Many of its major earthworks had been drawn and recorded in the late 19th century by researchers for the Smithsonian Institution, but he also used evidence from artifacts to describe its culture.

While his early work dealt with linguistics, by the 1920s Keyes focused his research almost exclusively on sites and artifacts in Iowa.

The people of this culture had centers throughout the Mississippi Valley and its tributaries, including the Ohio, from the upper Midwest to the Southeast.

Keyes and Orr surveyed a territory of extensive prehistoric earthwork mounds in northeastern Iowa.

They had two daughters, Catherine Ann, a librarian at the New York City Public Library, and Margaret Naumann Keyes.

Margaret became a professor of Home Economics at the University of Iowa, and recognized as a national leader in the field of historic preservation.