Variability of Thermal Subthreshold Retinal Laser Treatment Plans

Variability of Thermal Subthreshold Retinal Laser Treatment Plans | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Variability of Thermal Subthreshold Retinal Laser Treatment Plans Ulrike Rahn, Christian-Dennis Rahn, Supriya Arora, Eugene Ng, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4445582/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Sep, 2024 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Purpose To investigate the variability in subthreshold laser treatment plans for patients with diabetic macular edema or central serous chorioretinopathy. Methods Diagnostic images from 20 patients were utilized, and 25 retina specialists generated subthreshold treatment plans along with a self-rated experience level. Evaluation comprised of i)Area Variability(AV): quantifies the consensus regarding the covered area and is the difference between the areas planned by 75% and 25% of the participants ii)mean Centroid Distance(CD): level of agreement on the localization of a treatment. Subgroup analysis investigated the impact of participants' experience levels, utilizing the Mann-Whitney-Wilcoxon test. Results The predominant plan style is a targeted treatment approach(92%) and avoidance of subfoveal region(89%). Mean CD is 71.0 ± 37.5 pixels (≈half disc diameter) and mean AV is 9.8%±8.9%. A slight difference is observed between the 50%-75% areas, but a notable distinction exists between the 25%-50% areas. Subgroup analysis revealed CD and AV value of 75.9 pixels and 24% in the lower experience level group as opposed to 55.9 pixels and 8.6% in the higher experience level group. Conclusions There is significant variability in treatment planning which reduces with increased experience of retina specialists. While consensus is observed around focal points, differences in the surrounding extents persist. Figures Figure 1 Figure 2 Figure 3 Introduction Threshold retinal laser treatments were introduced over 30 years ago through the Early Treatment of Diabetic Retinopathy Studies (ETDRS) to address Diabetic Macular Edema (DME), effectively preventing vision loss in patients with diabetic retinopathy 1 . Despite the extensive documentation of threshold lasers, varying treatment plans have been observed. Van Dijk et al investigated the concordance of treatment spot locations among experts, comparing optical coherence tomography (OCT)-based plans with biomicroscopy-based plans 2 . Results indicated only a 50% overlap within each expert, accompanied by significant variability in the number of laser spots applied for the same patient among the various experts 2 . Similarly, Kozak et al noted substantial differences in spot counts when plans were based on OCT versus fluoresceine angiography (FA) 3 . While there had not been a study comparing if these spot number difference lead to different clinical outcomes, the comparison of different plan strategies such as the ETDRS grid with a mild macular grid approach demonstrated significantly different treatment outcomes 4 , suggesting that distinct laser strategies may impact clinical results. A newer approach to retinal laser treatments involves using thermal subthreshold retinal laser treatment for managing conditions like central serous chorioretinopathy (CSCR) and DME 5 . The initial concept involves breaking down a continuous wave laser into microsecond pulses, achieving a Duty Cycle below 20% 6 . This reduction in total applied energy still induces a thermal increase to stimulate retinal pigment-epithelial cells while avoiding structural damage to the cells 6 . Another thermal subthreshold laser, known as the endpoint management system (EPM), maintains a local thermal increase by reducing the pulse duration to a range between 5ms and 10ms, simultaneously lowering the power below the damaging threshold as defined by the Arrhenius integral 7 . Both strategies have been applied and demonstrated promise in treating DME as well as CSCR 8,9 . Despite their widespread application, a shortage of large-scale clinical trials exists to substantiate their clinical efficacy. Consequently, numerous small-scale studies with highly variable outcomes have been conducted, leading to low-grade evaluations in meta-analyses. Meta-analyses, such as Wu et al.'s comparison of the photodynamic therapy (PDT) and microsecond pulse subthreshold laser (MSPL) for CSCR 10 , underscore the considerable variability in the benefits of micropulse subthreshold laser treatments. Multiple parameters, including physical laser settings like duty cycle, spot size, and pulse duration, vary significantly between studies, may result in different energies applied to the retina. 11 A few publications address this issue by comparing two set of parameters, such as 5% vs. 10% Duty Cycle (DC) 12 or fixed vs. variable 13 parameters. In addition to the physical parameters itself, it also remains uncertain whether differences in plan strategies contribute as an additional factor for the variability. Despite thorough descriptions and analyses of threshold laser concepts, a notable gap exists defining principles for subthreshold laser use across all indications. To address this, the Subthreshold Ophthalmic Laser Society (SOLS) and the International Retinal Laser Society (LIGHT) were established to standardize the approach to MSPL treatment in terms of laser parameters, but also in terms of subthreshold laser plan. The LIGHT group advocates a panmacular treatment, covering the entire retina between vascular arcades with confluent laser spots in a single session to ensure comprehensive coverage and prevent undertreatment 14 . In contrast, SOLS recommends treating edematous areas, including subfoveal regions, with a confluent grid of laser spots without spacing, with optional focal treatment of microaneurysms 15 . However, the verbal descriptions of these treatment plans pose a risk of ambiguity and variable interpretation. SOLS guidelines lack a precise definition of the "edematous" area, leading to edema size variability of up to 50% 2,3 . Similarly, the LIGHT group's suggestion of treating "inside the arcades" does not consider the natural pathways of the arcades, introducing significant variability. Interpretations of the "panmacular" grid may differ, as it may be interpreted as “everything between arcades” or “within the ETDRS macula grid” giving rise to varying absolute area of retina treated; fluence is a function of energy delivered divided by area treated. This linguistic ambiguity may introduce a variability across predominantly mono-centric studies leading to variable study outcomes. Consequently, the objective of this study is to assess and quantify the variability of subthreshold laser treatments utilizing a laser system capable of tracking confluent, non-geometric (freeform) treatment plans. Methods Study Population The image data used for participants' planning in this study was obtained from a retrospective study approved by the Clinical Research Ethics Committee of the Cork Teaching Hospitals, Ireland under ECM 4 (v) on 13/4/2021, aligning with the principles of the Declaration of Helsinki. The original study included patients who underwent laser treatment (either threshold or subthreshold) with the navigated retinal laser. Informed consent was obtained from all the patients to include their retrospective data in the study. For this pre-planned sub-study, we randomly selected patients meeting specific criteria, which included having a complete dataset of high-quality images. This irreversibly anonymized dataset comprised a thickness map from OCT, a fluorescein angiography (FA) image, and a fundus color image from the Navilas laser system of 10 DME and 10 CSCR patients. Plan collection Process Retinal specialists were then invited to create subthreshold laser treatment plans using the Navigate App (OD-OS GmbH). This free online planning tool allows users to upload diagnostic images and facilitates the placement of both titration and treatment spots, allowing adjustments in treatment area directly on the diagnostic images. The operator can choose from either a color + FA image, color + OCT, or a combination of all three as the basis for the plan. Subsequently, the retinal specialists determine the exact location of the spots on the particular patient using a mouse or touchscreen. Other parameters such as duty cycle (DC), power, and pulse duration are typically selected during treatment; therefore, the Navigate App does not allow for presetting these parameters. The plan layout is then saved but remains concealed from other retinal specialists. The plans, along with additional participant information (Age, Gender, Region of residence, 10-point self-rated subthreshold laser experience scale), were anonymized and exported for subsequent evaluation. A classification of the submitted plans into either “panmacular” or “targeted” was done, and each plan was classified as either “covering fovea” or “avoiding fovea” by a masked reader. Consensus/Difference quantification The absence of a standardized comparison of such patterns consisting of points for retinal laser plans prompted the development of quantifiable parameters for assessing differences in the submitted plans. In order to establish a well-defined