A method for determining whether a chromosome imbalance exists within a biological sample of a female subject pregnant with a fetus, wherein the biological sample includes nucleic acid molecules from the female subject and from the fetus, the method comprising: receiving data from a plurality of reactions involving nucleic acid molecules from the biological sample, wherein each reaction indicates a presence or absence of one or more clinically relevant nucleic acid sequences and one or more background nucleic acid sequences, wherein the data includes: a first set of quantitative data indicating a first amount of reactions that are positive for a presence of the one or more clinically relevant nucleic acid sequences of a first chromosome, each clinically relevant nucleic acid sequence having a first epigenetic marker that is fetal-specific; and a second set of quantitative data indicating a second amount of reactions that are positive for a presence of the one or more background nucleic acid sequences of one or more reference chromosomes, each background nucleic acid sequence being different from the one or more clinically relevant nucleic acid sequences and having a second epigenetic marker that is fetal-specific, wherein the one or more first epigenetic markers and the one or more second epigenetic markers exhibit fetal-specific DNA methylation patterns that differentiate fetal sequences and maternal sequences for determining the first amount and the second amount; determining a parameter from the two data sets, wherein the parameter includes a ratio between the first amount and the second amount; comparing the parameter to one or more cutoff values determined using a first expected ratio between the first amount and the second amount if a chromosome imbalance exists, wherein the one or more cutoff values are further determined based on an average concentration determined from the number of reactions and at least one of the first amount and the second amount, wherein the one or more cutoff values are selected to be between the first expected ratio and a second expected ratio if the chromosome imbalance does not exist; and based on the comparison, determining a classification of whether a chromosome imbalance exists in the fetal genome for the clinically relevant nucleic acid sequence. receiving data from a plurality of reactions involving nucleic acid molecules from the biological sample, wherein each reaction indicates a presence or absence of one or more clinically relevant nucleic acid sequences and one or more background nucleic acid sequences, wherein the data includes: a first set of quantitative data indicating a first amount of reactions that are positive for a presence of the one or more clinically relevant nucleic acid sequences of a first chromosome, each clinically relevant nucleic acid sequence having a first epigenetic marker that is fetal-specific; and a second set of quantitative data indicating a second amount of reactions that are positive for a presence of the one or more background nucleic acid sequences of one or more reference chromosomes, each background nucleic acid sequence being different from the one or more clinically relevant nucleic acid sequences and having a second epigenetic marker that is fetal-specific, wherein the one or more first epigenetic markers and the one or more second epigenetic markers exhibit fetal-specific DNA methylation patterns that differentiate fetal sequences and maternal sequences for determining the first amount and the second amount; a first set of quantitative data indicating a first amount of reactions that are positive for a presence of the one or more clinically relevant nucleic acid sequences of a first chromosome, each clinically relevant nucleic acid sequence having a first epigenetic marker that is fetal-specific; and a second set of quantitative data indicating a second amount of reactions that are positive for a presence of the one or more background nucleic acid sequences of one or more reference chromosomes, each background nucleic acid sequence being different from the one or more clinically relevant nucleic acid sequences and having a second epigenetic marker that is fetal-specific, wherein the one or more first epigenetic markers and the one or more second epigenetic markers exhibit fetal-specific DNA methylation patterns that differentiate fetal sequences and maternal sequences for determining the first amount and the second amount; determining a parameter from the two data sets, wherein the parameter includes a ratio between the first amount and the second amount; comparing the parameter to one or more cutoff values determined using a first expected ratio between the first amount and the second amount if a chromosome imbalance exists, wherein the one or more cutoff values are further determined based on an average concentration determined from the number of reactions and at least one of the first amount and the second amount, wherein the one or more cutoff values are selected to be between the first expected ratio and a second expected ratio if the chromosome imbalance does not exist; and based on the comparison, determining a classification of whether a chromosome imbalance exists in the fetal genome for the clinically relevant nucleic acid sequence.