydrogel components.

The influence of protein deposition on contact lens tear film stability.

When contact lenses (CLs) are worn, they are subject to deposition of the surrounding biomolecules found in the tear film (TF) of the eye. There is a correlation between protein deposition on CLs and feelings of discomfort in patients, but it has not been well understood if these feelings of discomfort arise solely from immunogenic reactions to the protein deposits or a physical instability of the tear film on protein-fouled CLs. This study compared two hydrogel CLs: etafilcon A (polyhydroxyethylmethacrylate-based hydrogel) and senofilcon A (silicone hydrogel with internal wetting agent) to elucidate how lysozyme and mucin sorption affect the wettability of CLs and understand the potential impact on TF stability in vivo. Here, we use "wettability" to refer to the stability of a film of phosphate buffered saline on the CL surface. A custom-built platform was used to conduct experiments that monitored the stability of phosphate-buffered saline (PBS) and artificial tear solution (ATS) on clean and fouled CLs. PBS was more stable (wettable) on etafilcon A than senofilcon A, and both CLs showed increased wettability after protein-fouling. However, surface wettability in PBS did not correlate with the stability of ATS on the CLs. The viscoelastic interface of ATS slowed drainage, making evaporation the primary thinning factor, in addition to the presence of a disjoining pressure that stabilized the thin film. From this, we conclude that protein deposition increases CL wettability, but does not alter tear film stability and we predict that CL susceptibility to evaporation is a better predictor of TF stability than wettability.

Reducing Friction in the Eye: A Comparative Study of Lubrication by Surface-Anchored Synthetic and Natural Ocular Mucin Analogues.

Biomaterials used in the ocular environment should exhibit specific tribological behavior to avoid discomfort and stress-induced epithelial damage during blinking. In this study, two macromolecules that are commonly employed as ocular biomaterials, namely, poly(vinylpyrrolidone) (PVP) and hyaluronan (HA), are compared with two known model glycoproteins, namely bovine submaxillary mucin (BSM) and α1-acid glycoprotein (AGP), with regard to their nonfouling efficiency, wettability, and tribological properties when freely present in the lubricant, enabling spontaneous adsorption, and when chemisorbed under low contact pressures. Chemisorbed coatings were prepared by means of photochemically triggered nitrene insertion reactions. BSM and AGP provided boundary lubrication when spontaneously adsorbed in a hydrophobic contact with a coefficient of friction (CoF) of ∼0.03-0.04. PVP and HA were found to be excellent boundary lubricants when chemisorbed (CoF ≤ 0.01). Notably, high-molecular-weight PVP generated thick adlayers, typically around 14 nm, and was able to reduce the CoF below 0.005 when slid against a BSM-coated poly(dimethylsiloxane) pin in a tearlike fluid.

Facile synthetic procedure for omega, primary amine functionalization directly in water for subsequent fluorescent labeling and potential bioconjugation of RAFT-synthesized (co)polymers.

We describe a facile method to amine functionalize and subsequently fluorescently label polymethacrylamides synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. RAFT-generated poly(N-(2-hydroxypropyl) methacrylamide-b-N-[3-(dimethylamino)propyl] methacrylamide) (poly(HPMA-b-DMAPMA)), a water soluble biocompatible polymer, is first converted to a polymeric thiol and functionalized with a primary amine through a disulfide exchange reaction with cystamine and subsequently reacted with the amine-functionalized fluorescent dye, 6-(fluorescein-5-carboxamido)hexanoic acid, succinimidyl ester (5-SFX). Poly(HPMA258-b-DMAPMA13) (Mn = 39 700 g/mol, Mw/Mn = 1.06), previously synthesized by RAFT polymerization, was used to demonstrate this facile labeling method. The problem with labeling the omega-terminal chain end of a RAFT-synthesized polymethacrylamide is that the reduced end yields a tertiary thiol with low reactivity. The key to labeling poly(HPMA-b-DMAPMA) is to first reduce the dithioester chain end with a strong reducing agent such as NaBH4, and then functionalize the tertiary polymeric thiol with a primary amine through a disulfide exchange reaction with dihydrochloride cystamine. We show that the disulfide exchange reaction is efficient and that the amine-functionalized poly(HPMA-b-DMAPMA) can be easily labeled with the fluorescent dye, 5-SFX. This concept is proven by using a ninhydrin assay to detect primary amines and UV-vis spectroscopy to measure the degree of conjugation.

Fluorescent labeling of RAFT-generated poly(N-isopropylacrylamide) via a facile maleimide-thiol coupling reaction.

We report a facile labeling technique in which the telechelic thiocarbonylthio functionality of well-defined poly(N-isopropylacrylamide) (PNIPAM) prepared by room temperature RAFT polymerization is first converted to the thiol and subsequently reacted with a maleimido-functional fluorescent dye, N-(1-pyrene)maleimide (PM). Nearly monodisperse PNIPAM (M(n) = 39 500 g/mol, M(w)/M(n) = 1.07) was synthesized using a trithiocarbonate-based CTA, 2-dodecylsulfanylthiocarbonylsulfanyl-2-methyl propionic acid (DMP), and a conventional azo-initiator, namely, 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70), as the primary source of radicals. The key to successful conjugation of PM to PNIPAM is the implementation of a two-step reduction process involving (1) the cleavage of the trithiocarbonate with a strong reducing agent, in this case, NaBH4, to form a mixture of polymeric thiols and disulfides and (2) the conjugation of PM to the pure polymeric thiol in the presence of tris(2-carboxyethyl)phosphine.HCl (TCEP). We show that TCEP efficiently eliminates the formation of polymeric disulfides and thus allows for the desired addition of the free polymeric thiol across the maleimide double bond. This concept is demonstrated using SEC-MALLS and UV-vis spectroscopy measurements.

Direct, controlled synthesis of the nonimmunogenic, hydrophilic polymer, poly(N-(2-hydroxypropyl)methacrylamide) via RAFT in aqueous media.

Poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) is a nonimmunogenic, neutral-hydrophilic polymer currently employed in the delivery of anticancer drugs. Herein, we report conditions that facilitate the direct, controlled RAFT polymerization of HPMA in aqueous media. We demonstrate that the use of 4-cyanopentanoic acid dithiobenzoate and 4,4'-azobis(4-cyanopentanoic acid) as the chain transfer agent (CTA) and initiating species, respectively, in the presence of an acetic acid buffer solution at 70 degrees C is a suitable condition leading to controlled polymerization. The "living" nature of these polymerizations is demonstrated via chain-extension of an HPMA macroCTA to yield the corresponding poly(HPMA-b-HPMA) "homopolymer".

Facile, controlled, room-temperature RAFT polymerization of N-isopropylacrylamide.

Poly(N-isopropyl acrylamide) is a thermoresponsive polymer that has been widely investigated for drug delivery. Herein, we report conditions facilitating the controlled, room-temperature RAFT polymerization of N-isopropylacrylamide (NIPAM). The key to success is the appropriate choice of both a suitable RAFT chain transfer agent (CTA) and initiating species. We show that the use of 2-dodecylsulfanylthiocarbonylsulfanyl-2-methyl propionic acid, a trithiocarbonate RAFT CTA, in conjunction with the room-temperature azo initiator 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), in DMF, at 25 degrees C, yields conditions leading to NIPAM homopolymerizations which bear all of the characteristics of a controlled/"living" polymerization. We also demonstrate facile size exclusion chromatographic analysis of PNIPAM samples in DMF at 60 degrees C, directly on aliquots withdrawn during the polymerizations, which avoids the problems previously reported in the literature.