and quantified metric, all submitted plans were transformed into a binarized image representation, and the planned grids were extracted as areas from these images through image dilation, as illustrated in Fig. 1a. The centroid (center of mass, red crosses in Fig. 1b) of each individual plan was then determined using image processing techniques, and corresponding coordinates were documented 16 . Subsequently, all plans per patient were merged to generate a comprehensive heat map, depicted in Fig. 1b. Contour lines outlining the areas planned by at least 25%, 50%, and 75% of the participants were overlaid, as demonstrated in Fig. 1c. Notably, all image processing procedures were executed using Python 17 programming language. Figure 1: Sample Images of image processing chain for extraction of plan area parameters (a) is an example of the area extracted of the sample plan of single participant after image dilation, (b) is the representative heat map of several participants for the same case, including red spots for the centroids, (c) is the representative heat map with contour lines for the same case. A visual examination of the contour line map provided an initial insight into the level of agreement among participants. The distance between these lines emerged as a representative parameter indicating the degree of similarity in their planned treatment areas. The closer the contour lines, the stronger the agreement. To quantify this "distance" mathematically (lines being closer together or further apart), we computed the difference between the two contour lines. The area planned by at least 75% of the participants was subtracted from the area planned by at least 25% of the participants. This concept is visualized in Fig. 1c. The resulting value represents the "area variability" (AV) in this study. A smaller AV value denoted a higher consensus among the plans, as the distance between the two contour lines is small. Additionally, we calculated the median Euclidean distance in pixels between the centroid points derived from all plans for the same patient. This metric, referred to as "Centroid Distance" (CD), reflects the level of agreement concerning the treatment focus for a specific case. A smaller median distance signifies a greater concordance on the focus of treatment among the proposed treatment plans. Sample Size and Statistical Considerations A formal sample size calculation was not feasible for this study due to the absence of similarly designed studies and the novelty of treatment area definitions used in this study. Descriptive statistics were provided for all parameters. For subgroup comparisons, a Mann-Whitney-Wilcoxon test was employed to evaluate differences in the parameters within each group, after defining non-normal distribution of the CD and AV parameters, using the Shapiro-Wilk Test. A p-value of < 0.05 was denoted statistically significant. Results A cohort of 25 retinal specialists, predominantly male (76%), with a median age of 43 years (ranging from 33 to 62), contributed a total of 412 plans for 10 DME and 10 CSCR patients. The demographic details of these patients are summarized in Table 1 . Table 1 Patient Characteristics Total DME CSCR Number 20 10 10 Age (median, range) 66 (30–88) 69 (59–74) 50 (30–88) Gender (m/f) 14/6 6/4 8/2 Disease Type - 8/10 NPDR 1/10 severe NPDR 1/10 PDR 5/10 referrals with unclear type 3/10 persistent 2/10 recurrent m – male, f – female, NPDR – non-proliferative Diabetic Retinopathy, PDR – proliferative diabetic retinopathy, DME – diabetic macula edema, CSCR – central serous chorioretinopathy, After excluding plans with single spots, 344 plans were evaluated. Among the participants, a slight majority (52%) self-assess their experience levels as high, with levels of 8, 9, or 10. Of these, 72% plans employed a combination of OCT and FA images, while 9% exclusively used OCT, and 19% exclusively used FA, indicating no clear preference for a specific image combination. There were 7 different plan classifications, with only 2 participants (8%) opting for a panmacular approach. Notably, both participants initially using this approach transitioned to a more targeted style for at least one patient, resulting in the panmacular approach being utilized in 9.3% of plans. Additional to the panmacular plan styles, the following variants of a targeted style (312 plans from 25 participants) plan patterns included: • Four participants combining spaced and confluent grids in 8 plans with or without single spots Fourteen participants using confluent grids in 176 plans with or without single spots. Sixteen participants using spaced grids in 128 plans with or without single spots. Additionally, 30 plans (9.6% of targeted plans and 8.7% of all plans) incorporated single spots, added by 10 participants. A majority of 89% of the plans exhibited an avoidance of the foveal area. Table 2 Plan parameter overview per disease Characteristics All patients DME CSCR P Number of spots Mean ± SD (CoV) 335 ± 372 423 ± 409 261 ± 322 < 0.001 AV Distance 25% − 75% Mean ± SD (CoV) 9.8 ± 8.9% 12.5 ± 10.5% 7.02 ± 6.34% 0.075 CD Mean ± SD (CoV) 71.0 ± 37.5 72.9 ± 24.2 69.1 ± 48.8 0.6305 DME: diabetic macular edema; CSCR: central serous chorioretinopathy; SD – Standard deviation; CoV – Coefficient of variation, statistical significance by Mann-Withney-Wilcoxon test, p < 0.05 is statistically significant; AV: area variability; CD: centroid distance Table 2 provides numerical parameters for the overall plans, as well as separate values for DME and CSCR. In the comprehensive evaluation, the mean CD value is 71.0 ± 37.5 across all cases, equivalent to approximately 640 µm, representing half the size of the optic disc. Figure 2 illustrates the differences between the disease groups. While there is an observable difference in the mean Centroid Distance (CD) values between CSCR and DME, indicating that CSCR patients, on average, exhibit a smaller distance of CDs, reflecting more consistency in the treatment focus, this difference does not attain statistical significance. Interestingly, the CD values within the CSCR groups exhibit greater variability around their mean compared to the CD value of the DME patients. This observation suggests that, while overall consistency is generally lower in DME, CSCR patients display a spectrum, with some being very "consistent" and others very "inconsistent" regarding the treatment focus. Figure 3 visually represents the area covered by 25% (upper whisker end), 50% (red dot), and 75% (lower whisker end) of participants per patient. The length of this whisker is the average distance between the 25% and the 75% contour line and represents the Area Variability (AV). Across all patients the AV averages 9.8 ± 8.9%. Notably, the graph reveals a relatively smaller difference between the areas planned by 50% and 75% (3.2 ± 3.1%), while a substantial distance exists between the areas planned by 25% and 50% of participants (13 ± 0.12%). The percentage of the whole image area covered by 25% (upper end of the line), 50% of participants (red dot) and 75% of the participants (lower end of the line) is shown. The distance between the lower end line and the upper end of the line is the Area Variability (AV) In the subgroup analysis, participants were classified into two experience levels: "lower," encompassing those with a self-rated experience level of seven or below, and "higher" for those with a self-rated experience level of eight or above. This categorization resulted in two well-defined and relatively equal-sized cohorts. Table 3 Plan parameter overview grouped by level of experience Characteristics Number of particpants/plans Lower experience 12 / 131 Higher experience 13 / 213 p Number of spots Mean ± SD (CoV) 331. ± 401. (1.2) 288. ± 332. (1.2) 0.7258 AV Distance 25% − 75% Mean ± SD (CoV) 0.24 ± 0.22 (0.92) 0.086 ± 0.071 (0.83) 0.007331 CD Mean ± SD (CoV) 75.9 ± 48.1 (0.63) 55.9 ± 34.0 (0.61) 0.2012 SD – Standard deviation; CoV – Coefficient of variation, statistical significance by Mann-Withney-Wilcoxon test Upon reviewing the cohort with lower experience levels, a notable distinction is apparent exclusively in the AV parameter, as depicted in Table 3 . The group with lower experience demonstrates a higher AV value in contrast to the "higher" experience group. Discussion A potential cause for variable outcome in clinical studies using thermal subthreshold laser 10 and threshold laser treatments 2 , 3 may be due to the variability of treating plans. Therefore, this study assessed the variability of subthreshold laser treatment plans. In our cohort of treatment plans, a predominant plan style emerged, with 92% adopting a targeted approach. Notably, a considerable number of experts utilized a spaced pattern, avoiding the subfoveal area, and a minority incorporated single spots. The concurrent use of OCT and FA images was observed to be advantageous for planning with 75% of the participants. Quantifiable parameters, including Centroid Distance (CD) and Area Variability (AV), revealed significant variability. The CD, representing the treatment focus, is mathematically defined as the median distance between the centroids of all plans for the same patient, averaging 71 pixels (approximately half the size of the optic disc). The distance between the