Systems and devices for sequence by synthesis analysis

A system for detecting fluorescence emitted from a sample, the system comprising:

• a) a stage configured to hold a solid substrate having the sample;
• b) a fluid direction system for controllably moving one or more reagents into contact with the sample;
• c) an illumination system for exciting fluorescent labels in the sample via total internal reflection (TIR), the illumination system comprising a mode scrambler and a multimode optical fiber that provides a fluorescent-excitation illumination beam having multiple propagating modes, the mode scrambler scrambling the modes of the illumination beam to provide a substantially uniform illumination footprint to excite the fluorescent labels, wherein the illumination beam is directed to be incident on the solid substrate so that the footprint excites the fluorescent labels through TIR;
• and
• d) a detector component for detecting fluorescence produced from excitation of the fluorescent labels by the footprint thereby providing fluorescent data;
• e) a computer component comprising an instruction set to process the fluorescent data and determine sequence information for nucleic acids in the sample.