I don't think I've ever driven an inline engine that got better economy in a lower gear, at any speed. I'm of the opinion that the devil really is in the details with engine geometry though. The only hard and fast rule I can think of, is that you're best off getting the smallest engine and the tallest gearing, because the exceptions are exceedingly rare.
If you're building an engine, gains are probably more accessible through cam changes than bottom-end work.
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