Low Luminance Mobility Test

Abstract

The present disclosure relates to a system and method for testing functional vision of a subject that utilizes multiple obstacle courses, multiple contrast levels of the obstacle courses, multiple illuminances, video recordings, and a robust scoring algorithm to assess the mobility of the subject.

Description

[Technical field]

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 145,228, filed February 3, 2021, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to functional vision testing that (1) measures the level of visual impairment cross-sectionally and longitudinally in a cohort, and (2) with or without therapeutic intervention. [Background technology]

[0003] Various forms of mobility testing or maze testing have been used for many years as functional efficacy measures and, for at least one test variant, as endpoints in US FDA-approved clinical trials, particularly in patients with inherited retinal dystrophies (IRDs), e.g., Leber congenital retinal dystrophy type 2 with RPE65 mutations, and other IRDs. The use of mobility testing and maze testing in retinitis pigmentosa (RP) in the broader sense has not yet been formally validated. Mobility as a functional task encompasses multiple visual functions, including contrast sensitivity, visual field, depth perception, and visual acuity. A maze navigation test, the Multi-Luminance Mobility Test (MLMT), has been used successfully as the primary endpoint in a clinical trial of gene therapy for severely visually impaired patients with a retinal degenerative disease (Leber congenital amaurosis type 2 with RPE65 gene mutations). Although some parameters of the traditional test have been validated, insufficient details are available to accurately reproduce and test the most important determinants in the RP population, namely, contrast and luminance changes, and the specific settings of the maze.

[0004] In the absence of validated, regulatory approved mobility / maze tests for a wide range of retinal dystrophies beyond those in patients with RPE65 mutations, there is a significant unmet need to accurately measure functional outcomes in subjects with retinal degenerative diseases. Summary of the Invention

[0005] The present disclosure provides systems and methods for testing a subject's functional vision. Typically, the subject is asked to move a pre-printed pattern in a room illuminated with an intended illumination level.

[0006] In one aspect, the disclosure provides a method of testing functional visual acuity of a subject, the method including: (a) selecting a first course from a plurality of courses, each course having a grid of segments including a start point, at least one turn, at least one obstacle, and an end point, the grid of segments being pre-printed on a global map of the subject, each of the plurality of segments including signage, the signage forming a path for the subject to walk, at least one of the segments including at least one obstacle, the at least one obstacle including a physical object that requires avoidance, circumvention, crossing, and / or evasion; and (b) selecting a first illuminance from 13 levels of illuminance, the 13 levels of illuminance ranging from about 0.12 lux to about 500 lux, each illuminance being approximately 0.3 log units (0.3 log (c) illuminating the first course with a first illuminance; (d) video recording a first movement of the subject along the first course beginning at a starting point; and (e) determining a first walking speed of the subject based on the first movement.

[0007] In some embodiments, the method further includes (f) selecting a second course from the plurality of courses, the second course different from the first course; (g) selecting a second illuminance from the thirteen illuminance levels, the second illuminance different from the first illuminance; (h) illuminating the second course at the second illuminance; (i) video recording a second movement of the subject on the second course beginning at a starting point; (j) determining a second walking speed of the subject based on the second movement; (k) creating a mobility curve illustrating the first and second walking speeds as a function of illuminance; and (l) determining a critical illuminance (CIL) for the subject based on the mobility curve.

[0008] In some embodiments, the method further comprises determining the time it takes the subject to complete each course.

[0009] In some embodiments, the method further determines the number of major errors as the subject completes each course, each major error being selected from among stepping into an area outside the course, skipping one sign, moving at least one obstacle more than four inches, misidentifying the height of at least one obstacle, stepping more than half a foot into a black square, and misidentifying the end of the path but successfully completing the path.

[0010] In some embodiments, each walking speed is calculated by the following formula: walking speed=[(24-number of major errors*2)*60] / time to complete each course, where the time to complete each course has units of seconds.

[0011] In some embodiments, the walking speed is zero if the subject makes a significant error, where a significant error is selected from among skipping two or more legs on the path, being lost for at least five seconds, and misidentifying the height of all three raised obstacles in the path.

[0012] In some embodiments, the subject has normal functional vision.

[0013] In some embodiments, the subject is suspected of having a vision impairment or deficiency in one or both eyes based on other functional assessments, such as visual acuity.

[0014] In some embodiments, the subject is a candidate for a local or systemic ophthalmic treatment.

[0015] In some embodiments, the local or systemic ophthalmic treatment is an ophthalmic treatment, surgery, gene therapy, or a combination thereof, for one or both eyes.

[0016] In some embodiments, the ophthalmic treatment, surgery, or gene therapy is for the treatment of retinitis pigmentosa (RP), Leber's congenital amaurosis (LCA), Stargardt's disease, Usher syndrome, choroideremia, rod-cone-rod dystrophic ciliopathies, mitochondrial disorders, progressive retinal atrophy, retinal degenerative diseases, age-related macular degeneration (AMD), wet AMD, dry AMD, geographic atrophy, familial or acquired maculopathy, retinal photoreceptor diseases, retinal pigment epithelial diseases, diabetic retinopathy, cystoid macular edema, uveitis, retinal detachment, traumatic retinal damage, iatrogenic retinal damage, macular hole, macular telangiectasia, ganglion cell disease, optic nerve cell disease, glaucoma, optic nerve cell disease, ischemic retinal disease, retinopathy of prematurity, retinal vascular occlusion, familial aortic aneurysm, retinal vascular disease, ocular vascular disease, vascular disease, or ischemic optic neuropathy.

[0017] In some embodiments, the method is performed before the subject undergoes a systemic or local ophthalmic treatment, eg, an ophthalmic treatment, surgery, and / or gene therapy.

[0018] In some embodiments, the method is performed while the subject is undergoing systemic or local ophthalmic treatment, eg, ophthalmic treatment, surgery, and / or gene therapy.

[0019] In some embodiments, the method is performed after the subject has undergone a systemic or local ophthalmic treatment, eg, an ophthalmic treatment, surgery, and / or gene therapy.

[0020] In some embodiments, the method is repeated over the subject's recovery period to observe improvement or deterioration associated with systemic or local ophthalmic treatment, e.g., ophthalmic treatment, surgery, and / or gene therapy.

[0021] In some embodiments, each course includes from 1 to about 15 turns.

[0022] In some embodiments, each course includes between 7 and 9 turns.

[0023] In some embodiments, each course includes from 1 to about 15 obstacles.

[0024] In some embodiments, the at least one obstacle is selected from among an object disposed within the path, an object disposed adjacent to the path, a raised section, a section having a color indicating an obstacle, and an edge of a step.

[0025] In some embodiments, each course consists of three obstacles in the path and seven obstacles adjacent to the path.

[0026] In some embodiments, each course route consists of 22 to 24 segments.

[0027] In some embodiments, the plurality of courses comprises at least 12 courses.

[0028] In some embodiments, the method further includes instructing a first grader and a second grader to view each video, each grader determining the time to complete each course, the number of major errors the subject made when completing each course, and each walking speed, comparing the walking speed determined by the first grader with the walking speed determined by the second grader, and averaging the walking speeds determined by the first and second graders if the difference in the time to complete each course by the first and second graders is within 5 seconds. In some embodiments, the CIL for subjects with normal functional vision is about 0.12 lux.

[0029] In some embodiments, the method further comprises determining a maximum walking speed (MSS) of the subject, where the MSS is an average of the walking speeds determined for illumination at or above the CIL.

[0030] In some embodiments, the MSS for a subject with normal functional vision is about 61 steps per minute (spm).

[0031] In some embodiments, if the subject's CIL is 1 lux or less, the method further comprises selecting a course having a Weber contrast value of about 10% to about 50%.

[0032] In some embodiments, the Weber contrast value is about 10%, about 25%, about 30%, or about 50%.

