Prediction and causal inference in the transition from acute to chronic low back pain

Abstract

The overarching aim of this thesis was to enhance our understanding of the neurobiological risk factors associated with the transition from acute to chronic Low back pain (LBP). To achieve this aim, the Understanding persistent Pain Where it ResiDes (UPWaRD) study was conducted. In this thesis, six chapters describe the background, methods, and results of the UPWaRD study. Chapter 2 describes the protocol, published 'a priori' for developing a multivariable prediction model, including candidate predictors selected from the neurobiological (e.g. sensorimotor cortical excitability assessed by sensory and motor evoked potentials, Brain Derived Neurotrophic Factor [BDNF] genotype), psychological (e.g. depression and anxiety), symptom-related (e.g. LBP history) and demographic domains. Chapter 3 builds on the study protocol in the form of a cohort profile, describing baseline characteristics of 120 people experiencing an acute LBP episode and 57 pain-free control participants that form the UPWaRD cohort. Chapter 4 reports the results of the multivariable prediction model developed in 120 people experiencing acute LBP. To further understand the importance of these prognostic factors we developed a causal model of chronic LBP using directed acyclic graphs. The methodology and statistical analysis plan for drawing causal inferences, thus transparently reporting our causal assumptions, are reported in Chapter 5. Chapter 6 then provides the first evidence that low sensory cortex excitability during an acute LBP episode is a causal mechanism underpinning the development of chronic LBP. Finally, in Chapter 7, we report the results of a proteomic analysis, using hydrophobic interaction chromatography and electrospray ionization tandem mass spectrometry. Taken together this thesis makes an extensive and original contribution to our understanding of neurobiological risk factors involved in the transition from acute to chronic LBP. Not only is the inclusion of neurobiological prognostic factors in multivariable clinical prediction models a promising direction for future research that aims to identify people at high risk of poor outcome, but low sensory cortex excitability during acute LBP may be a promising causal mechanism that future treatments could target during acute LBP in the hope of expediting recovery and preventing the development of chronic LBP. Further, this thesis provides some of the earliest evidence to suggest sex-specific differential expression of proteins, measured from human serum, contributes to recovery status at three-month follow-up. This work provides foundational evidence for future research exploring strategies targeting distinct immune system processes in males and females that may interfere with the transition from acute to chronic LBP.

Date of Award	2022
Original language	English