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I have a SHP file that contains all counties in the USA. I also have roughly 100 million GPS locations. I need to tally the number of GPS locations per county.

A linear search through the counties for each coordinate is obviously a bad idea. I'm guessing I need some sort of spatial data structure that will prune candidate counties drastically and was hoping this was a common enough query that canned solutions were already available. In other words, I pass in SHP records for the counties and then query the resultant data structure for some unique identifier (FIPS code) of the county from a GPS coordinate (represented as some Point object).

My toolset is Python, shapely, fiona, etc.

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Just use a Spatial Join. You can do this with QGIS (free to download; you may already be using it). Here is a tutorial that does exactly what you are trying to do using nursing homes as points (you'd use your GPS locations instead) and boroughs as polygons (you'd use Counties).

Tutorial

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