A method of determining whether a test subject has homologous recombination deficiency, the method comprising: at a computer system having one or more processors, and memory storing one or more programs for execution by the one or more processors: obtaining a first plurality of sequence reads, in electronic form, of a DNA sample from the test subject, the DNA sample comprising DNA molecules from a cancerous tissue of the subject; obtaining a second plurality of sequence reads, in electronic form, of an RNA sample from the test subject, the RNA sample comprising RNA molecules from the cancerous tissue of the subject; determining, based on the first plurality of sequence reads, a first prediction for a homologous recombination pathway status of the cancerous tissue of the subject based on a measure of genome-wide loss of heterozygosity for the cancerous tissue of the subject, wherein the method further comprises obtaining a fourth plurality of sequence reads, in electronic form, of a second DNA sample from the test subject, the second DNA sample comprising DNA molecules from a non-cancerous tissue of the subject, and the determining is based on the first plurality of sequence reads and the fourth plurality of sequence reads through determination of a germline variant allele fraction and deviation of B-allele frequency from normal expectation of each SNP in both the first plurality of sequence reads and fourth plurality of sequence reads; determining, based on the second plurality of sequence reads, a second prediction for the homologous recombination pathway status of the cancerous tissue of the subject based on the expression levels of a plurality of genes in the cancerous tissue of the subject; determining, based on the second plurality of sequence reads, a third prediction for the homologous recombination pathway status of the cancerous tissue of the subject based on a measure of transcriptome-wide rearrangements for the cancerous tissue of the subject; generating a subject data construct comprising (i) the first prediction for the homologous recombination pathway status of the cancerous tissue of the subject, (ii) the second prediction for the homologous recombination pathway status of the cancerous tissue of the subject, and (iii) the third prediction for the homologous recombination pathway status of the cancerous tissue of the subject; and inputting the subject data construct into a HRD ensemble model that distinguishes between cancers with homologous recombination pathway deficiencies and cancers without homologous recombination pathway deficiencies, thereby determining whether the test subject has HRD. obtaining a first plurality of sequence reads, in electronic form, of a DNA sample from the test subject, the DNA sample comprising DNA molecules from a cancerous tissue of the subject; obtaining a second plurality of sequence reads, in electronic form, of an RNA sample from the test subject, the RNA sample comprising RNA molecules from the cancerous tissue of the subject; determining, based on the first plurality of sequence reads, a first prediction for a homologous recombination pathway status of the cancerous tissue of the subject based on a measure of genome-wide loss of heterozygosity for the cancerous tissue of the subject, wherein the method further comprises obtaining a fourth plurality of sequence reads, in electronic form, of a second DNA sample from the test subject, the second DNA sample comprising DNA molecules from a non-cancerous tissue of the subject, and the determining is based on the first plurality of sequence reads and the fourth plurality of sequence reads through determination of a germline variant allele fraction and deviation of B-allele frequency from normal expectation of each SNP in both the first plurality of sequence reads and fourth plurality of sequence reads; determining, based on the second plurality of sequence reads, a second prediction for the homologous recombination pathway status of the cancerous tissue of the subject based on the expression levels of a plurality of genes in the cancerous tissue of the subject; determining, based on the second plurality of sequence reads, a third prediction for the homologous recombination pathway status of the cancerous tissue of the subject based on a measure of transcriptome-wide rearrangements for the cancerous tissue of the subject; generating a subject data construct comprising (i) the first prediction for the homologous recombination pathway status of the cancerous tissue of the subject, (ii) the second prediction for the homologous recombination pathway status of the cancerous tissue of the subject, and (iii) the third prediction for the homologous recombination pathway status of the cancerous tissue of the subject; and inputting the subject data construct into a HRD ensemble model that distinguishes between cancers with homologous recombination pathway deficiencies and cancers without homologous recombination pathway deficiencies, thereby determining whether the test subject has HRD.