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Novel methods for the detection, risk stratification and management of early colorectal cancer and pre-malignant lesions
Get PDFColorectal cancer (CRC) is the 4th most common cancer in the United Kingdom (UK) with approximately 44,000 cases each year, and with 16,800 deaths, is the 2nd most common cause of cancer-related mortality. Outcome is directly linked to stage at diagnosis with 5-year survival estimated to be 90.9% for those with stage I disease, 84.3% for stage II, 65.0% for stage III and 10.5% for stage IV(1). Pathway to diagnosis in Scotland can be via symptomatic referral to an outpatient clinic, emergency symptomatic presentation or via the Scottish Bowel Screening Programme or surveillance colonoscopy. Screening in Scotland utilises a quantitative faecal immunochemical test (FIT) in individuals aged 50 to 74 years, followed by colonoscopy for those patients testing positive, at a faecal haemoglobin (f-Hb) threshold of 80 µg Hb/ g of faeces(2). Screening in this fashion increases the number of early-stage cancers diagnosed, reduces CRC-mortality and may reduce the incidence of CRC through the removal of precursor polyps(3-8). Unfortunately, screening only accounts for 19% of CRCs diagnosed in the West of Scotland(9). While the symptoms of CRC, including rectal bleeding, persistent change in bowel habit, abdominal pain and weight loss, are commonly present at the time of diagnosis, considerable symptomatic overlap exists with other significant bowel disease (advanced polyps and inflammatory bowel disease (IBD)) and functional bowel disorders. Therefore, the positive predictive value of such symptoms for CRC is low. Indeed, in a study of 384,510 colonoscopies performed in the UK, rectal bleeding and anaemia were associated with the highest adjusted positive predictive values (aPPV) for CRC (2.5% and 2.1% respectively), while all other symptoms were associated with a CRC aPPV of <1%(10). Conversely, FIT is a powerful objective biomarker of CRC-risk in symptomatic patients, with a linear relationship between f-Hb and CRC-risk observed(11). Consequently, in addition to its use in screening, FIT has now been widely embedded into symptomatic referral pathways as an effective means of triaging patients(11-22).
Chapter 1 provides a broad overview of the epidemiology, aetiology, signs and symptoms, investigation, staging and management of CRC.
In Chapter 2 the impact of integrating FIT into referral pathways from primary care to colorectal and gastroenterology was assessed in a cohort of 4968 symptomatic patients. Additionally, the association between CRC risk, symptoms, faecal haemoglobin (f-Hb) and anaemia were examined. GP referral and secondary care investigation patterns were indeed influenced by FIT, with a raised f-Hb correlating both with the decision to refer to secondary care and to perform colonoscopy. While rectal bleeding showed a positive correlation with CRC risk, no individual symptom independently predicted CRC on multivariate analysis. Conversely, both f-Hb and anaemia independently predicted CRC risk and represent valuable objective markers of risk in symptomatic patients. The combined absence of a raised f-Hb or anaemia effectively excluded CRC in 99.96% of cases.
In chapter 3 the results of a multicentred study of 5,761 patients investigating the prevalence of repeat FIT testing in primary care are presented. The study aimed to examine the relationship between serial f-Hb concentrations and CRC risk in symptomatic patients. Consecutive FIT tests submitted within 12 months of each other accounted for 9.1% of all FIT tests submitted to the laboratories of the Scottish health boards under investigation. CRC prevalence amongst patients with such serial FIT measurements was 0.7%, lower than the CRC rate observed in single FIT symptomatic cohorts. Patients with two f-Hb measurements <10µg/g had a significantly lower CRC risk (0.1%) than those with at least one f-Hb ≥10µg/g. As the number of FIT tests performed within a year rose, the likelihood of having a positive test rose, while the CRC rate fell. Performing two FITs within a year for patients with persistent symptoms therefore seems to be an effective safety netting practice, while performing more than two within this timeframe is unlikely to be beneficial.
In chapter 4, a cohort of 1,272 symptomatic patients who underwent FIT testing followed by colonoscopy was used to explore demographics and alternative lower gastrointestinal pathologies associated with a raised f-Hb. In addition to CRC, advanced adenomas, non advanced polyps and IBD independently predicted a raised f-Hb, as did older age, deprivation, use of oral anticoagulants and self-reported rectal bleeding. Deprivation independently predicted a raised f-Hb in patients with no pathology found at colonoscopy.