contour lines, denoting Area Variability, averages 9.8% and serves as a representative measure for the variability in the treated area. The AV underscored a notable "hot spot" with high agreement for treatment, yet the extent of treatment surrounding this area exhibited higher variabilities, particularly evident in CSCR cases. Subgroup analysis disclosed more consistent plans from experienced surgeons compared to those with less extensive experience, with the CD and AV parameters being better for the higher experienced groups. This indicates that Ophthalmologists undergo a learning curve leading to “more effective” laser plans. Notably, no prior literature has examined the variability in subthreshold laser plans, and the parameters established in this study are unique. However, attempts to assess variability in threshold laser plans by van Dijk et al. and Kozak et al. revealed substantial differences among operators in threshold laser applications 2 , 3 , aligning with the variability in subthreshold laser plans observed in our study. Similarly, no study has compared different experience levels for laser treatment outcomes or plans. Nonetheless, Starnawska et al. compared the accuracy of laser applications between a non-experienced operator and a highly experienced operator using the Navilas laser 18 . While this study found no difference when using a navigated laser, it was initiated upon the assumption of smaller application accuracy with less experience. In our study, accuracy is not the primary outcome; rather, we focus on consistency, which is lower in less experienced operators compared to their more experienced counterparts, aligning with the base assumption by Starnwaska et al of seeing quality differences upon variable experience levels. Consistently, an analysis of the time required for laser application revealed a learning curve, especially when transitioning from a slit lamp-based laser to a navigated laser concept. 19 The existing variability in subthreshold plans shown in this analysis emphasizes the need for caution in clinical studies. Although, the discussion about the true impact of different plans on clinical outcomes remains open, yet the substantial variability of the area treated by different ophthalmologists as represented by the AV and CD measure in this study could be a potential factor to influence clinical treatment outcomes. It is evident that the "Truth" about the optimal plan remains unknown, also necessitating large-scale trials with consistent plan styles for meaningful comparisons. One of the few studies comparing different plan styles is by Lavinsky et al. 20 , who contrasted an ETDRS grid-style treatment with a confluent concept. They identified a confluent (high-density) pattern as more efficient. Another study by Alharif et al. compared a concept labeled "targeted directly to the edematous area" with "directly targeting peripheral areas," noting a significant improvement in both groups at 6 months, with the "peripheral group" demonstrating a faster improvement compared to the directly targeted group 21 . However, the absence of visualized treatment plan layouts raises questions about the consistency between the "peripheral approach" and the "panmacular approach" described by the LIGHT group, and whether the "directly targeted approach" is equivalent to the "targeted approach" as described by the SOLS group. Even though the linguistic ambiguity does not allow a correlation to the SOLS and LIGHT concept, it emphasizes, that the subthreshold laser plan style also impacts the treatment outcome. The development of the quantifiable parameters in this study opens avenues to assess the success of training measures. If CD and AV parameters show improvement after the training, it may indicate successful training. Alternatively, the contour line heatmap of a particular case may be shown upon request in the Navigate App, to allow the resident a self-check for the planning and critically appraise the “average” plan of a well experienced laser group. The study's strengths lie in the robust, quantifiable parameters, a large number of participating experts, and a realistic planning environment using the Navigate App. The study also included a large variety of experts from around the world with participants from 11 countries (Austria, France, Germany, Italy, Peru, Russia, Spain, Sweden, United Arab Emirates, Ukraine, United States of America). However, the lack of panmacular plans represents a limitation, leaving the extent of variability in this approach uncertain, although the plans from the two participants also demonstrate an ambiguous interpretation of panmacular upon visual inspection. Intriguingly, despite two influential societies defining different approaches, only one approach was represented in our cohort. Another limitation for the subgroup analysis, however, is the number of participating experts. Although we collected feedback from 25 participants, a post-hoc power calculation for group comparisons indicates insufficient power for a subgroup comparison. Therefore, further data collection would be necessary to compare two groups of participants. In summary, our findings suggest a need for a more nuanced discussion about treated areas to enhance understanding and reduce variability. Future studies should aim to minimize variability, especially in multicentered trials, and explore the impact of different plan strategies on treatment outcomes in different diseases. This plan standardization can be supported through digital pre-planning with a modern, navigated laser system, by centralized treatment plan outline or by more thorough visualized education. Broader expert inclusion in data collection may further refine our understanding of optimal plans, particularly when including the most experienced subthreshold laser specialists. Declarations Commercial relationships disclosures: Ulrike Rahn: Consultant to OD-OS GmbH Jay Chhablani: Consultant to OD-OS, Salutaris Medical Devices, Allergan, Novartis and Biogen. Data availability : Data is available on request to corresponding author. Images used in the study are owned by authors. Acknowledgement: Authors express appreciation to the team from OD-OS GmbH for their support in realizing the paper and project. Subthreshold Laser Planning Group : Ulrike Rahn, Christian-Dennis Rahn (UR Projects, Hamburg, Germany); Supriya Arora (Bahamas Vision Centre and Princess Margaret Hospital, Nassau NP, Bahamas); Jay Chhablani (University of Pittsburgh, United States); Eugene Ng (Institute of Eye Surgery, UPMC Whitfield Hospital, Ireland); Igor Kozak (Moorfields Eye Hospital, Abu Dhabi, UAE); Claudio Iovino (Department of Surgical Sciences, Eye Clinic, University of Cagliari, Cagliari, Italy); Dmitrii S. Maltsev (Department of Ophthalmology, Military Medical Academy, St. Petersburg, Russian Federation); Imadeddin Abu Ishkeidem (Sahlgrenska university hospital, Sweden); Francesca Amoroso (Department of Ophthalmology, University of Paris Est-Créteil, Créteil, France); Ignacio Ares (OD-OS GmbH, Germany); Caroline Bormann (Universitätsaugenklinik Leipzig, Germany); Luis Cordovés Dorta (Tenerife, Spain); Per Heuvels (Augenärzte Niederelbe, Cuxhaven, Germany); Yoko Miura (Institute of Biomedical Optics, Department of Ophthalmology, University of Lübeck, Germany); Javier Montero Hernandez (General University Hospital of Valencia, Spain); Giuseppe Querques (Department of Ophthalmology , University Vita-Salute , IRCCS San Raffaele Scientific Institute, Italy); Alejandro Rius Filloy (Clinica Oftalologia Tarragona, Spain); José Antonio Roca Fernandez (Universidad Peruana Cayetano Heredia, Universidad Nacional Federico Villarreal, Peru); Jose Fernandez Vigo (Médico especialista en Oftalmología. Dpto de Retina, Hospital Clínico San Carlos, Madrid , Centro Internacional de Oftalmología Avanzada, Madrid, Spain); Martin Ziegler (Augenzentrum am St. Franziskus-Hospital, Germany); Focke Ziemmssen (Universitätsaugenklinik Leipzig, Germany); Pradeep Prasad (Stein Eye Institute, Geffen School of medicine, UCLA, USA) References National Eye Institute. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology . 1991;98(5 Suppl):766-785. van Dijk HW, Verbraak FD, Kok PHB, et al. Variability in photocoagulation treatment of diabetic macular oedema. Acta Ophthalmologica . 2013;91(8):722-727. doi:10.1111/j.1755-3768.2012.02524.x Kozak I, El-Emam SY, Cheng L, et al. Fluorescein angiography versus optical coherence tomography-guided planning for macular laser photocoagulation in diabetic macular edema. Retina (Philadelphia, Pa) . 2014;34(8):1600. 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Comparative study between subthreshold (micropulse) laser direct application to the edematous macula versus direct application to the peripheral healthy retina in the treatment of diabetic macular edema. Al-Azhar International Medical Journal . 2023;4(5). doi:10.58675/2682-339X.1800 Považay B, Brinkmann R, Stoller M, Kessler R. Selective Retina Therapy. In: Bille JF, ed. High Resolution Imaging in Microscopy and Ophthalmology . Springer International Publishing; 2019:237-259. doi:10.1007/978-3-030-16638-0_11 Chehade L, Chidlow G, Wood J, Casson RJ. Short-pulse duration retinal lasers: a review. Clinical & Experimental Ophthalmology . 