Methods and processes for non-invasive assessment of genetic variations

A method comprising:

• (I) sequencing circulating cell-free (CCF) nucleic acid from a heterogeneous test sample comprising a minority nucleic acid fragment species and a majority nucleic acid fragment species by a massively parallel sequencer, thereby generating sequence reads;
• (II) obtaining, using a microprocessor, counts of the sequence reads mapped to a plurality of portions of a reference genome;
• (III) estimating a minority fraction of the nucleic acid fragment species in the heterogeneous test sample by a computer-implemented process comprising:
• (a) receiving onto memory a set of weighting factors associated with portions corresponding to one or more autosomes in the reference genome, wherein each of the weighting factors has been determined from a fitted relation for the associated portion between:
• (i) a minority fraction of the nucleic acid fragment species for each of multiple euploid samples in a training set, and
• (ii) counts of sequence reads mapped to the associated portion for the multiple samples;
• (b) converting, using a microprocessor, the counts of the sequence reads mapped to each portion to portion-specific minority fractions of a nucleic acid fragment species according to the respective weighting factors independently associated with each portion, thereby providing portion-specific fraction estimates according to the weighting factors;
• and
• (c) estimating, using a microprocessor, a minority fraction of the nucleic acid fragment species for the test sample by quantifying the portion-specific minority fraction estimates, wherein the estimating excludes detection of a polymorphism for the test sample;
• and
• (IV) generating a report for
• (i) the minority fraction of the nucleic acid fragment species for the test sample estimated in (c);
• and
• (ii) a presence or absence of a copy number variation for the test sample detected according to a quantification of the sequence reads generated in (I), or a no-call for the copy number variation according to a quantification of the sequence reads generated in (I) and the minority fraction of the nucleic acid fragment species for the test sample estimated in (c).