[0033] In one aspect, the disclosure provides a method of testing functional visual acuity of a subject, the method including: (a) selecting a first course from a plurality of courses, each course having a grid of segments including a start point, at least one turn, at least one obstacle, and an end point, the grid of segments being pre-printed on a global map of the subject, each of the plurality of segments including a directional arrow, the directional arrow forming a path for the subject to walk, at least one of the segments including at least one obstacle, the at least one obstacle including a physical object that needs to be avoided, circumvented, traversed, and / or evaded; (b) selecting a first illuminance from a plurality of illuminances; (c) illuminating the first course with the first illuminance; and (d) illuminating the first course starting at the start point. (e) determining a first walking speed of the subject based on the first movement; (f) selecting a second course from the plurality of courses, the second course different from the first course; (g) selecting a second illuminance from the plurality of illuminances, the second illuminance different from the first illuminance; (h) illuminating the second course at a second illuminance; (i) video recording a second movement of the subject on the second course beginning at a starting point; (j) determining a second walking speed of the subject based on the second movement; (k) generating a mobility curve showing the first and second walking speeds as a function of illuminance; and (l) determining a critical illuminance (CIL) for the subject based on the mobility curve, below which the walking speed of the subject significantly decreases.

[0034] In some embodiments, the multiple courses are characterized by multiple Weber contrast values.

[0035] In some embodiments, if the subject's CIL is 1 lux or less, the method further comprises selecting a course having a Weber contrast value of about 10% to about 50%.

[0036] In one aspect, the present disclosure provides a system for testing functional visual acuity of a subject, the system comprising: (a) a plurality of courses configured to facilitate performance of the test, each course having a grid of segments including a start point, at least one turn, at least one obstacle, and an end point, the grid of segments being pre-printed on a global map of the subject, each of the plurality of segments including directional arrows, the directional arrows forming a path for the subject to walk, at least one of the segments including at least one obstacle, the at least one obstacle including a physical object that requires avoidance, circumvention, crossing, and / or evasion; (b) a plurality of lights configured to control illuminance; (c) a luminance meter configured to determine illuminance; (d) a video recorder configured to record the subject's movements as the subject walks on the courses; and (e) a computational process configured to determine a Critical Illuminance (CIL) for the subject.

[0037] In one aspect, the disclosure provides a method of monitoring the progress of a subject undergoing or having undergone a topical or systemic ophthalmic treatment, the method comprising: (a) determining a first CIL of the subject at a first time point using the method described above; (b) determining a second CIL of the subject at a second time point using the method described above, the second time point being later than the first time point; (c) comparing the first CIL to the second CIL; and (d) determining that the subject is (i) in an improved state if the second CIL is significantly less than the first CIL, or (ii) in an unimproved state or with increasing visual impairment if the second CIL is the same as or greater than the first CIL.

[0038] In one aspect, the disclosure provides a method of monitoring the progress of a subject undergoing or having undergone a topical or systemic ophthalmic treatment, the method comprising: (a) determining a first MSS of the subject at a first time point using the method described above; (b) determining a second MSS of the subject at a second time point using the method described above, the second time point being later than the first time point; (c) comparing the first MSS to the second MSS; and (d) determining the subject to be in an improved state (i) if the second MSS is significantly greater than the first MSS, or in an unimproved or increasingly visually impaired state (ii) if the second MSS is the same as or lower than the first MSS.

[0039] In some embodiments of the methods and systems described herein, the subject is a human. [Brief description of the drawings]

[0040] [Figure 1A] FIG. 1A shows the high-contrast arrow pattern, high-contrast obstacles, lighting and room set-up for mobility testing. [Figure 1B] FIG. 1B shows the computer panel that controls the lighting. [Diagram 2] 2 shows a flow chart illustrating the process for scoring a subject performing a mobility test of the present disclosure. In the event that the first and second scorers disagree, an adjudication process is provided. [Diagram 3] Figure 3 shows a video trial from the view point of the grader. [Figure 4] FIG. 4 shows an example of a subject's R-curve, with the vertical dotted line intersecting the x-axis representing the critical illuminance (CIL), the light level below which the subject's function deteriorates significantly. [Diagram 5]Figure 5 shows a cross-visit comparison of CIL scores between RP and visually normal (VN) subjects, where circles are RP subjects, triangles are VN subjects, and the solid line is the line of equality. "LLMT" means low luminance mobility test. [Figure 6A] Figure 6A shows the change in mobility CIL scores across two visits for RP subjects, with the middle line representing the mean and the upper and lower lines representing two standard deviations from the mean. [Figure 6B] Figure 6B shows the change in mobility CIL scores across the two visits for VN subjects, with the middle line representing the mean and the upper and lower lines representing two standard deviations from the mean. [Figure 7] FIG. 7 shows the relationship between CIL score and peak log contrast sensitivity (CS). [Figure 8] FIG. 8 shows the relationship between maximum walking speed (MSS) and peak logCS. [Figure 9] FIG. 9 shows the relationship between CIL and logarithm of the visual field. [Figure 10A] FIG. 10A shows the margin of error (LOA) of the assessment of mobility images between grader 1 (G1) and grader 2 (G2). [Figure 10B] FIG. 10B shows the LOA of the assessment of mobility images between G1 and G2 using a Bland-Altman graph. [Figure 11A] FIG. 11A shows the LOA of the mobility video assessment between G2 and grader 4 (G4). [Figure 11B] FIG. 11B shows the LOA of the assessment of mobility images between G2 and G4 using the Bland-Altman graph. [Figure 12A] FIG. 12A shows the consistency of G1 when assessing the same video twice. [Figure 12B] Figure 12B shows the Bland-Altman graph of G1's consistency when rating the same video twice. [Figure 13A] FIG. 13A shows the consistency of G2 when assessing the same video twice. [Figure 13B]Figure 13B shows the Bland-Altman graph of G2's consistency when rating the same video twice. [Figure 14A] Figure 14A shows the consistency of G4 when rating the same video twice. [Figure 14B] Figure 14B shows the Bland-Altman graph of the consistency of G4 when rating the same video twice. [Figure 15] Figure 15 shows the evaluation worksheet for validation study subjects with an average time trial of approximately 40 seconds and corresponding walking speeds of 32 steps / minute and 42 steps / minute (SPM). [Figure 16] FIG. 16 is a schematic diagram of a low-contrast course according to some embodiments. The yellow pentagonal symbols represent small waist-high traffic signs with a get off sign. The grey circle represents a trash can obstacle (e.g., a small plastic oval bin). The red stop sign is like a yield sign. The open circle represents two white traffic cones (no contrast). The raised square represents a lightly weighted Styrofoam square obstacle. The black square represents a hole in the ground with a large penalty if the foot is not completely within the square. All printed locations are adjacent to arrows. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] definition All definitions defined and used herein should be understood to supersede dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0042] The indefinite articles "a" and "an," as used in the specification and claims, unless clearly indicated to the contrary, should be understood to mean "at least one." All ranges cited herein are inclusive.

[0043] The term "and / or" as used herein and in the claims should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., to mean "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and / or" clause, whether related to the specifically identified elements or not. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," may refer in one embodiment to A only (optionally including elements other than B), in another embodiment to B only (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), etc.

[0044] As used herein and in the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be construed to be inclusive, i.e., including at least one, but not more than one, of a number or list of elements, and optionally including additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of," "exactly one of," or, when used in the claims, "consisting of," refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall be construed to indicate exclusive alternatives (i.e., "one or the other, but not both") only when preceded by an exclusive term, such as "either," "either one," "only one of," or "exactly one of." As used in the claims, "consisting essentially of" shall have its ordinary meaning as used in the field of patent law.

[0045] As used herein and in the claims, the phrase "at least one" referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows that elements other than those specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether or not related to the specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") may refer in one embodiment to at least one, optionally more than one, A, where B is absent (and optionally including elements other than B); in another embodiment to at least one, optionally including one or more B, where A is absent (and optionally including elements other than A); in yet another embodiment to at least one, optionally including one or more A, and at least one, optionally including one or more B (and optionally including other elements);

[0046] As in the specification above, in the claims, all transitional phrases such as "comprises," "includes," "carries," "has," "including," "involves," "holds," "comprises," and the like, shall be understood to be open-ended, i.e., to mean including, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as provided for in the U.S. Patent Office Manual of Patent Examining Procedure § 2111.03.