2016;44(8):714-721. doi:10.1111/ceo.12754 Additional Declarations Competing interest reported. Ulrike Rahn: Consultant to OD-OS GmbH Jay Chhablani: Consultant to OD-OS Christian-Dennis Rahn: no competing interests, no financial disclosures Supriya Arora: no competing interests, no financial disclosures Eugene Ng: no competing interests, no financial disclosures Igor Kozak: no competing interests, no financial disclosures Cite Share Download PDF Status: Published Journal Publication published 30 Sep, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 02 Aug, 2024 Reviews received at journal 24 Jul, 2024 Reviewers agreed at journal 24 Jul, 2024 Reviews received at journal 28 Jun, 2024 Reviewers agreed at journal 17 Jun, 2024 Reviewers invited by journal 04 Jun, 2024 Editor assigned by journal 04 Jun, 2024 Editor invited by journal 29 May, 2024 Submission checks completed at journal 23 May, 2024 First submitted to journal 19 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4445582","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":309963977,"identity":"a22f12de-82c9-49ee-a039-35802089de40","order_by":0,"name":"Ulrike Rahn","email":"","orcid":"","institution":"UR Projects","correspondingAuthor":false,"prefix":"","firstName":"Ulrike","middleName":"","lastName":"Rahn","suffix":""},{"id":309963979,"identity":"d8100003-6f71-4d11-9cb1-3ff034855721","order_by":1,"name":"Christian-Dennis Rahn","email":"","orcid":"","institution":"UR Projects","correspondingAuthor":false,"prefix":"","firstName":"Christian-Dennis","middleName":"","lastName":"Rahn","suffix":""},{"id":309963981,"identity":"11e667d1-fc71-4ab7-b901-a5c4c7b718d0","order_by":2,"name":"Supriya Arora","email":"","orcid":"","institution":"Bahamas Vision Centre and Princess Margaret Hospital","correspondingAuthor":false,"prefix":"","firstName":"Supriya","middleName":"","lastName":"Arora","suffix":""},{"id":309963983,"identity":"9e5d1013-246c-4644-91be-32ecb53f2a2b","order_by":3,"name":"Eugene Ng","email":"","orcid":"","institution":"UPMC Whitfield Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eugene","middleName":"","lastName":"Ng","suffix":""},{"id":309963985,"identity":"35188f28-898c-41e7-a425-a58c5e98318b","order_by":4,"name":"Igor Kozak","email":"","orcid":"","institution":"Moorfields Eye Hospital","correspondingAuthor":false,"prefix":"","firstName":"Igor","middleName":"","lastName":"Kozak","suffix":""},{"id":309963988,"identity":"8b31113f-babf-4438-b2ba-23c051d27eb1","order_by":5,"name":"Jay Chhablani","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYBACxgYwcYDBgB3ISKgAEszMDURqYQZpOQPSwohfC1QfVAtjG9wY3IC5/YwBw88dd+TNmZmfPXg4rzaavx2o5UfFNtwW9OQYMPaeeWa4s5nN3CBx2/HcGYcZGxh7ztzG46YcA2bGtsOMGw4zmEkkbjuW2wDUAhTBo6X/DViL/YbD7N8kEuccy51PUMsMiC2JGw7zAG1pqMndQFjLs4KDvW2Hk3c285RJJBw7kLsRqOUgPr8Y9idvfPCz7bDtdvb2bZI/aupy550/fPDBjwo8Who4DA4g8Q+DyQPYlMKAPAP7A2R+HT7Fo2AUjIJRMEIBALDAYffoekhUAAAAAElFTkSuQmCC","orcid":"","institution":"University of Pittsburgh","correspondingAuthor":true,"prefix":"","firstName":"Jay","middleName":"","lastName":"Chhablani","suffix":""}],"badges":[],"createdAt":"2024-05-19 20:38:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4445582/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4445582/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-73763-4","type":"published","date":"2024-09-30T15:57:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57942771,"identity":"e0f9d478-83b3-40fc-bdce-fbe5f583647c","added_by":"auto","created_at":"2024-06-07 19:02:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1153103,"visible":true,"origin":"","legend":"\u003cp\u003eSample Images of image processing chain for extraction of plan area parameters (a) is an example of the area extracted of the sample plan of single participant after image dilation, (b) is the representative heat map of several participants for the same case, including red spots for the centroids, (c) is the representative heat map with contour lines for the same case.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4445582/v1/6e781ff28b8f79ba220ac936.png"},{"id":57942679,"identity":"ff7b0dc3-d2cd-4eae-a75f-d5d7f9152d02","added_by":"auto","created_at":"2024-06-07 19:01:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":27884,"visible":true,"origin":"","legend":"\u003cp\u003eCentroid Distance per disease\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4445582/v1/d388968bfb4f91d6e501e118.png"},{"id":57942759,"identity":"bd58da6f-7930-4128-8127-41798d68b810","added_by":"auto","created_at":"2024-06-07 19:01:56","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":77665,"visible":true,"origin":"","legend":"\u003cp\u003eAV per patient sorted by disease.\u003cbr\u003e\nThe percentage of the whole image area covered by 25% (upper end of the line), 50% of participants (red dot) and 75% of the participants (lower end of the line) is shown. The distance between the lower end line and the upper end of the line is the Area Variability (AV)\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4445582/v1/0cd7978e2630e812c74bd580.png"},{"id":66096730,"identity":"92f2d253-72c0-4b93-8743-259f7f943bd7","added_by":"auto","created_at":"2024-10-07 16:08:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2073124,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4445582/v1/e169f02d-f6f3-4b52-9ac9-114cdf39ad58.pdf"}],"financialInterests":"Competing interest reported. Ulrike Rahn: Consultant to OD-OS GmbH\nJay Chhablani: Consultant to OD-OS\n\nChristian-Dennis Rahn: no competing interests, no financial disclosures\nSupriya Arora: no competing interests, no financial disclosures\nEugene Ng: no competing interests, no financial disclosures\nIgor Kozak: no competing interests, no financial disclosures","formattedTitle":"Variability of Thermal Subthreshold Retinal Laser Treatment Plans","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThreshold retinal laser treatments were introduced over 30 years ago through the Early Treatment of Diabetic Retinopathy Studies (ETDRS) to address Diabetic Macular Edema (DME), effectively preventing vision loss in patients with diabetic retinopathy\u003csup\u003e1\u003c/sup\u003e. Despite the extensive documentation of threshold lasers, varying treatment plans have been observed. Van Dijk et al investigated the concordance of treatment spot locations among experts, comparing optical coherence tomography (OCT)-based plans with biomicroscopy-based plans\u003csup\u003e2\u003c/sup\u003e. Results indicated only a 50% overlap within each expert, accompanied by significant variability in the number of laser spots applied for the same patient among the various experts\u003csup\u003e2\u003c/sup\u003e. Similarly, Kozak et al noted substantial differences in spot counts when plans were based on OCT versus fluoresceine angiography (FA)\u003csup\u003e3\u003c/sup\u003e. While there had not been a study comparing if these spot number difference lead to different clinical outcomes, the comparison of different plan strategies such as the ETDRS grid with a mild macular grid approach demonstrated significantly different treatment outcomes\u003csup\u003e4\u003c/sup\u003e, suggesting that distinct laser strategies may impact clinical results.\u003c/p\u003e\n\u003cp\u003eA newer approach to retinal laser treatments involves using thermal subthreshold retinal laser treatment for managing conditions like central serous chorioretinopathy (CSCR) and DME\u003csup\u003e5\u003c/sup\u003e. The initial concept involves breaking down a continuous wave laser into microsecond pulses, achieving a Duty Cycle below 20%\u003csup\u003e6\u003c/sup\u003e. This reduction in total applied energy still induces a thermal increase to stimulate retinal pigment-epithelial cells while avoiding structural damage to the cells\u003csup\u003e6\u003c/sup\u003e. Another thermal subthreshold laser, known as the endpoint management system (EPM), maintains a local thermal increase by reducing the pulse duration to a range between 5ms and 10ms, simultaneously lowering the power below the damaging threshold as defined by the Arrhenius integral\u003csup\u003e7\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eBoth strategies have been applied and demonstrated promise in treating DME as well as CSCR\u003csup\u003e8,9\u003c/sup\u003e. Despite their widespread application, a shortage of large-scale clinical trials exists to substantiate their clinical efficacy. Consequently, numerous small-scale studies with highly variable outcomes have been conducted, leading to low-grade evaluations in meta-analyses. Meta-analyses, such as Wu et al.\u0026apos;s comparison of the photodynamic therapy (PDT) and microsecond pulse subthreshold laser (MSPL) for CSCR\u003csup\u003e10\u003c/sup\u003e, underscore the considerable variability in the benefits of micropulse subthreshold laser treatments. Multiple parameters, including physical laser settings like duty cycle, spot size, and pulse duration, vary significantly between studies, may result in different energies applied to the retina.