  Scientists use mathematical modelling to understand and predict the
properties of complex physical systems. In highly parameterised models there
often exist relationships between parameters over which model predictions are
identical, or nearly so. These are known as structural or practical
unidentifiabilities, respectively. They are hard to diagnose and make reliable
parameter estimation from data impossible. They furthermore imply the existence
of an underlying model simplification. We describe a scalable method for
detecting unidentifiabilities, and the functional relations defining them, for
generic models. This allows for model simplification, and appreciation of which
parameters (or functions thereof) cannot be estimated from data. Our algorithm
can identify features such as redundant mechanisms and fast timescale
subsystems, as well as the regimes in which such approximations are valid. We
base our algorithm on a novel quantification of regional parametric
sensitivity: multiscale sloppiness. Traditionally, the link between parametric
sensitivity and the conditioning of the parameter estimation problem is made
locally, through the Fisher Information Matrix. This is valid in the regime of
infinitesimal measurement uncertainty. We demonstrate the duality between
multiscale sloppiness and the geometry of confidence regions surrounding
parameter estimates made where measurement uncertainty is non-negligible.
Further theoretical relationships are provided linking multiscale sloppiness to
the Likelihood-ratio test. From this, we show that a local sensitivity analysis
(as typically done) is insufficient for determining the reliability of
parameter estimation, even with simple (non)linear systems. Our algorithm
provides a tractable alternative. We finally apply our methods to a
large-scale, benchmark Systems Biology model of NF-$\kappa$B, uncovering
previously unknown unidentifiabilities.