[0047] As used throughout this specification and claims, the terms "substantially," "approximately," and "about" generally mean plus or minus 10% of the stated value, e.g., about 100 includes 90 to 110.

[0048] In this specification, the terms "illuminance" and "light level" are used interchangeably.

[0049] As used herein, the term "significantly" means statistically different using descriptive statistics, where the difference is subject to any statistical analysis with a p-value of less than 0.05, preferably less than 0.01, more preferably less than 0.001. In some embodiments, the term "significantly" means two standard deviations below the mean of the plateau of the curve.

[0050] As used herein, the term "maximum walking speed", abbreviated as MSS, refers to the average fastest repeatable walking speed based on a subject's walking speed at or above the CIL.

[0051] As used herein, the terms "complete a route" and "complete a course" are used interchangeably.

[0052] Functional vision is how a person functions or performs in vision-related activities. Such activities include reading, orientation, movement, navigation, visual communication, visual vocational skills, etc. Functional vision is therefore a behavioral outcome of visual function. Changes in functional vision (e.g., vision improvement, correction, rehabilitation) can be ascertained by the objective performance of controlled tasks that require vision. Task performance is scored based on time and error rate. Patient Reported Outcome is a measure of change in daily activities or patient symptoms, for example, reflected by daily performance requiring vision or the severity of vision impairment.

[0053] Utilizing maze patterns and obstacles, the MLMT has been used to assess functional vision in patients with inherited retinal dystrophies. See, for example, Chung et al., "Novel mobility test to assess functional vision in patients with inherited retinal dystrophies," Clin. Exp. Ophthalmol. 2018,46,247-259, US 10448823. The MLMT has drawbacks such as a limited number of lighting levels, uneven variation in high and low lighting levels, and an evaluation process in measuring absolute pass / fail performance that may be an inconsistent indicator of functional vision. Furthermore, when performing the MLMT, the "fail" zones may be very challenging for patients as they may stumble in illumination that is too low for the subject, leading to frustration that is known to have a significant impact on the subject's further test performance and variability when evaluating. All of the above-mentioned characteristics of MLMTs result in measurement ceiling effects that either meaningfully limit the patient population or disease that can be assessed or lead to imprecise or highly variable assessments.

[0054] The present disclosure provides an improved mobility test compared to MLMT. The mobility test described herein and MLMT differ in one or more aspects of extending illumination levels to much lower lux, evenly distributing illumination levels in steps of about 0.3 log units, and a more reliable and objective scoring algorithm that measures low-light mobility function for a very wide range of disease severity. In some embodiments, the mobility test described herein includes a low-contrast version to extend the sensitivity of the test.

[0055] In one aspect, the present disclosure provides a system for testing the functional visual acuity of a subject, the system comprising: (a) a plurality of courses configured to facilitate the administration of the test; (b) a plurality of lights configured to control illuminance; (c) a luminometer configured to determine illuminance; (d) a video recorder configured to record the subject's movements as the subject walks through the courses; and (e) a computational process configured to determine the subject's critical illuminance (CIL). The CIL is the lighting level at which a lower lighting level significantly reduces the subject's function. In some embodiments, the CIL is the lighting level at which a lower light level will reduce the walking speed of the subject by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%.

[0056] In some embodiments, the computational process is further configured to determine a maximum walking speed (MSS) of the subject. The computational process may be executed on a computing device.

[0057] This course can be used at a single assessment site or the same course set up can be used at multiple sites.

[0058] Each course is pre-defined. In some embodiments, each course has a grid of segments including a start point, at least one turn, at least one obstacle, and an end point, the grid of segments being pre-printed on an overall map for the subject, each of the segments including directional arrows that form a path for the subject to walk, at least one of the segments including at least one obstacle, the at least one obstacle including a physical object that needs to be avoided, circumvented, crossed, and / or evaded.

[0059] In some embodiments, the multiple courses can have different contrast levels.

[0060] Subjects travelling along each course under predetermined lighting conditions are instructed to start at the beginning point, follow the arrows to avoid obstacles, and exit the course at the end point.

[0061] In some embodiments, each course includes from 1 to about 15 turns, e.g., from 3 to 15 turns, from 5 to 12 turns, from 5 to 10 turns, or from 7 to 9 turns, in some embodiments, each course includes from 7 to 9 turns.

[0062] The obstacles allow the grader to measure how well the subject perceives the obstacles. In some embodiments, each course can include 1 to about 15 obstacles. For example, each course can include 8 obstacles, 9 obstacles, 10 obstacles, 11 obstacles, or 12 obstacles. Each obstacle can be selected from among objects located within the path, objects located adjacent to the path, raised sections ("in-path raised obstacles"), sections with a color indicating the obstacle (e.g., a solid black section), and the edge of a step. In some embodiments, each course can consist of 3 obstacles within the path and 7 obstacles adjacent to the path.

[0063] To avoid examiner bias, each course can be pre-printed with obstacles adjacent to the path.

[0064] The obstacles in the path can be placed on the course by the examiner before the start of the test while the subject's eyes are covered or closed (so that the subject does not see the pre-start configuration). In some embodiments, the obstacles in the path can be selected from 1-inch high steps, triangular step obstacles, and 2-inch high steps. Generally, the obstacles in the path are placed in straight sections of the path with at least four directional arrows. Also, the obstacles in the path should not be placed immediately after a corner arrow, because the subject will have time to find a straight path and may see the next obstacle. For example, a low step obstacle (e.g., a 1-inch high step) can be placed on the third arrow in a straight section of five or more arrows, a triangular step obstacle can be placed on the third arrow in a straight section of four or more arrows, and a high step obstacle (e.g., a 2-inch high step) can be placed on the third or fourth arrow in a straight section of six or more arrows.

[0065] Each course has at least one feature that distinguishes it from the other courses, but all courses can have the same three obstacles arranged along the path in different configurations. Having all courses have the same features in this way is important for repeatability and consistency of the test. The different configurations are used to avoid memorization.

[0066] In some embodiments, the path of each course can have two or three straight sections, each with four or more arrows. These long straight sections allow subjects with limited vision time to find obstacles on the section.

[0067] In some embodiments, each path can have between 22 and 24 arrows, for example, 22 arrows, 23 arrows, or 24 arrows.

[0068] In some embodiments, the plurality of courses includes at least 12 courses, at least 13 courses, at least 14 courses, at least 15 courses, at least 16 courses, at least 17 courses, at least 18 courses, at least 19 courses, or at least 20 courses.

[0069] In some embodiments, the plurality of lights may comprise light emitting diodes (LEDs). For example, the plurality of lights may comprise eight theater-style LED panel lights. Illuminance may be controlled with a large LED panel that provides indirect lighting, e.g., LED panels directed toward the ceiling for indirect reflection to eliminate shadows. Each panel may be programmed with a computer program (e.g., see FIG. 1B) for consistent color and brightness. Each illuminance may be verified with a light meter placed at at least three locations on the maze pattern to ensure that the luminance is within 10% of the expected level and is uniform throughout the room. Testing may be performed by staff trained in low vision evaluation, such as an optometrist, in an environment where the test items can be controlled to perform a functional evaluation.

[0070] In some embodiments, the plurality of lights comprises six or more panels of LEDs utilizing a broad wavelength spectrum.

[0071] Multiple lights can be spaced around the perimeter of the end of the course to create uniform illumination, as confirmed by repeated lux meter measurements over time.

[0072] In some embodiments, a plurality of lights are interfaced with a computer and each illuminance, including an even distribution of color temperature and luminance, is programmed with established preset settings.

[0073] In some embodiments, the lights are programmed in uniform increments, with each setting being 0.3 log steps higher or lower than the previous setting.

[0074] In some embodiments, the light settings have 13 or more unique increments covering a lighting range from an extremely dim room to a bright indoor office.

[0075] In some embodiments, multiple lights in the form of LED panels with metal flanges on each side are individually positioned in some cases with the flanges partially open, or in other cases more widely open, and the panels are then carefully aimed at the upper wall area and ceiling to create indirect and evenly distributed reflected lighting, thereby reducing or eliminating shadows over the course.