\u003csup\u003e11\u003c/sup\u003e A few publications address this issue by comparing two set of parameters, such as 5% vs. 10% Duty Cycle (DC)\u003csup\u003e12\u003c/sup\u003e or fixed vs. variable\u003csup\u003e13\u003c/sup\u003e parameters. In addition to the physical parameters itself, it also remains uncertain whether differences in plan strategies contribute as an additional factor for the variability. Despite thorough descriptions and analyses of threshold laser concepts, a notable gap exists defining principles for subthreshold laser use across all indications. To address this, the Subthreshold Ophthalmic Laser Society (SOLS) and the International Retinal Laser Society (LIGHT) were established to standardize the approach to MSPL treatment in terms of laser parameters, but also in terms of subthreshold laser plan. The LIGHT group advocates a panmacular treatment, covering the entire retina between vascular arcades with confluent laser spots in a single session to ensure comprehensive coverage and prevent undertreatment\u003csup\u003e14\u003c/sup\u003e. In contrast, SOLS recommends treating edematous areas, including subfoveal regions, with a confluent grid of laser spots without spacing, with optional focal treatment of microaneurysms\u003csup\u003e15\u003c/sup\u003e. However, the verbal descriptions of these treatment plans pose a risk of ambiguity and variable interpretation. SOLS guidelines lack a precise definition of the \u0026quot;edematous\u0026quot; area, leading to edema size variability of up to 50%\u003csup\u003e2,3\u003c/sup\u003e. Similarly, the LIGHT group\u0026apos;s suggestion of treating \u0026quot;inside the arcades\u0026quot; does not consider the natural pathways of the arcades, introducing significant variability. Interpretations of the \u0026quot;panmacular\u0026quot; grid may differ, as it may be interpreted as \u0026ldquo;everything between arcades\u0026rdquo; or \u0026ldquo;within the ETDRS macula grid\u0026rdquo; giving rise to varying absolute area of retina treated; fluence is a function of energy delivered divided by area treated. This linguistic ambiguity may introduce a variability across predominantly mono-centric studies leading to variable study outcomes.\u003c/p\u003e\n\u003cp\u003eConsequently, the objective of this study is to assess and quantify the variability of subthreshold laser treatments utilizing a laser system capable of tracking confluent, non-geometric (freeform) treatment plans.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Population\u003c/h2\u003e\n \u003cp\u003eThe image data used for participants\u0026apos; planning in this study was obtained from a retrospective study approved by the Clinical Research Ethics Committee of the Cork Teaching Hospitals, Ireland under ECM 4 (v) on 13/4/2021, aligning with the principles of the Declaration of Helsinki. The original study included patients who underwent laser treatment (either threshold or subthreshold) with the navigated retinal laser. Informed consent was obtained from all the patients to include their retrospective data in the study. For this pre-planned sub-study, we randomly selected patients meeting specific criteria, which included having a complete dataset of high-quality images. This irreversibly anonymized dataset comprised a thickness map from OCT, a fluorescein angiography (FA) image, and a fundus color image from the Navilas laser system of 10 DME and 10 CSCR patients.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003ePlan collection Process\u003c/h2\u003e\n \u003cp\u003eRetinal specialists were then invited to create subthreshold laser treatment plans using the Navigate App (OD-OS GmbH). This free online planning tool allows users to upload diagnostic images and facilitates the placement of both titration and treatment spots, allowing adjustments in treatment area directly on the diagnostic images. The operator can choose from either a color\u0026thinsp;+\u0026thinsp;FA image, color\u0026thinsp;+\u0026thinsp;OCT, or a combination of all three as the basis for the plan. Subsequently, the retinal specialists determine the exact location of the spots on the particular patient using a mouse or touchscreen. Other parameters such as duty cycle (DC), power, and pulse duration are typically selected during treatment; therefore, the Navigate App does not allow for presetting these parameters. The plan layout is then saved but remains concealed from other retinal specialists. The plans, along with additional participant information (Age, Gender, Region of residence, 10-point self-rated subthreshold laser experience scale), were anonymized and exported for subsequent evaluation. A classification of the submitted plans into either \u0026ldquo;panmacular\u0026rdquo; or \u0026ldquo;targeted\u0026rdquo; was done, and each plan was classified as either \u0026ldquo;covering fovea\u0026rdquo; or \u0026ldquo;avoiding fovea\u0026rdquo; by a masked reader.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eConsensus/Difference quantification\u003c/h2\u003e\n \u003cp\u003eThe absence of a standardized comparison of such patterns consisting of points for retinal laser plans prompted the development of quantifiable parameters for assessing differences in the submitted plans. In order to establish a well-defined and quantified metric, all submitted plans were transformed into a binarized image representation, and the planned grids were extracted as areas from these images through image dilation, as illustrated in Fig.\u0026nbsp;1a. The centroid (center of mass, red crosses in Fig.\u0026nbsp;1b) of each individual plan was then determined using image processing techniques, and corresponding coordinates were documented\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Subsequently, all plans per patient were merged to generate a comprehensive heat map, depicted in Fig.\u0026nbsp;1b. Contour lines outlining the areas planned by at least 25%, 50%, and 75% of the participants were overlaid, as demonstrated in Fig.\u0026nbsp;1c. Notably, all image processing procedures were executed using Python\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e programming language.\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eFigure 1: Sample Images of image processing chain for extraction of plan area parameters (a) is an example of the area extracted of the sample plan of single participant after image dilation, (b) is the representative heat map of several participants for the same case, including red spots for the centroids, (c) is the representative heat map with contour lines for the same case.\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eA visual examination of the contour line map provided an initial insight into the level of agreement among participants. The distance between these lines emerged as a representative parameter indicating the degree of similarity in their planned treatment areas. The closer the contour lines, the stronger the agreement. To quantify this \u0026quot;distance\u0026quot; mathematically (lines being closer together or further apart), we computed the difference between the two contour lines. The area planned by at least 75% of the participants was subtracted from the area planned by at least 25% of the participants. This concept is visualized in Fig.\u0026nbsp;1c. The resulting value represents the \u0026quot;area variability\u0026quot; (AV) in this study. A smaller AV value denoted a higher consensus among the plans, as the distance between the two contour lines is small.\u003c/p\u003e\n \u003cp\u003eAdditionally, we calculated the median Euclidean distance in pixels between the centroid points derived from all plans for the same patient. This metric, referred to as \u0026quot;Centroid Distance\u0026quot; (CD), reflects the level of agreement concerning the treatment focus for a specific case. A smaller median distance signifies a greater concordance on the focus of treatment among the proposed treatment plans.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eSample Size and Statistical Considerations\u003c/h2\u003e\n \u003cp\u003eA formal sample size calculation was not feasible for this study due to the absence of similarly designed studies and the novelty of treatment area definitions used in this study. Descriptive statistics were provided for all parameters. For subgroup comparisons, a Mann-Whitney-Wilcoxon test was employed to evaluate differences in the parameters within each group, after defining non-normal distribution of the CD and AV parameters, using the Shapiro-Wilk Test. A p-value of \u0026lt;\u0026thinsp;0.05 was denoted statistically significant.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA cohort of 25 retinal specialists, predominantly male (76%), with a median age of 43 years (ranging from 33 to 62), contributed a total of 412 plans for 10 DME and 10 CSCR patients. The demographic details of these patients are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDME\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCSCR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66 (30\u0026ndash;88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 (59\u0026ndash;74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50 (30\u0026ndash;88)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (m/f)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14/6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6/4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8/2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease Type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8/10 NPDR\u003c/p\u003e \u003cp\u003e1/10 severe NPDR\u003c/p\u003e \u003cp\u003e1/10 PDR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/10 referrals with unclear type\u003c/p\u003e \u003cp\u003e3/10 persistent\u003c/p\u003e \u003cp\u003e2/10 recurrent\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003em \u0026ndash; male, f \u0026ndash; female, NPDR \u0026ndash; non-proliferative Diabetic Retinopathy, PDR \u0026ndash; proliferative diabetic retinopathy, DME \u0026ndash; diabetic macula edema, CSCR \u0026ndash; central serous chorioretinopathy,\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAfter excluding plans with single spots, 344 plans were evaluated. Among the participants, a slight majority (52%) self-assess their experience levels as high, with levels of 8, 9, or 10.