A system for sequencing comprising: an imaging system (100,200) to image one or more portions of a substrate having a sample associated with a surface of the substrate; and a processing system configured to: initiate a first imaging cycle for the imaging system to image a portion of the substrate with the imaging system to detect one or more optical signals using at least one or more fluorescently labeled nucleotides associated with the sample; subdivide an image of the portion of the substrate into a plurality of tiles, each of the plurality of tiles comprising a plurality of imaging spots and a predetermined number of fiducials characterized in that the processing system is further configured to calculate a set of image distortion correction coefficients for each of the plurality of tiles using the predetermined number of fiducials; and an affine transform for each of the plurality of tiles is estimated using the fiducials, wherein calculating a set of image distortion correction coefficients for each of the plurality of tiles, includes: estimating an affine transform of the tile; sharpening the tile; and iteratively searching for an optimal set of distortion coefficients for the tile; initiate a second imaging cycle for the imaging system to image the portion of the substrate with the imaging system to detect one or more optical signals using at least one or more fluorescently labeled nucleotides associated with the sample; and apply the set of image distortion correction coefficients calculated for each of the plurality of tiles corresponding to each of the plurality of tiles of an image from the second imaging cycle. an imaging system (100,200) to image one or more portions of a substrate having a sample associated with a surface of the substrate; and a processing system configured to: initiate a first imaging cycle for the imaging system to image a portion of the substrate with the imaging system to detect one or more optical signals using at least one or more fluorescently labeled nucleotides associated with the sample; subdivide an image of the portion of the substrate into a plurality of tiles, each of the plurality of tiles comprising a plurality of imaging spots and a predetermined number of fiducials characterized in that the processing system is further configured to calculate a set of image distortion correction coefficients for each of the plurality of tiles using the predetermined number of fiducials; and an affine transform for each of the plurality of tiles is estimated using the fiducials, wherein calculating a set of image distortion correction coefficients for each of the plurality of tiles, includes: estimating an affine transform of the tile; sharpening the tile; and iteratively searching for an optimal set of distortion coefficients for the tile; initiate a second imaging cycle for the imaging system to image the portion of the substrate with the imaging system to detect one or more optical signals using at least one or more fluorescently labeled nucleotides associated with the sample; and apply the set of image distortion correction coefficients calculated for each of the plurality of tiles corresponding to each of the plurality of tiles of an image from the second imaging cycle. initiate a first imaging cycle for the imaging system to image a portion of the substrate with the imaging system to detect one or more optical signals using at least one or more fluorescently labeled nucleotides associated with the sample; subdivide an image of the portion of the substrate into a plurality of tiles, each of the plurality of tiles comprising a plurality of imaging spots and a predetermined number of fiducials characterized in that the processing system is further configured to calculate a set of image distortion correction coefficients for each of the plurality of tiles using the predetermined number of fiducials; and an affine transform for each of the plurality of tiles is estimated using the fiducials, wherein calculating a set of image distortion correction coefficients for each of the plurality of tiles, includes: estimating an affine transform of the tile; sharpening the tile; and iteratively searching for an optimal set of distortion coefficients for the tile; initiate a second imaging cycle for the imaging system to image the portion of the substrate with the imaging system to detect one or more optical signals using at least one or more fluorescently labeled nucleotides associated with the sample; and apply the set of image distortion correction coefficients calculated for each of the plurality of tiles corresponding to each of the plurality of tiles of an image from the second imaging cycle.