[0076] In some embodiments, the illuminance during every test trial is checked in a minimum of three locations using a luminometer placed on the surface of the course.

[0077] Each illuminance level represents a 0.3 log unit change in illuminance, or half the previous illuminance level in lux (a factor of 2). The 0.3 log levels are selected to resemble clinically meaningful visual acuity changes (e.g., 3 lines of visual acuity or 0.3 logMAR, which are conservative estimates of clinically meaningful changes) and to provide a practically noticeable change in illumination. There are 13 light levels available for testing, ranging from 0.12 lux to 500 lux.

[0078] The determination of the CIL is explained in further detail below.

[0079] The present disclosure provides a method for testing functional visual acuity of a subject, the method including: (a) selecting a first course from the plurality of courses described above; (b) selecting a first illuminance from 13 illuminance levels, where the 13 illuminance levels range from about 0.12 lux to about 500 lux, each illuminance level being spaced from an adjacent illuminance level by about 0.3 log units; (c) illuminating the first course at the first illuminance; (d) video-recording a first movement of the subject on the first course starting from a starting point; and (e) determining a first walking speed of the subject based on the first movement.

[0080] The first course can be selected randomly from a number of courses. In some embodiments, a dry run can be conducted on the subject to select the first illuminance. In the dry run, a high illuminance (e.g., about 250 lux) and course that does not cause glare is used, rules for running the course are introduced, and the time to complete the course is measured. Then, one or more lower illuminances are introduced. The subject is explained the illuminance at which he or she begins to have difficulty and can perform some walking at the lower illuminance to test his or her ability (e.g., estimate the preliminary CIL). Then, a level at which the subject can move at a faster speed just above the preliminary CIL is selected, and the new course is used, which is videotaped and conducted exactly as the test will be conducted, and a practice "p" is recorded on the sheet. After allowing the subject to dark adapt for about 20-30 minutes, the test begins with a light level that is 2-3 steps lower than the preliminary CIL. Furthermore, the test begins with a low illumination level, and the illumination level is gradually increased. The subject does not need to fail the start test, but the initial low dark level may be the failure level (i.e., the level at which the subject makes a major error). The requirement is that the starting light level (i.e., the first light level) is at least two light levels below the preliminary CIL and the subject is significantly slower (e.g., more than 5 seconds slower) than the walking speed recorded at the preliminary CIL. The light level is then increased and each trial is conducted with a different course configuration. This process continues until at least three trials have been conducted and each course is completed in less than 5 seconds. Subjects may gain confidence with repeated trials at higher light levels (above the CIL) and gradually increase their speed. In such cases, trials close to the preliminary CIL should be retested to ensure that light level is the only factor causing poor performance.

[0081] Thus, in some embodiments, the method further includes (f) selecting a second course from the plurality of courses, the second course different from the first course; (g) selecting a second illuminance from the 13 levels of illuminance, the second illuminance different from the first illuminance; (h) illuminating the second course at the second illuminance; (i) video recording a second movement of the subject on the second course beginning at the starting point; and (j) determining a second walking speed of the subject based on the second movement.

[0082] In some embodiments, the second illuminance is lower than the first illuminance. In some embodiments, the second illuminance is higher than the first illuminance. The subject can be tested on any number of additional courses necessary to create a mobility curve showing walking speed as a function of illuminance. For example, the subject can be tested on 4 courses to 8 courses, for example, 3 courses, 4 courses, 5 courses, 6 courses, 7 courses, or 8 courses.

[0083] The video recordings are sent to one or more raters for blind scoring, who determine (a) the time it takes the subject to complete each course, (b) the number of major errors the subject made as he or she completed each course, (c) whether the subject made any major errors, and / or (d) the walking speed for each course.

[0084] In some embodiments, each major error is selected from placing the majority of the foot in an area outside the path, skipping a directional arrow, moving at least one obstacle more than 4 inches, misjudging the height of at least one obstacle, placing more than half a foot in a solid square (because the solid square is not part of the path), and misjudging the end of the path but successfully completing the path. In some embodiments, the subject misjudges the height of an obstacle when the subject trips over the obstacle or when the subject lifts the foot too high relative to the obstacle.

[0085] Each walking speed can be calculated using the following formula: Walking speed = [(24-number of major errors*2)*60] / time to complete each course wherein the time to complete each course is in seconds. If there is more than one grader, the method further includes comparing the walking speed determined by the first grader with the walking speed determined by the second grader, and averaging the walking speeds determined by the first and second graders if the times to complete each course do not differ by more than 5 seconds by the first and second graders.

[0086] If the subject makes a significant error, the walking speed is set to zero. In some embodiments, a significant error is selected from skipping two or more segments on the path, being lost for at least five seconds, and misjudging the height of all three raised obstacles in the path. In some embodiments, the subject is lost when he or she remains stuck on a segment and appears unable to take the next step.

[0087] A mobility curve is then drawn, showing the walking speed as a function of illuminance. Based on the mobility curve, the method further includes determining the CIL of the subject, below which the walking speed of the subject significantly decreases by 2 standard deviations (SD) from the average walking speed of the tests performed at or above the CIL (or 2 SD from the MSS). This plateau is where the subject performs fairly consistently, and where the subject's speed significantly decreases and errors increase in tests below the performance threshold. The mobility curve can also be used to calculate the MSS of the subject. In some embodiments, the CIL and MSS of a subject with normal functional vision are about 0.12 lux and 61 steps per minute, respectively, when first performed on a high-contrast course. 0.12 lux is the lowest practically usable lighting level. Less than 0.12 lux is technically possible, but makes no medical difference. Therefore, the CIL of a subject with normal functional vision is set to about 0.12 lux.

[0088] In some embodiments, the determination of CIL and / or MSS is based on a scoring algorithm programmed in the R language, originally designed for the functional readout test MNREAD, but modified for the mobility test described herein. The modified programmed scoring algorithm generates a mobility curve from which the CIL and MSS are derived.

[0089] Further performance improvement in mobility testing can be pursued by adding tests at low contrast settings. When the mobility curve is plotted, the CIL is the last point on the plateau before the next functional decline. In contrast, the MLMT determines the sub-threshold (fail) and super-threshold (pass) lighting levels. Tests in the sub-threshold or fail range of the subject are very challenging and emotionally upsetting for the subject (and also have a negative effect on further tests on the same day and subsequent evaluations), and have been found to change considerably as the subject becomes more confident. As shown in the validation study in the Examples section, the testing method disclosed herein, which has most of its presence in the supra-threshold range of the subject, is more consistent. The CIL approach a priori limits the influence of various personal characteristics such as anxiety and risk-taking behavior, which may be a huge improvement in limiting confounding factors for adults who have lifelong anxiety from reduced motor performance due to RP. It also limits outliers due to subject demotivation due to failure.

[0090] The disclosed systems and methods can be used to monitor the progress of subjects undergoing or having undergone local or systemic ophthalmic treatments, such as ophthalmic treatments, surgery, and / or gene therapy, to one or both eyes. In some embodiments, the monitoring method includes: (a) determining a first CIL of the subject at a first time point using the methods described herein; (b) determining a second CIL of the subject at a second time point using the methods described herein, the second time point being later than the first time point; (c) comparing the first CIL to the second CIL; and (d) determining that the subject is (i) in an improved state if the second CIL is significantly less than the first CIL, or (ii) in a non-improved state or with increased visual impairment if the second CIL is equal to or greater than the first CIL.

[0091] In some embodiments, the subject has normal functional vision. In some embodiments, the subject is suspected of having a vision impairment or defect in one or both eyes. In some embodiments, the subject has a retinal or ocular disease affecting the photoreceptors in one or both eyes. In some embodiments, the subject is a candidate for local or systemic ophthalmic treatment, e.g., ophthalmic therapy, surgery, gene therapy, or a combination thereof, in one or both eyes. Ophthalmic treatments, surgery, or gene therapy can be used to treat retinitis pigmentosa (RP), Leber's congenital amaurosis (LCA), Stargardt's disease, Usher syndrome, choroideremia, rod-cone-rod dystrophy, ciliopathy, mitochondrial disorders, progressive retinal atrophy, retinal degenerative diseases, age-related macular degeneration (AMD), wet AMD, dry AMD, geographic atrophy, familial or acquired macular degeneration, retinal photoreceptor diseases, retinal pigment epithelial diseases, diabetic retinopathy, cystoid macular edema, uveitis, retinal detachment, traumatic retinal damage, ectopic retinal damage, macular hole, macular telangiectasia, ganglion cell disease, optic nerve cell disease, glaucoma, optic nerve cell disease, ischemic retinal disease, retinopathy of prematurity, retinal vascular occlusion, familial aneurysm, retinal vascular disease, ocular vascular disease, vascular disease, or ischemic optic neuropathy.