\u003c/p\u003e \u003cp\u003eOf these, 72% plans employed a combination of OCT and FA images, while 9% exclusively used OCT, and 19% exclusively used FA, indicating no clear preference for a specific image combination. There were 7 different plan classifications, with only 2 participants (8%) opting for a panmacular approach. Notably, both participants initially using this approach transitioned to a more targeted style for at least one patient, resulting in the panmacular approach being utilized in 9.3% of plans. Additional to the panmacular plan styles, the following variants of a targeted style (312 plans from 25 participants) plan patterns included:\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e\u0026bull; Four participants combining spaced and confluent grids in 8 plans with or without single spots\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eFourteen participants using confluent grids in 176 plans with or without single spots.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSixteen participants using spaced grids in 128 plans with or without single spots.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAdditionally, 30 plans (9.6% of targeted plans and 8.7% of all plans) incorporated single spots, added by 10 participants. A majority of 89% of the plans exhibited an avoidance of the foveal area.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlan parameter overview per disease\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDME\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCSCR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of spots\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (CoV)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e335\u0026thinsp;\u0026plusmn;\u0026thinsp;372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e423\u0026thinsp;\u0026plusmn;\u0026thinsp;409\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e261\u0026thinsp;\u0026plusmn;\u0026thinsp;322\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAV\u003c/b\u003e\u003c/p\u003e \u003cp\u003eDistance 25% \u0026minus;\u0026thinsp;75%\u003c/p\u003e \u003cp\u003e\u003cem\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (CoV)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e7.02\u0026thinsp;\u0026plusmn;\u0026thinsp;6.34%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCD\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (CoV)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e71.0\u0026thinsp;\u0026plusmn;\u0026thinsp;37.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e72.9\u0026thinsp;\u0026plusmn;\u0026thinsp;24.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e69.1\u0026thinsp;\u0026plusmn;\u0026thinsp;48.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.6305\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eDME: diabetic macular edema; CSCR: central serous chorioretinopathy; SD \u0026ndash; Standard deviation; CoV \u0026ndash; Coefficient of variation, statistical significance by Mann-Withney-Wilcoxon test, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 is statistically significant; AV: area variability; CD: centroid distance\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e provides numerical parameters for the overall plans, as well as separate values for DME and CSCR. In the comprehensive evaluation, the mean CD value is 71.0\u0026thinsp;\u0026plusmn;\u0026thinsp;37.5 across all cases, equivalent to approximately 640 \u0026micro;m, representing half the size of the optic disc. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates the differences between the disease groups. While there is an observable difference in the mean Centroid Distance (CD) values between CSCR and DME, indicating that CSCR patients, on average, exhibit a smaller distance of CDs, reflecting more consistency in the treatment focus, this difference does not attain statistical significance. Interestingly, the CD values within the CSCR groups exhibit greater variability around their mean compared to the CD value of the DME patients. This observation suggests that, while overall consistency is generally lower in DME, CSCR patients display a spectrum, with some being very \"consistent\" and others very \"inconsistent\" regarding the treatment focus.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e visually represents the area covered by 25% (upper whisker end), 50% (red dot), and 75% (lower whisker end) of participants per patient. The length of this whisker is the average distance between the 25% and the 75% contour line and represents the Area Variability (AV). Across all patients the AV averages 9.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9%. Notably, the graph reveals a relatively smaller difference between the areas planned by 50% and 75% (3.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1%), while a substantial distance exists between the areas planned by 25% and 50% of participants (13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12%).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eThe percentage of the whole image area covered by 25% (upper end of the line), 50% of participants (red dot) and 75% of the participants (lower end of the line) is shown. The distance between the lower end line and the upper end of the line is the Area Variability (AV)\u003c/em\u003e \u003c/p\u003e \u003cp\u003eIn the subgroup analysis, participants were classified into two experience levels: \"lower,\" encompassing those with a self-rated experience level of seven or below, and \"higher\" for those with a self-rated experience level of eight or above. This categorization resulted in two well-defined and relatively equal-sized cohorts.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlan parameter overview grouped by level of experience\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003cp\u003e\u003cem\u003eNumber of particpants/plans\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLower experience\u003c/p\u003e \u003cp\u003e12 / 131\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHigher experience\u003c/p\u003e \u003cp\u003e13 / 213\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of spots\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (CoV)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e331. \u0026plusmn; 401. (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e288. \u0026plusmn; 332. (1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7258\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAV\u003c/b\u003e\u003c/p\u003e \u003cp\u003eDistance 25% \u0026minus;\u0026thinsp;75%\u003c/p\u003e \u003cp\u003e\u003cem\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (CoV)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.24\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22 (0.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.086\u0026thinsp;\u0026plusmn;\u0026thinsp;0.071 (0.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.007331\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCD\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (CoV)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e75.9\u0026thinsp;\u0026plusmn;\u0026thinsp;48.1 (0.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e55.9\u0026thinsp;\u0026plusmn;\u0026thinsp;34.0 (0.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.2012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eSD \u0026ndash; Standard deviation; CoV \u0026ndash; Coefficient of variation, statistical significance by Mann-Withney-Wilcoxon test\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eUpon reviewing the cohort with lower experience levels, a notable distinction is apparent exclusively in the AV parameter, as depicted in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The group with lower experience demonstrates a higher AV value in contrast to the \"higher\" experience group.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eA potential cause for variable outcome in clinical studies using thermal subthreshold laser\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e and threshold laser treatments\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e may be due to the variability of treating plans. Therefore, this study assessed the variability of subthreshold laser treatment plans. In our cohort of treatment plans, a predominant plan style emerged, with 92% adopting a targeted approach. Notably, a considerable number of experts utilized a spaced pattern, avoiding the subfoveal area, and a minority incorporated single spots. The concurrent use of OCT and FA images was observed to be advantageous for planning with 75% of the participants.