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The phrase "a substantially different methodology" is correct and usable in written English.
It can be used when discussing research, processes, or approaches that differ significantly from existing methods.
Example: "The study employed a substantially different methodology compared to previous research, leading to new insights."
Alternatives: "a markedly different approach" or "a significantly altered method."
Exact(1)
For example, for rapid on-site analysis for the purpose of directing a site remediation project, a substantially different methodology can be used compared to that required for legal action.
Similar(59)
The results of this analysis are also similar to those of Solberg et al. [ 44] in the USA who estimated an ICER of $1755 (equivalent to €1721 in 2008 prices) and Tariq et al. [ 45] in the Netherlands who estimated an ICER of €5400, although these studies both use substantially different methodologies.
The Devils will have a substantially different look next season.
Side-scrolling platformer Limbo is a substantially different affair.
It must have a substantially different approach to the Conservatives.
Protecting civilian populations requires a substantially different approach (see article).
In June, the Senate Finance Committee approved a substantially different bill, 13 to 8.
(A substantially different 1972 rewrite by Williams was produced in 2001 in Westport, Conn).
The bill will now go to a conference with the House, which passed a substantially different tax cut package last week.
Had things gone otherwise, audiences might have been left with a substantially different feeling.
His labor and his livelihood, however, have taken a substantially different course.
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Since I tried Ludwig back in 2017, I have been constantly using it in both editing and translation. Ever since, I suggest it to my translators at ProSciEditing.

Justyna Jupowicz-Kozak
CEO of Professional Science Editing for Scientists @ prosciediting.com