A method for nucleic acid sequencing, comprising: for each of a plurality of defined spaces of a chip or substrate, wherein each defined space is in communication with a respective sensor and wherein at least some of the defined spaces comprise one or more sample nucleic acids, receiving, from the respective sensor for each defined space, a signal indicative of a parameter observed or measured for the defined space in response to a nucleotide flow to the defined space, to provide a measured signal value representative of a non-incorporation or an incorporation of a base corresponding to the nucleotide flow by the sample nucleic acid in the defined space, wherein each defined space is a space in which at least some of a molecule, fluid, and/or solid can be confined, retained and/or localized; generating, for the defined spaces comprising one or more sample nucleic acids, a set of candidate sequences of bases for the one or more sample nucleic acids of the defined space; generating a set of predicted signal values for the set of candidate sequences based on a simulation framework for modeling responses by an active polymerase associated with the sample nucleic acid to a series of nucleotide flows, wherein the simulation framework includes possible states, state transitions and state transition parameters, wherein a first state of the possible states represents a non-incorporation of a particular base at a particular flow and a second state of the possible states represents an incorporation of the particular base at the particular flow by the active polymerase associated with the sample nucleic acid; applying one or more metrics adapted to associate a score or a penalty to each of the candidate sequences of bases, wherein at least one of the metrics depends on a residual between the measured signal value and the predicted signal value generated by the simulation framework, wherein the residual comprises a difference between the predicted signal value and the measured signal value; and selecting from the set of candidate sequences of bases the candidate sequence leading to a highest score or a lowest penalty as corresponding to a correct sequence for the one or more sample nucleic acids in the defined space. generating, for the defined spaces comprising one or more sample nucleic acids, a set of candidate sequences of bases for the one or more sample nucleic acids of the defined space; generating a set of predicted signal values for the set of candidate sequences based on a simulation framework for modeling responses by an active polymerase associated with the sample nucleic acid to a series of nucleotide flows, wherein the simulation framework includes possible states, state transitions and state transition parameters, wherein a first state of the possible states represents a non-incorporation of a particular base at a particular flow and a second state of the possible states represents an incorporation of the particular base at the particular flow by the active polymerase associated with the sample nucleic acid; applying one or more metrics adapted to associate a score or a penalty to each of the candidate sequences of bases, wherein at least one of the metrics depends on a residual between the measured signal value and the predicted signal value generated by the simulation framework, wherein the residual comprises a difference between the predicted signal value and the measured signal value; and selecting from the set of candidate sequences of bases the candidate sequence leading to a highest score or a lowest penalty as corresponding to a correct sequence for the one or more sample nucleic acids in the defined space.