[0092] In some embodiments, the method is performed before the subject undergoes ophthalmic therapy, e.g., ophthalmic treatment, surgery, and / or gene therapy. In some embodiments, the method is performed while the subject is undergoing ophthalmic treatment, surgery, and / or gene therapy. In some embodiments, the method is performed after the subject has undergone ophthalmic treatment, surgery, and / or gene therapy. In some embodiments, the method is repeated over the subject's recovery period to observe improvement or deterioration associated with ophthalmic treatment, surgery, and / or gene therapy. In some embodiments, the subject is a human.

[0093] The methods described herein can be modified to test subjects with less severe ocular or retinal diseases, for example, subjects with a CIL of 1 lux or less. For example, during a preliminary test, the subject's CIL is determined to be 1 lux or less, and the subject is then asked to travel one or more courses with a low Weber contrast value of about 10% to about 50%. In some embodiments, the Weber contrast value is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

[0094] Use of the low-contrast version is believed to eliminate a ceiling effect in the test, when initial pretesting in one or both eyes reveals near-normal performance with the high-contrast version.

[0095] In some embodiments, if the CIL on initial testing with the high contrast version is estimated to be 1 lux or less, a 10% or 25% version is introduced. If the 10% version can be performed at any lighting level, it is selected and testing continues with the 10% contrast version over time. For patients with performance levels from high contrast to 10%, the use of the 25% contrast version can be considered.

[0096] In some embodiments, different versions (eg, 10% and high contrast) can be used to assess the function of each eye.

[0097] In some embodiments, if the 10% version cannot be reliably completed at any level, the 25% contrast version is used at baseline and all subsequent visits.

[0098] While the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those skilled in the art.

[0099] Although various inventive embodiments have been described and illustrated herein, one of ordinary skill in the art can readily envision various other means and / or structures for obtaining one or more of the functions and / or results and / or advantages described herein, and each such variation and / or modification is deemed to be within the scope of the inventive embodiments described herein. More generally, one of ordinary skill in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the particular use or application in which the teachings of the present invention are / are used. One of ordinary skill in the art will recognize many equivalents to the specific inventive embodiments described herein. Thus, the foregoing embodiments are presented by way of example only, and it will be understood that within the scope of the appended claims and their equivalents, the inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. Furthermore, any combination of two or more such features, systems, articles, materials, kits, and / or methods is within the inventive scope of the present disclosure, provided that such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0100] The claims should not be construed as limited to the described order or elements unless specifically stated to that effect. Those skilled in the art will recognize that various changes in form and detail can be made without departing from the spirit and scope of the appended claims. All embodiments that come within the spirit and scope of the following claims and equivalents thereto are claimed.

[0101] Working Example [Table 1]

[0102] Example 1. Low-Luminance Mobility Test (LLMT) Mobility Study Design As part of an ongoing program to develop more sophisticated clinical endpoints to conduct informative registration-based clinical trials in patients with RP, JCyte has developed a proprietary low-luminance / low-contrast mobility test, the LLMT, intended to evaluate subjects with a range of vision impairments. In addition to standardized maze patterns, obstacles, independent and blinded raters, and video recording of the test, the LLMT features 13 levels of light intensity (0.12-500 lux) and, according to some embodiments, a novel and robust scoring paradigm.

[0103] Design modifications were intended to improve assessment across a broad functional range in the studied RP population (not limited to a specific genotype): (1) expanding the range of lighting levels with additional low illuminance to reduce potential ceiling effects, (2) generating equal increments between each lighting level of 0.3 log units (by a factor of 2), (3) creating a more objective scoring and precise algorithm compared to the MLMT described by Chung et al. (2018), and (4) improving sensitivity in less severely impaired subjects with the introduction of 10% and 25% low-contrast arrow patterns.

[0104] The LLMT requires custom lighting, specialized videography, and independent trained scorers. Because it requires very specialized equipment, dedicated space, and consistency of testing, the mobility test was set up in a centralized testing facility separate from the clinical trial facilities (see Figure 1A). The conditions set there are standardized and can be set up in other similar testing facilities to allow testing in many facilities. There are 12 different arrow patterns with varying arrow directions to avoid memorization. In addition, subjects wear special socks with rubber grips to keep their footwear uniform. The lighting is a minimum of six large LED panels facing the ceiling, with indirect lighting to eliminate shadows. Each panel has a movable flange that is carefully set to illuminate the entire maze pattern evenly, and each lighting level is programmed to be of a constant color and brightness using a computer (see Figure 1B). Although the lighting position, flange, and light distribution (color and brightness) of each panel at each level can be flexibly adjusted, the specific settings of the lighting in the LLMT are fairly strict and constant, so in practice this is rarely necessary. Each level is verified with a light meter placed at three points on the maze pattern to ensure the luminance is within 10% of the expected level and consistent throughout the room; the luminance is extremely stable and has rarely had to be reset, typically only when a light panel becomes dislodged for cleaning etc. The test is conducted in an environment where staff trained in low vision assessment, such as optometrists, can provide a reliable functional assessment using elements such as specific lighting with LED panels in specified configurations, the use of 12 specific movement patterns, the use of an optional low contrast version, and the use of a scoring algorithm.

[0105] Each light level represents a 0.3 log unit change in illuminance, or half the previous illuminance in lux (factor 2). The 0.3 log level was chosen because it is similar to a clinically meaningful visual acuity change (e.g., 3 lines of visual acuity or 0.3 logMAR) and also produces a practically noticeable change in lighting. There are 13 light levels available for testing, ranging from 0.12 lux to 500 lux, with corresponding scale scores ranging from -1 to 13 for simple statistical analysis, and with the room lights off (see Table 1 below). Table 1 also shows a comparison of the lighting levels of the MLMT with the increments between each level (approximated from Chung et al. (2018)). Changes over time are primarily represented using the CIL score of this scale, but can also be determined by the MSS as a secondary or complementary measure. [Table 2]

[0106] These data indicate that the LLMT design has a broad and even range of increases in lighting levels, a lighting level that corresponds to an early significant decline in mobility performance (CIL), and a scoring algorithm (see below) that identifies a mean walking speed (MSS) that exceeds the CIL.

[0107] LLMT Scoring The test aims to capture functional performance at each visit across a range of light levels through a series of tests (videotaped) for each subject. The subject-adjusted walking speed is plotted, including speed and accuracy across a range of light levels. There is no pre-set fail time limit, as there is considerable variability in subject age and balance ability. Each subject is compared to their own pre-test baseline performance. Attention is paid to safety, as elderly patients with limited vision often have balance problems. Because the lights are dimmed, subjects are instructed to stop the test at any time if they feel unsafe due to the steps or raised obstacles in each maze.

[0108] Two independent trained raters, certified as experts in orientation and mobility, remotely evaluate the test footage using standardized criteria to assess time and error for each illuminance level tested. A third trained rater is employed when there are discrepancies in scoring, and any results that require some arbitration are evaluated by a supervisor to determine whether the original rater should reassess (e.g., typos, overlooking obvious errors) or whether the task is so difficult that a third evaluation would be beneficial (see Figure 2). Raters are blinded to treatment assignment, illuminance, and time point of assessment (e.g., pre-treatment, post-treatment) (Figure 3). The footage test is blinded to lighting levels by adjusting the camera ISO setting for each test so that the downloaded black-and-white footage appears similarly bright. A printed grid outlining the specific ISO settings for each lighting level is posted in the testing room to allow examiners to efficiently prepare for the test.