In chapter 5 attention was turned to the bowel screening programme. A cohort was established of 770 patients who underwent potentially curative resection for CRC. Patients were grouped based on diagnosis via screening or symptomatic pathways and the impact of important covariables, comorbidity and the systemic inflammatory response (SIR), on outcome was assessed. Patients with screen-detected disease had tumours of an earlier stage, were significantly less comorbid as measured by the American Society of Anaesthesiologists (ASA) score and had a significantly lower SIR as compared to non-screen-detected patients. Despite this, after adjusting for numerous covariables, non-screen-detection and a raised SIR independently predicted poorer overall and cancer specific survival.
In chapter 6 a prospective observational study of the management and outcomes of 236 patients with T1 polyp CRCs is presented. Male sex, older age, distally located lesions and pedunculated morphology were more likely to be managed with polypectomy only, while proximally located lesions and larger polyp size were more likely to proceed directly to formal colorectal resection. Younger age, requirement for piecemeal polypectomy and an involved polypectomy margin were associated with a higher chance of progressing to formal colorectal resection after polypectomy. Poor differentiation independently predicted lymph node involvement, submucosal venous invasion (SMVI) and mucinous-subtype predicted recurrence and SMVI predicted CRC-specific survival. Although 64.4% of polypectomy only patients had margin involvement or other high-risk factors, zero developed recurrence. Of 94 with polypectomy margin involvement, only 5 had confirmed residual tumour. Overall, lymph node metastases (7.1%), recurrence (4.2%) and cancer-specific mortality (3.0%) were rare. Surveillance following local excision of T1 CRC polyps may be safe for many patients.
Chapter 7 presents preliminary data from the Integrated Technologies for Improved Polyp Surveillance (INCISE) project; a large, retrospective, multi-partner collaborative aiming to use patient characteristics, digital pathology, immunohistochemistry (IHC), genomic and transcriptomic features of index polyp tissue to predict metachronous polyp risk and refine post-polypectomy surveillance. The INCISE cohort is formed of 2,643 patients who underwent polypectomy during screening colonoscopy followed by subsequent surveillance colonoscopy. In this particular sub-study, the most recent British Society of Gastroenterology post-polypectomy surveillance risk criteria (BSG-2020) were retrospectively applied to the cohort, such that 51.5% of patients would no longer qualify for surveillance. After a median 36 months, the metachronous advanced polyp/ CRC rate in BSG-2020 high risk patients was found to be only marginally greater than low risk individuals (16.3% vs 13.0%). Furthermore, while BSG 2020 risk stratification group was associated with a significant difference in overall metachronous lesion rate, it did not differentiate advanced and non-advanced metachronous lesions and was not significantly associated with late metachronous lesions detected after 2 years from index polypectomy, suggesting that current surveillance protocols would benefit from refinement.
In chapter 8 a review of established risk factors for metachronous polyp development is given, including patient demographics and comorbidities, chemopreventive medications and conventional polyp pathology. This precedes the results of a formal systematic review of all studies exploring genomics, transcriptomics, immunohistochemistry or features of the microbiome as novel biomarkers of metachronous polyp risk, following colorectal polypectomy. 4,165 paper titles, 303 abstracts and 215 full manuscripts were reviewed, with 25 papers included in the final study. 49 mutations/ SNPs/ haplotypes in 23 genes/ chromosomal regions (KRAS, APC, EGFR, COX1/2, IL23R, DRD2, CYP2C9/24A1/7A1, UGT1A6, ODC, ALOX12/15, PGDH, SRC, IGSF5, KCNS3, EPHB1/ KY, FAM188b, 3p24.1, 9q33.2, 13q33.2) were found to predict metachronous adenoma / advanced adenoma risk, while the expression levels of 6 proteins correlated with metachronous adenoma (p53, β-catenin, COX2, Adnab-9, ALDH1A1) or sessile serrated polyp (ANXA10) risk.
