A method for sequencing a target nucleic acid using a sequencing-by-synthesis approach, the method comprising: a) providing a first plurality of a first nucleotide base, a second plurality of a second nucleotide base, a third plurality of a third nucleotide base, and a fourth plurality of a fourth nucleotide base wherein: a first ratio of a first portion of the first plurality labeled with a first label relative to a second portion of the first plurality labeled with a second label; and a second ratio of a third portion of the second plurality labeled with the first label relative to a fourth portion of the second plurality labeled with the second label, are detectably different from each other; b) incorporating by polymerization the first plurality of the first nucleotide base, the second plurality of the second nucleotide base, the third plurality of the third nucleotide base, or the fourth plurality of the fourth nucleotide base into a plurality of copies of a nucleic acid that is complementary to the target nucleic acid; c) determining a signal ratio produced from the first plurality of the first nucleotide base or a signal ratio produced from the second plurality of the second nucleotide base in the plurality of copies of a nucleic acid that is complementary to the target nucleic acid, wherein a first signal ratio produced by the first plurality of the first nucleotide base is detectably different than a second signal ratio produced by the second plurality of the second nucleotide base and wherein the signal ratio produced from the first plurality is produced by at least two labels emitting at two distinguishable wavelengths and the signal ratio produced from the second plurality is produced by at least two labels emitting at two distinguishable wavelengths; d) associating the signal ratio or signal with the first nucleotide base or the second nucleotide base to identify the nucleotide base in the plurality of copies of a nucleic acid that is complementary to the target nucleic acid; and e) analyzing a dataset of ordered signal ratios to produce a nucleotide sequence of the target nucleic acid, wherein the SBS method is an ensemble based sequencing approach the sequence of the target nucleic acid is determined by detecting the signal produced after each base incorporation, and wherein: (i) each of the nucleotides comprises a 3' hydroxyl group that is chemically blocked and all four nucleotides are added simultaneously to a reaction comprising DNA polymerase and clusters of template-primer complexes; or (ii) each nucleotide is added one at a time to a reaction mixture containing a nucleic acid target-primer complex and a polymerase. a) providing a first plurality of a first nucleotide base, a second plurality of a second nucleotide base, a third plurality of a third nucleotide base, and a fourth plurality of a fourth nucleotide base wherein: a first ratio of a first portion of the first plurality labeled with a first label relative to a second portion of the first plurality labeled with a second label; and a second ratio of a third portion of the second plurality labeled with the first label relative to a fourth portion of the second plurality labeled with the second label, are detectably different from each other; a first ratio of a first portion of the first plurality labeled with a first label relative to a second portion of the first plurality labeled with a second label; and a second ratio of a third portion of the second plurality labeled with the first label relative to a fourth portion of the second plurality labeled with the second label, are detectably different from each other; b) incorporating by polymerization the first plurality of the first nucleotide base, the second plurality of the second nucleotide base, the third plurality of the third nucleotide base, or the fourth plurality of the fourth nucleotide base into a plurality of copies of a nucleic acid that is complementary to the target nucleic acid; c) determining a signal ratio produced from the first plurality of the first nucleotide base or a signal ratio produced from the second plurality of the second nucleotide base in the plurality of copies of a nucleic acid that is complementary to the target nucleic acid, wherein a first signal ratio produced by the first plurality of the first nucleotide base is detectably different than a second signal ratio produced by the second plurality of the second nucleotide base and wherein the signal ratio produced from the first plurality is produced by at least two labels emitting at two distinguishable wavelengths and the signal ratio produced from the second plurality is produced by at least two labels emitting at two distinguishable wavelengths; d) associating the signal ratio or signal with the first nucleotide base or the second nucleotide base to identify the nucleotide base in the plurality of copies of a nucleic acid that is complementary to the target nucleic acid; and e) analyzing a dataset of ordered signal ratios to produce a nucleotide sequence of the target nucleic acid, (i) each of the nucleotides comprises a 3' hydroxyl group that is chemically blocked and all four nucleotides are added simultaneously to a reaction comprising DNA polymerase and clusters of template-primer complexes; or (ii) each nucleotide is added one at a time to a reaction mixture containing a nucleic acid target-primer complex and a polymerase.