[0109] Graders measure the time to complete the maze and tally errors as major or critical based on the scoring criteria. Errors are defined as major (e.g., majority of feet in area outside the indicated path, obstacle hit and displaced, misjudged obstacle height) or critical (e.g., skipped one or more path squares, off path for more than 5 seconds, misjudged 3 / 3 height of raised obstacle in path). Graders tally errors and times in a scoring spreadsheet with a formula (maze algorithm) that automatically adjusts the time score based on time penalty for the type of error, as shown in Equation 1:

number

[0110] An adjusted time in steps per minute (SPM) is set for each video test. If a significant error is determined, the adjusted SPM is set to 0. The spreadsheet is sent back to the testing center where the scores are decoded, averaged (two raters scored each test) and recorded for each subject and time point. Table 2 shows the video tests scored by one rater for six tests by one subject, along with the time, errors and adjusted steps. The Excel template creates an adjusted steps per minute value once the rater enters the start and stop times. [Table 3]

[0111] The LLMT algorithm is based on the scoring algorithm also used in MNREAD, a functional reading test. In MNREAD, patients or subjects read standardized paragraphs of text of various sizes, and trained examiners time the subjects and count the errors until the patient is unable to read the print or makes too many errors. The error-adjusted reading speed is then plotted on a graph, and the size of text that coincides with the inflection point of the curve is considered the critical print size, and the fastest speed or highest plateau of the curve is considered the maximum reading speed. Previously, this inflection point was calculated by manually drawing a two-limb function based on the intersection of two straight lines. Recently, a new curve function using "R" (open source coding) has been used to create a smooth curve fitting process.

[0112] In our initial exploratory work on mobility testing, we determined that a single pass / fail score for mobility testing can be challenging and variable depending on the severity of the subject's impairments, balance, and anxiety / risk-taking behaviors in dim lighting, especially in older patients who may have more comorbid motor impairments, such as joint pain, dizziness, and generalized balance problems, whether or not related to vision. Additionally, some patients in the early stages of RP may not strictly "fail" at low lighting levels, but their adjusted walking speed (i.e., speed and accuracy) may decrease significantly at certain mesopic lighting levels. The LLMT application is designed to identify the first decrease in lighting level that results in a significant decrease in performance by conducting several trials that create a performance curve. The mobility curve represents (i) the lowest illuminance at which speed and accuracy are maintained (i.e., CIL: Critical Illuminance), and (ii) the average fastest and repeatable walking speed (i.e., MSS: Maximum Walking Speed) used to complete the course (see Figure 4). These two aspects of function will be valuable in understanding the maximal benefit of clinical treatments for visual impairments such as jCell in future clinical trials in RP and potentially other diseases.If subjects have mild visual impairments and near-normal levels of vision (estimated CIL below 1 lux), a 10% or 25% low-contrast light gray version can be used to increase the sensitivity of the assessment.

[0113] LLMT Credibility There was a wide range of mobility test performance levels in RP subjects, as the inclusion criteria were BCVA 20 / 80 to 20 / 800 (Table 3 ). [Table 4]

[0114] The median CIL was 32 lux (e.g., restaurant lighting level) at both visits, but three subjects performed in their usual low-light functional range (0.12 lux or 0.25 lux), and two were unable to complete the study at the highest lighting level. The mean MSS of RP patients who completed the study was 33.6 ± 14.9 steps / min, with no significant difference between visits in either CIL or MSS. This walking speed corresponds to a pace of approximately 2 seconds per step, with the slowest subject taking just under 5 seconds per step. Meanwhile, the mean maximum walking speed of VN subjects was 61.00 ± 11.01 spm, which corresponds to a pace of approximately one step per second, and the mean CIL was 0.12 lux, the lowest level measurable.

[0115] The Bland-Altman plots in Figures 6A and 6B show that both RP and VN subjects were spread around the mean. Reproducibility was good for RP subjects at 75%, with no change from visit to visit, and the Pearson correlation was high at 0.98. Four subjects had a CIL change of one illuminant level and one subject had a change of three levels (see Figure 6A), resulting in a mean change across all subjects of less than half a illuminant level (0.35 + / - 0.75). The median CIL for RP subjects was a scale score of 4, which corresponds to 32 lux, whereas the median CIL for VN subjects was 12, which corresponds to 0.12 lux. Of the five subjects who showed a change at the next visit, all had very small visual fields, less than 12° in diameter, with no peripheral islands. Due to the small visual field area, it is difficult for these subjects to locate and relocate the arrow on the LLMT when they lose fixation. The time it takes to find the next arrow is extremely challenging, with a random element to it, as well as variability when navigating sides and raised obstacles to step on or climb over.

[0116] Three of the 16 VN subjects showed variation in light levels only once across visits (see Figure 6B), but the source of this variation appears to be quite different from that of the impaired subjects. All three subjects were able to complete the LLMT in lights-off conditions (no measurable light cracks under the door) at the first visit, but performed somewhat slower at the second visit. However, at faster walking speeds, even high light levels with small deviations from the mean may result in lower CILs with only small decreases in speed. In contrast, no visit-to-visit changes were associated with this exception for the RP subjects, as performance at faster walking speeds and with the room lights off was associated with no change across visits.

[0117] Content validity of LLMT Content validity refers to the ability of a test to measure what it is intended to measure. Thus, an indication of the content validity of a mobility test is whether the low-light mobility test (i) distinguishes between people with good and poor vision, and / or (ii) correlates performance results with other known visual function tests that have previously been shown to be related to mobility. As mentioned above, there were significant differences in the mean and range of mobility scores between the RP and VN groups.

[0118] As RP progresses, many visual function measures, including contrast sensitivity and residual visual field area, deteriorate, although high-contrast and high-luminance visual acuity is often relatively preserved until the later stages of the disease. Therefore, visual function measures are expected to covary with LLMT performance. Due to non-normal sample distributions, logarithms were used to calculate visual field, peak contrast sensitivity, and logarithmic VFQ scores. CIL MSS and scale scores were normally distributed and were used in the analysis. Pearson correlations were used for individual measures to examine relationships in smaller samples (N=20). Multiple regression (MR) was considered, but R was used because of the small sample size and the possibility of the model overfitting the data. 2Only relationships with strong values ​​(above 0.4) were used. In the MR model exploring the variance of CIL and with independent variables including age, BCVA, VF, CS, and VFQ, CS, BCVA, and logVF were the largest factors explaining the variance of CIL. However, because BCVA and CS are strongly correlated (r=0.67), both variables should not be put into the same model. Thus, when assessed by single correlation, CIL scores were strongly and significantly associated with peak logCS (r=0.72, p<0.001), borderline of figure 7, and logVF area (r=42, p=0.06). No significant correlation was found between age and CIL, indicating that patients' performance in low light is not strongly dependent on age. Finally, overall visual performance of the VFQ-48 was not correlated with CIL, but three items (looking at package labels, looking at pictures, and moving outdoors) were significant. There were no significant correlations with the patient-reported overall mobility scale of the VFQ-48, which is not surprising since many RP patients adapt to their significant vision impairments by using visual guides, canes, dog guides, orientation, and mobility training. These patients often do not answer the mobility section of the VFQ-48 with “great difficulty.” These patients may perform poorly on the LLMT because they are unable to use assistive devices. In addition, although the test is, at face value, a gait test, for the reasons mentioned above, it is not designed to, and does not, proxy for the real-life mobility abilities of RP patients. Instead, it is a functional ability test (walking or ambulation) that measures changes in ability and function with light and contrast levels.

[0119] In a separate calculation, lower mean luminance / higher CIL scale scores (i.e., ability to complete mobility tests under reduced lighting levels) were significantly associated with faster mean walking speed (p=0.039).

[0120] In studies of RP across a wide range of subject ages, the CIL is a useful measure of functional low-light and / or low-contrast mobility. As expected, individuals with better low-light function also have better visual acuity, contrast sensitivity, and a reasonably large visual field, whereas individuals with poorer low-light function are slower and have poorer measures of visual function (e.g., more advanced RP).