\u003c/p\u003e \u003cp\u003eQuantifiable parameters, including Centroid Distance (CD) and Area Variability (AV), revealed significant variability. The CD, representing the treatment focus, is mathematically defined as the median distance between the centroids of all plans for the same patient, averaging 71 pixels (approximately half the size of the optic disc). The distance between the contour lines, denoting Area Variability, averages 9.8% and serves as a representative measure for the variability in the treated area. The AV underscored a notable \"hot spot\" with high agreement for treatment, yet the extent of treatment surrounding this area exhibited higher variabilities, particularly evident in CSCR cases. Subgroup analysis disclosed more consistent plans from experienced surgeons compared to those with less extensive experience, with the CD and AV parameters being better for the higher experienced groups. This indicates that Ophthalmologists undergo a learning curve leading to \u0026ldquo;more effective\u0026rdquo; laser plans.\u003c/p\u003e \u003cp\u003eNotably, no prior literature has examined the variability in subthreshold laser plans, and the parameters established in this study are unique. However, attempts to assess variability in threshold laser plans by van Dijk et al. and Kozak et al. revealed substantial differences among operators in threshold laser applications\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e, aligning with the variability in subthreshold laser plans observed in our study. Similarly, no study has compared different experience levels for laser treatment outcomes or plans. Nonetheless, Starnawska et al. compared the accuracy of laser applications between a non-experienced operator and a highly experienced operator using the Navilas laser\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. While this study found no difference when using a navigated laser, it was initiated upon the assumption of smaller application accuracy with less experience. In our study, accuracy is not the primary outcome; rather, we focus on consistency, which is lower in less experienced operators compared to their more experienced counterparts, aligning with the base assumption by Starnwaska et al of seeing quality differences upon variable experience levels. Consistently, an analysis of the time required for laser application revealed a learning curve, especially when transitioning from a slit lamp-based laser to a navigated laser concept.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe existing variability in subthreshold plans shown in this analysis emphasizes the need for caution in clinical studies. Although, the discussion about the true impact of different plans on clinical outcomes remains open, yet the substantial variability of the area treated by different ophthalmologists as represented by the AV and CD measure in this study could be a potential factor to influence clinical treatment outcomes. It is evident that the \"Truth\" about the optimal plan remains unknown, also necessitating large-scale trials with consistent plan styles for meaningful comparisons. One of the few studies comparing different plan styles is by Lavinsky et al.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, who contrasted an ETDRS grid-style treatment with a confluent concept. They identified a confluent (high-density) pattern as more efficient. Another study by Alharif et al. compared a concept labeled \"targeted directly to the edematous area\" with \"directly targeting peripheral areas,\" noting a significant improvement in both groups at 6 months, with the \"peripheral group\" demonstrating a faster improvement compared to the directly targeted group\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. However, the absence of visualized treatment plan layouts raises questions about the consistency between the \"peripheral approach\" and the \"panmacular approach\" described by the LIGHT group, and whether the \"directly targeted approach\" is equivalent to the \"targeted approach\" as described by the SOLS group. Even though the linguistic ambiguity does not allow a correlation to the SOLS and LIGHT concept, it emphasizes, that the subthreshold laser plan style also impacts the treatment outcome.\u003c/p\u003e \u003cp\u003eThe development of the quantifiable parameters in this study opens avenues to assess the success of training measures. If CD and AV parameters show improvement after the training, it may indicate successful training. Alternatively, the contour line heatmap of a particular case may be shown upon request in the Navigate App, to allow the resident a self-check for the planning and critically appraise the \u0026ldquo;average\u0026rdquo; plan of a well experienced laser group.\u003c/p\u003e \u003cp\u003eThe study's strengths lie in the robust, quantifiable parameters, a large number of participating experts, and a realistic planning environment using the Navigate App. The study also included a large variety of experts from around the world with participants from 11 countries (Austria, France, Germany, Italy, Peru, Russia, Spain, Sweden, United Arab Emirates, Ukraine, United States of America). However, the lack of panmacular plans represents a limitation, leaving the extent of variability in this approach uncertain, although the plans from the two participants also demonstrate an ambiguous interpretation of panmacular upon visual inspection. Intriguingly, despite two influential societies defining different approaches, only one approach was represented in our cohort. Another limitation for the subgroup analysis, however, is the number of participating experts. Although we collected feedback from 25 participants, a post-hoc power calculation for group comparisons indicates insufficient power for a subgroup comparison. Therefore, further data collection would be necessary to compare two groups of participants.\u003c/p\u003e \u003cp\u003eIn summary, our findings suggest a need for a more nuanced discussion about treated areas to enhance understanding and reduce variability. Future studies should aim to minimize variability, especially in multicentered trials, and explore the impact of different plan strategies on treatment outcomes in different diseases. This plan standardization can be supported through digital pre-planning with a modern, navigated laser system, by centralized treatment plan outline or by more thorough visualized education. Broader expert inclusion in data collection may further refine our understanding of optimal plans, particularly when including the most experienced subthreshold laser specialists.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCommercial relationships disclosures:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUlrike Rahn: Consultant to OD-OS GmbH\u003c/p\u003e\n\u003cp\u003eJay Chhablani:\u0026nbsp;Consultant to OD-OS, Salutaris Medical Devices, Allergan, Novartis and Biogen.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eData availability\u003c/strong\u003e: Data is available on request to corresponding author.\u003c/p\u003e\n\u003cp\u003eImages used in the study are owned by authors.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u003c/strong\u003e Authors express appreciation to the team from OD-OS GmbH for their support in realizing the paper and project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubthreshold Laser Planning Group\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUlrike Rahn, Christian-Dennis Rahn \u0026nbsp;(UR Projects, Hamburg, Germany); Supriya Arora (Bahamas Vision Centre and Princess Margaret Hospital, Nassau NP, Bahamas); Jay Chhablani (University of Pittsburgh, United States); Eugene Ng (Institute of Eye Surgery, UPMC Whitfield Hospital, Ireland); Igor Kozak (Moorfields Eye Hospital, Abu Dhabi, UAE); Claudio Iovino (Department of Surgical Sciences, Eye Clinic, University of Cagliari, Cagliari, Italy); Dmitrii S. Maltsev (Department of Ophthalmology, Military Medical Academy, St. Petersburg, Russian Federation); Imadeddin Abu Ishkeidem (Sahlgrenska university hospital, Sweden); Francesca Amoroso (Department of Ophthalmology, University of Paris Est-Cr\u0026eacute;teil, Cr\u0026eacute;teil, France);\u0026nbsp;Ignacio\u0026nbsp;Ares (OD-OS GmbH, Germany); Caroline Bormann (Universit\u0026auml;tsaugenklinik Leipzig, Germany); Luis Cordov\u0026eacute;s Dorta (Tenerife, Spain); Per Heuvels (Augen\u0026auml;rzte Niederelbe, Cuxhaven, Germany); Yoko Miura (Institute of Biomedical Optics, Department of Ophthalmology, University of L\u0026uuml;beck, Germany); Javier Montero Hernandez (General University Hospital of Valencia, Spain); Giuseppe Querques (Department of Ophthalmology , University Vita-Salute , IRCCS San Raffaele Scientific Institute, Italy); Alejandro Rius Filloy (Clinica Oftalologia Tarragona, Spain); Jos\u0026eacute; Antonio Roca Fernandez (Universidad Peruana Cayetano Heredia, Universidad Nacional Federico Villarreal, Peru); Jose Fernandez Vigo (M\u0026eacute;dico especialista en Oftalmolog\u0026iacute;a. Dpto de Retina, Hospital Cl\u0026iacute;nico San Carlos, Madrid , Centro Internacional de Oftalmolog\u0026iacute;a Avanzada, Madrid, Spain); Martin Ziegler \u0026nbsp;(Augenzentrum am St. Franziskus-Hospital, Germany); Focke Ziemmssen (Universit\u0026auml;tsaugenklinik Leipzig, Germany); Pradeep Prasad (Stein Eye Institute, Geffen School of medicine, UCLA, USA)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNational Eye Institute. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. \u003cem\u003eOphthalmology\u003c/em\u003e. 1991;98(5 Suppl):766-785.\u003c/li\u003e\n\u003cli\u003evan Dijk HW, Verbraak FD, Kok PHB, et al. 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Subthreshold Compared with Threshold Macular Photocoagulation for Diabetic Macular Edema: A Systematic Review and Meta-Analysis. \u003cem\u003eOphthalmology Retina\u003c/em\u003e. Published online October 5, 2023. doi:10.1016/j.oret.2023.09.022\u003c/li\u003e\n\u003cli\u003eFriberg TR, Karatza EC. The treatment of macular disease using a micropulsed and continuous wave 810-nm diode laser. \u003cem\u003eOphthalmology\u003c/em\u003e. 1997;104(12):2030-2038. doi:10.1016/s0161-6420(97)30061-x\u003c/li\u003e\n\u003cli\u003eLavinsky D, Sramek C, Wang J, et al. SUBVISIBLE RETINAL LASER THERAPY: Titration Algorithm and Tissue Response. \u003cem\u003eRetina\u003c/em\u003e. 2014;34(1):87-97. doi:10.1097/IAE.0b013e3182993edc\u003c/li\u003e\n\u003cli\u003eScholz P, Altay L, Fauser S. A Review of Subthreshold Micropulse Laser for Treatment of Macular Disorders. \u003cem\u003eAdv Ther\u003c/em\u003e. 2017;34(7):1528-1555. doi:10.1007/s12325-017-0559-y\u003c/li\u003e\n\u003cli\u003eLavinsky D, Palanker D. Nondamaging photothermal therapy for the retina: initial clinical experience with chronic central serous retinopathy. \u003cem\u003eRetina\u003c/em\u003e. 2015;35(2):213-222.\u003c/li\u003e\n\u003cli\u003eWu Z, Wang H, An J. Comparison of the efficacy and safety of subthreshold micropulse laser with photodynamic therapy for the treatment of chronic central serous chorioretinopathy: A meta-analysis. \u003cem\u003eMedicine (Baltimore)\u003c/em\u003e. 2021;100(17):e25722. doi:10.1097/MD.0000000000025722\u003c/li\u003e\n\u003cli\u003eChhablani J, Alshareef R, Kim DT, Narayanan R, Goud A, Mathai A. Comparison of different settings for yellow subthreshold laser treatment in diabetic macular edema. \u003cem\u003eBMC Ophthalmology\u003c/em\u003e. 2018;18(1). doi:10.1186/s12886-018-0841-z\u003c/li\u003e\n\u003cli\u003eBeniwal A, Shaikh N, Chawla R, Azad SV, Kumar V, Vohra R. Comparison of two protocols of subthreshold micropulse yellow laser treatment for non-resolving central serous chorioretinopathy. \u003cem\u003eIndian J Ophthalmol\u003c/em\u003e. 2022;70(9):3341-3345. doi:10.4103/ijo.IJO_228_22\u003c/li\u003e\n\u003cli\u003eDonati MC, Murro V, Mucciolo DP, et al. Subthreshold yellow micropulse laser for treatment of diabetic macular edema: Comparison between fixed and variable treatment regimen. \u003cem\u003eEur J Ophthalmol\u003c/em\u003e. Published online April 14, 2020:1120672120915169. doi:10.1177/1120672120915169\u003c/li\u003e\n\u003cli\u003eKeunen JEE, Battaglia-Parodi M, Vujosevic S, Luttrull JK. International Retinal Laser Society Guidelines For Subthreshold Laser Treatment. \u003cem\u003eTrans Vis Sci Tech\u003c/em\u003e. 2020;9(9):15. doi:10.1167/tvst.9.9.15\u003c/li\u003e\n\u003cli\u003eChhablani J, SOLS (Subthreshold Laser Ophthalmic Society) writing committee, Chhablani J, et al. Subthreshold laser therapy guidelines for retinal diseases. \u003cem\u003eEye\u003c/em\u003e. Published online June 23, 2022. doi:10.1038/s41433-022-02136-w\u003c/li\u003e\n\u003cli\u003eGimond M. \u003cem\u003eChapter 11 Point Pattern Analysis | Intro to GIS and Spatial Analysis\u003c/em\u003e.; 2023. Accessed October 12, 2023. https://mgimond.github.io/Spatial/chp11_0.html\u003c/li\u003e\n\u003cli\u003eMatplotlib \u0026mdash; Visualization with Python. Published 2023. Accessed October 12, 2023. https://matplotlib.org/\u003c/li\u003e\n\u003cli\u003eStarnawska A, Schneider U, Hasler P. Vergleich der Laserbehandlung mit einem computergest\u0026uuml;tzten Lasersystem durch einen erfahrenen versus einen unerfahrenen behandelnden Arzt. \u003cem\u003eKlinische Monatsbl\u0026auml;tter f\u0026uuml;r Augenheilkunde\u003c/em\u003e. 2012;229(12):1223-1226. doi:10.1055/s-0032-1327904\u003c/li\u003e\n\u003cli\u003eOber MD, Kernt M, Cortes MA, Kozak I. Time required for navigated macular laser photocoagulation treatment with the Navilas\u0026reg;. \u003cem\u003eGraefe\u0026rsquo;s Archive for Clinical and Experimental Ophthalmology\u003c/em\u003e. 2013;251(4):1049-1053. doi:10.1007/s00417-012-2119-0\u003c/li\u003e\n\u003cli\u003eLavinsky D, Cardillo JA, Melo LAS, Dare A, Farah ME, Belfort R. Randomized clinical trial evaluating mETDRS versus normal or high-density micropulse photocoagulation for diabetic macular edema. \u003cem\u003eInvest Ophthalmol Vis Sci\u003c/em\u003e. 2011;52(7):4314-4323. doi:10.1167/iovs.10-6828\u003c/li\u003e\n\u003cli\u003eAlharif EMA, Taha HNE din, Rashed MA. Comparative study between subthreshold (micropulse) laser direct application to the edematous macula versus direct application to the peripheral healthy retina in the treatment of diabetic macular edema. \u003cem\u003eAl-Azhar International Medical Journal\u003c/em\u003e. 2023;4(5). doi:10.58675/2682-339X.1800\u003c/li\u003e\n\u003cli\u003ePovažay B, Brinkmann R, Stoller M, Kessler R. Selective Retina Therapy. In: Bille JF, ed. \u003cem\u003eHigh Resolution Imaging in Microscopy and Ophthalmology\u003c/em\u003e. Springer International Publishing; 2019:237-259. doi:10.1007/978-3-030-16638-0_11\u003c/li\u003e\n\u003cli\u003eChehade L, Chidlow G, Wood J, Casson RJ. Short-pulse duration retinal lasers: a review. \u003cem\u003eClinical \u0026amp; Experimental Ophthalmology\u003c/em\u003e. 2016;44(8):714-721. doi:10.1111/ceo.12754\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4445582/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4445582/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo investigate the variability in subthreshold laser treatment plans for patients with diabetic macular edema or central serous chorioretinopathy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eDiagnostic images from 20 patients were utilized, and 25 retina specialists generated subthreshold treatment plans along with a self-rated experience level. Evaluation comprised of i)Area Variability(AV): quantifies the consensus regarding the covered area and is the difference between the areas planned by 75% and 25% of the participants ii)mean Centroid Distance(CD): level of agreement on the localization of a treatment. Subgroup analysis investigated the impact of participants' experience levels, utilizing the Mann-Whitney-Wilcoxon test.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe predominant plan style is a targeted treatment approach(92%) and avoidance of subfoveal region(89%). Mean CD is 71.0\u0026thinsp;\u0026plusmn;\u0026thinsp;37.5 pixels (\u0026asymp;half disc diameter) and mean AV is 9.8%\u0026plusmn;8.9%. A slight difference is observed between the 50%-75% areas, but a notable distinction exists between the 25%-50% areas. Subgroup analysis revealed CD and AV value of 75.9 pixels and 24% in the lower experience level group as opposed to 55.9 pixels and 8.6% in the higher experience level group.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThere is significant variability in treatment planning which reduces with increased experience of retina specialists. While consensus is observed around focal points, differences in the surrounding extents persist.\u003c/p\u003e","manuscriptTitle":"Variability of Thermal Subthreshold Retinal Laser Treatment Plans","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-07 19:01:24","doi":"10.21203/rs.3.rs-4445582/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-02T04:15:06+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-25T01:30:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"73295363311153464595656042360319990047","date":"2024-07-24T12:40:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-28T12:57:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"169290146457564528562603317492634553878","date":"2024-06-17T09:09:59+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-04T13:16:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-04T13:05:22+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-05-29T10:29:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-23T05:04:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-05-19T20:30:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"877ce915-d4b5-4785-8352-81d755fef0d7","owner":[],"postedDate":"June 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-07T15:59:28+00:00","versionOfRecord":{"articleIdentity":"rs-4445582","link":"https://doi.org/10.1038/s41598-024-73763-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-09-30 15:57:04","publishedOnDateReadable":"September 30th, 2024"},"versionCreatedAt":"2024-06-07 19:01:24","video":"","vorDoi":"10.1038/s41598-024-73763-4","vorDoiUrl":"https://doi.org/10.1038/s41598-024-73763-4","workflowStages":[]},"version":"v1","identity":"rs-4445582","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4445582","identity":"rs-4445582","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}