[0121] When exploring the relationships related to MSS (gait speed), an indicator of better high-light function in patients, age is a more significant factor. In a very powerful MR model with MSS (gait speed), age accounted for most of the variance, with CS and VF contributing less (R2=0.62, p=0.003). The correlation of MSS to peak logCS (r=0.60, p<0.01) and MSS to logVF area (r=0.49, p=0.03) can be seen in Figures 8 and 9.

[0122] Younger subjects tended to be faster than older subjects when measured above the CIL (higher illuminating functional ability). Although CS and VF explain some of the variance in MSS, age was the strongest variable. Such a relationship with age was seen in both visually normal and RP subjects, and may be due to other factors such as an overall decline in mobility, balance, or even anxiety related to falling.

[0123] Interrater (interscorer) reliability of the LLMT exam For interrater and interrater reliability, the scoring of the video tests across three studies was used to obtain the largest sample. At any given time, three orientation and mobility experts acted as raters to evaluate the performance of the video tests. They are referred to as raters in the study and are hereafter referred to as Rater 1 (G1), Rater 2 (G2), Rater 3 (G3), and Rater 4 (G4). All raters participated in the study and used the same scoring protocol. G1 and G2 were trained at the same time and started scoring mobility in the JC-01E study.

[0124] G3 was a vision scientist who understood the test well enough to act as a third judge to review complex trials if G1 and G2 or G2 and G4 disagreed. Results requiring some arbitration were reviewed by the supervisor, who decided whether the trial should be re-reviewed by the original grader (e.g., typos, overlooking obvious errors) or whether it was a difficult subject performance that would benefit from a third review. Because a very small number of trials (<1%) were sent to G3 and G3 is less experienced than the other graders, inter- and intra-rater agreement for G3 is not included. With regard to inter-rater reliability, all three "routine" graders (G1, G2, G4) performed a sufficient number of trials to be evaluated.

[0125] The margin of error (LOA) represents the range that encompasses most of the differences between the two raters. The bias (difference between the two measurements) for G1 and G2 was -0.0317, and the LOA was -0.0317 ± 6.91 (6.9, -6.94) (see Figures 10A and 10B). The data is similar for G2 and G4, with a bias of 0.4975 and a LOA of 0.4975 ± 6.36 (6.9, -5.9) (see Figures 11A and 11B). Most of the data for both G1 vs. G2 and G2 vs. G4 fall on the 1:1 line in each plot. The data point at "zero" occurs when one rater "failed" the footage and the other rater did not (e.g., 0, 19 seconds). This analysis suggests a strong correlation between the raters.

[0126] Regarding interrater reliability, two sample t-tests revealed no differences between the G1 and G2 data sets (t=0.025, df=776, p=0.98) or between the G2 and G4 data sets (t=-0.52, df=1264, p=0.60). Pearson correlations were 0.980, p<0.001 for G1 and G2, and 0.982, p<0.001 for G2 and G4, indicating a positive correlation.

[0127] Thus, for any given footage, it is rare to find a difference between the two raters of more than 6–7 SPMs. This supports the existing process of reviewing footage where the two raters' scores differ by more than 5 SPMs.

[0128] Intrarater reliability of the LLMT exam For intrarater reliability, G1 had 93 footage scored twice for comparison, and G2 had 173 footage scored twice. Scoring twice occurs as a natural progression of the study, as exams from various visits are sent along with the current exam with the study visit date concealed. G4 was recently recruited and therefore did not have footage scored twice as part of the study, but was sent the same 173 footage as G2 to be scored a second time. Footage was coded using a random coding system to conceal exam identity, as well as to eliminate identity by changing the date stamp, preventing G4 from comparing with previous scoring. Two sample t-tests showed no differences between the data sets when G1 scored the same 93 exams and re-scored them 6 months later. For G4, 172 exams were scored and re-scored, with similarly no differences. The extent of bias for each rater was similar (see Table 5 below). [Table 5]

[0129] As shown in Figures 12A, 12B, 13A, 13B, 14A, and 14B, all three raters show strong consistency. Pearson correlations were 0.98, p<0.0001 for G2 and G1, and 0.99, p<0.0001 for G4, indicating a positive correlation when rating the same footage twice. Therefore, it can be concluded that the raters were consistent and the criteria for scoring were simple enough to ensure consistent scoring.

[0130] When considering possible sources of variability in the mobility tests, the five subjects with visit-to-visit variability were all over 40 years old, and all had visual fields less than 12 degrees in diameter (subjects 5, 8, 13, 16, and 18). The subject with the greatest variability (three light levels) was the oldest (72 years old), who also had the greatest variability in the VA LV VFQ-48, with a visit-to-visit difference of 0.58 logit. This finding is consistent with conclusions of others that test-retest variability is greater in patients with severe visual field constriction.

[0131] When examining the pattern of the Bland-Altman plot, a consistent pattern is seen across all raters, as the graph is more spread out at slower speeds. When subjects walk at very slow speeds, scoring the test is difficult because subjects make multiple errors per test and must be judged for significant errors (SPM=0). If there is disagreement between raters on such tests, a review process is followed, in which raters must review their tests and reach a consensus or correct the errors they made in scoring. This results in an initial rating of 0 and subsequent ratings of some value (e.g., 12 SPM). Such intrarater changes result in greater variance than is typically seen. This variability in performance close to individual fail levels is inherent and is corrected by the LLMT CIL scoring algorithm. While one or two of the lowest lighting levels may be difficult to score, the majority of the tests are done at higher lighting levels, and the final scoring selects subjects who first show a significant decline in function at the higher lighting levels, rather than relying solely on passing or failing the lowest lighting point. When subjects perform fast trials at all lighting levels (e.g. 60 SPM), they usually make few errors, but when using a scoring algorithm, differences in scoring the trials can result in large differences in SPM if only one error is noted on one trial. For example, if a fast subject completes the trial in 20 seconds without any errors, the algorithm will give them a walking speed of 72 SPM. However, if the other rater counts the trial as having one error, the algorithm (adjusted walking speed = [(24-major error*2)*60] / time to complete trial) will give them 66 SPM. The difference between the two trials is 6 SPM, which is cause for a reconsideration to investigate the discrepancy between the two raters.

[0132] The algorithm is designed for most subjects whose walking speed is somewhere in the middle (e.g., 35 SPM). For example, if a subject has a test time of 34 seconds and no errors, the walking speed will be 42 SPM. Conversely, if the other grader points out one error, the speed will be 39 SPM. This difference between graders is only 3 SPM, which is within the range of reasonable differences and does not require a re-watch of the video test. See example test in Figure 15 for a subject with a range of average and consistent walking speeds.

[0133] In the VN group, three subjects varied by one light level across repeated trials, but because they were each nearly 40 years old, this variability was more likely due to very fast walking speeds or subtle assessment differences, as opposed to true variability in performance in low light or age-related factors.

[0134] Low contrast low luminance mobility test (LC-LLMT) It was determined that a different test method was necessary to eliminate the ceiling effect observed in a portion of subjects during testing of subjects with good LLMT performance at baseline (e.g., fast pace and CIL close to normal). The aim is to avoid variability when assessing and to avoid ceiling effects when testing more functional subjects (less severe stage) in treatment studies. In this validation study (n=20RP), three subjects had a CIL of 0.5 lux or higher, indicating better functional visual acuity, despite being in a visual acuity range generally corresponding to a severe stage.

[0135] Early in the development of the mobility test, a maze pattern with thin arrows was designed and used to test better performing subjects, along with thick or standard size arrows. In pilot studies, this was found to generally reduce the CIL by 1–2 levels. For example, patients who showed a CIL of 0.25 lux in the standard maze showed a CIL of 0.5 or 1.0 lux in the “thin arrow” maze. In this way, the test range could be expanded to some extent, so other versions of the test with greater sensitivity in a wider test range were also explored. A low-contrast version with thin gray arrows on a white background was designed and initially qualitatively explored in well-functioning subjects. In the development of the pilot study, different shades of gray arrows on a white background were qualitatively explored in RP patients. Maze patterns were designed with Weber contrast values ​​of 50%, 30%, 25%, and 10%. Each version was explored in RP subjects with various BCVA and visual field characteristics, clearing all levels of the high-contrast version (black and white). In the most sensitive version, participants were able to complete several lighting levels, including the 25% contrast and 10% versions, but not all lighting levels (see Figure 16). Most of these participants with higher function (lower severity of RP) will not be able to do the 10% version, especially if their peak contrast sensitivity is essentially flat or untestable, but the low contrast option allows for greater flexibility in testing for participants with more preserved visual function. The process for determining which version to use for a particular subject and eye (for monocular testing) is as follows: At the baseline visit, assess performance at a high contrast level (black and white, 95%). For subjects with a high contrast CIL (e.g., 1 lux or greater), assess the 25% and 10% contrast versions. Starting at 1 lux provides a range of mesopic lighting levels that extends to scotopic lighting levels during testing. This range provides several levels of potential improvement in treatment studies. If the 10% version cannot be completed at any lighting level, use the 25% gray version.For consistency, subsequent visits should be done with the same version (10%, 25%, high contrast). It is also possible to test one version (e.g. 10%) in one eye and the high contrast version in the other eye. In the case of binocular testing, use the more challenging version that has room for improvement.

[0136] Equivalent While the present invention has been described in conjunction with the specific embodiments above, many alternatives, modifications and other variations thereof will be apparent to those skilled in the art, and all such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

1. 1. A method for testing functional visual acuity in a subject, comprising: a) selecting a first course from a plurality of courses, each course having a grid of segments including a start point, at least one turn, at least one obstacle, and an end point, said grid of segments being pre-printed on an overall map for said subject, each of a plurality of said segments including directional arrows that form a path for said subject to walk, at least one of said segments including said at least one obstacle, said at least one obstacle including a physical object that needs to be avoided, circumvented, traversed, and / or evaded; b) selecting a first illuminance from 13 illuminance levels, the 13 illuminance levels ranging from about 0.12 lux to about 500 lux, each illuminance level being spaced apart from an adjacent illuminance level by about 0.3 log units; c) illuminating the first course with the first illuminance; d) video recording a first movement of the subject along the first course beginning at the starting point; e) determining a first walking speed for the subject based on the first movement; f) selecting a second course from said plurality of courses, said second course being different from said first course; g) selecting a second illuminance from the thirteen levels of illuminance, the second illuminance being different from the first illuminance; h) illuminating the second course with the second illuminance; i) video recording a second movement of the subject along the second course beginning at the starting point; j) determining a second walking speed of the subject based on the second movement; k) repeating steps f) to j) so that the subject is tested in 4 to 8 courses at different illuminance intensities; l) creating a mobility curve showing said walking speed as a function of said illuminance; m) determining a critical illuminance (CIL) for the subject based on the mobility curve, below which the walking speed of the subject significantly decreases; each walking speed is calculated by the formula: walking speed = [(24 - number of major errors * 2) * 60] / time to complete each course, said time to complete each course having units of seconds; Each major error is selected from stepping a majority of a foot in an area outside the path, skipping an arrow in one direction, moving the at least one obstacle more than four inches, misidentifying the height of the at least one obstacle, stepping more than half a foot into a solid rectangle, and misidentifying the end point of the path but successfully completing the path; Preferably, the subject is a human. The method includes:

2. 2. The method of claim 1, wherein the walking speed is zero if the subject makes a significant error, the significant error being selected from skipping two or more legs on the path, getting lost for at least five seconds, and misjudging the height of all three raised obstacles in the path.

3. The subject is i) have normal functional vision, or ii) suspected of having a vision impairment or defect in one or both eyes; The method according to claim 1 or 2.

4. the subject is a candidate for topical or systemic ophthalmic treatment; Preferably, the local or systemic ophthalmic treatment is an ophthalmic treatment, a surgery, a gene therapy, or a combination thereof, for one or both eyes; Preferably, the ophthalmic treatment, surgery or gene therapy is for the treatment of retinitis pigmentosa (RP), Leber's congenital amaurosis (LCA), Stargardt's disease, Usher syndrome, choroidopathy, rod-cone-rod dystrophy, ciliopathy, mitochondrial disorders, progressive retinal atrophy, retinal degenerative diseases, age-related macular degeneration (AMD), wet AMD, dry AMD, geographic atrophy, ciliopathy, familial or acquired maculopathy, retinal photoreceptor disease. the therapeutic agent is for the treatment of retinal vascular disease, retinal pigment epithelial disease, diabetic retinopathy, cystoid macular edema, uveitis, retinal detachment, traumatic retinal damage, ectopic retinal damage, macular hole, macular telangiectasia, ganglion cell disease, optic nerve cell disease, glaucoma, optic nerve cell disease, glaucoma, optic neuropathy, ischemic retinal disease, retinopathy of prematurity, retinal vascular occlusion, familial aneurysm, retinal vascular disease, ocular vascular disease, vascular disease, or ischemic optic neuropathy; 4. The method according to claim 1 .

5. The method comprises: i) performed before the subject undergoes the ophthalmic treatment, surgery, and / or gene therapy; ii) performed while the subject is undergoing the ophthalmic treatment, surgery, and / or gene therapy; iii) after the subject has undergone the ophthalmic treatment, surgery, and / or gene therapy; iv) repeated over the subject's recovery period to observe any improvement or deterioration associated with the ophthalmic treatment, surgery, and / or gene therapy; The method according to claim 4.

6. Each course contains from 1 to about 15 turns; Preferably, each course includes between 7 and 9 turns.

6. The method according to any one of claims 1 to 5.

7. Each course may contain from 1 to about 15 obstacles; Preferably, the at least one obstacle is selected from an object located on the path, an object located adjacent to the path, a raised section, a section having a color indicating an obstacle, and an edge of a step.

7. The method according to any one of claims 1 to 6.

8. Each course comprises three obstacles in the path and seven obstacles adjacent to the path; Preferably, the route of each course consists of 22 to 24 sections.

8. The method according to any one of claims 1 to 7.

9. The method of claim 1 , wherein the plurality of courses comprises at least twelve courses.

10. Further, instructing a first grader and a second grader to watch each video, and each grader determines the time to complete each course, the number of major errors when the subject completes each course, and each walking speed; comparing the walking speed determined by the first grader with the walking speed determined by the second grader; if the difference between the times taken by the first and second graders to complete each course is within 5 seconds, averaging the walking speeds determined by the first and second graders. The method of claim 1 , comprising:

11. 11. The method of claim 1, wherein the CIL for a subject with normal functional vision is about 0.12 lux.

12. determining a maximum walking speed (MSS) of the subject, the MSS being an average of the walking speeds determined for illuminances equal to or greater than the CIL; Preferably, the MSS for a subject with normal functional vision is about 61 spm.

12. The method according to any one of claims 1 to 11.

13. 2. The method of claim 1, wherein when the CIL of the subject is 1 lux or less, the method further comprises selecting a course having a Weber contrast value of about 10% to about 50%, preferably, the Weber contrast value is about 10%, about 25%, about 30%, or about 50%.

14. 1. A method for monitoring the progress of a subject undergoing or having undergone a topical or systemic ophthalmic treatment, comprising: determining a first CIL for the subject at a first time point using the method of any one of claims 1 to 13; 14. The method of any one of claims 1 to 13, further comprising determining a second CIL for the subject at a second time point, the second time point being later than the first time point. comparing the first CIL with the second CIL; The subject (a) determines that improvement is progressing when the second CIL is significantly smaller than the first CIL, and (b) determines that improvement is not progressing or that the visual impairment is getting worse when the second CIL is equal to or larger than the first CIL. The method includes:

15. 1. A method for monitoring the progress of a subject undergoing or having undergone a topical or systemic ophthalmic treatment, comprising: determining a first MSS for the subject at a first time point using the method of any one of claims 1 to 13; determining a second MSS for the subject using the method of any one of claims 1 to 13 at a second time point, the second time point being later than the first time point; comparing the first MSS with the second MSS; The subject (a) determines that the symptom has improved when the second MSS is significantly greater than the first MSS, and (b) determines that the symptom has not improved or that the visual impairment is getting worse when the second MSS is equal to or smaller than the first MSS. The method includes:

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