Chapter 9 explored the utility of COX2 and p53 expression as potential biomarkers for predicting metachronous polyp or CRC risk in INCISE cohort patients. 1,236 of 2,643 INCISE patients had tissue retrieved for immunohistochemical assessment, with 859 of those randomised to the training cohort and 377 to the test cohort. Formalin-fixed, paraffin-embedded tissue blocks of index polyp tissue were used to construct tissue microarrays (TMA) with four cores available per patient. The cores were stained with COX2 and p53 antibody and cytoplasmic COX2 expression and nuclear p53 expression were quantified digitally using QuPath software. On univariate analysis high cytoplasmic COX2 expression (p=0.019) predicted shorter time to detection of any metachronous lesion, as did key demographics such as increasing age (p=0.034) and pathological parameters such as increased polyp number at index colonoscopy (p<0.001) and BSG 2020 high risk (p<0.001). While high cytoplasmic COX2 expression retained significance as independent predictor of shorter time to development of any metachronous lesion on multivariate analysis (p=0.016), the positive association between COX2 expression and metachronous polyp or CRC risk could not be replicated within test cohort patients and therefore does not appear to represent a useful biomarker for this purpose.
Chapter 10 presents the results of a smaller pilot study, examining β-catenin as a potential biomarker for metachronous polyp or CRC risk. The same TMA constructed for chapter 9 was stained with β-catenin antibody. Nuclear β-catenin expression was assessed using QuPath software amongst 339 INCISE patients. Low β-catenin expression was found to predict a shorter time to detection of any metachronous polyp or CRC on both univariate and multivariate cox regression. Work is ongoing to score β-catenin expression in the whole cohort and validate these preliminary findings.
Finally, chapter 11 summarises the main findings of the thesis and lays out potential future work
Mental health challenges in the context of learning disabilities: a dual investigation of parental burnout and adolescent cyberbullying
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Modelling and mitigating optical turbulence in free-space optical communication systems
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Rubbish ritual performances in the use and disposition of clothing of rubbish value in Southwest Nigeria
Get PDFExtant theorisation following the social lives of consumption objects has yet to answer the question at the durable-rubbish interface of Thompson's (1979; 2017)Rubbish theory. Similarly, extant theorisation on divestment rituals has yet to transcend McCracken's (1986) transfer and reconfiguration of the cultural meanings of consumption objects. This is despite the bourgeoning works in both fields theorising the social lives of consumption objects that enter second-hand economies. Fashion objects remain consumption objects whose social life continues to attract significant attention since around the late 1960s (e.g. Winakor, 1969). The fashion industry is one of the world’s largest industries with a significant impact on both the environment and society. Fashion contributes significantly to global pollution (Brenot, Chuffart, Coste-Maniere, et al., 2019; Chavero, 2017; Colnago, 2019). The industry’s business model is one of “vertical disintegration and global dispersion of successive processes” (Niinimäki et al., 2020, 190). This model runs a linear system on a finite planet (Ellen MacArthur Foundation, 2017). Fashion's unsustainability is further complicated by ultra-fast fashion and throwaway consumption culture (Castellani et al., 2015; Hanson, 1980; Payne & Binotto, 2017; Weber, Lynes, & Young, 2017; Chavero, 2017; Dwyer, 2010; WRAP, 2012, 2017, 2017b; House of Commons, 2019).
The contributions of fashion to the current global climate crisis are necessitating actions like the value redefinition from unwanted to second-hand (Garcia Martin, 2016; Zamani, Sandin, & Peters, 2017) and other efforts to ‘fix fashion’ in the UK (DEFRA, 2018; House of Commons, 2019). Some UK fashion consumers are responding to calls to adopt reuse. Encouraged and supported by governance institutions and infrastructure, these consumers are diverting used clothing items from landfill by donating them to charity organisations (Bianchi & Birtwistle, 2010;Ha-Brookshire & Hodges, 2009a; Joung & Park-Poaps, 2013; Lee et al., 2013; Prosic-Dvornic, 2022; Shim, 1995; Wai Yee et al., 2016). However, millions of tonnes of the UK’s donated used clothing items are shipped to destinations outside the UK without traceability (House of Commons, 2021; WRAP, 2017b), where official trade records about the used clothing market are either missing or inaccurate (Brooks, 2019; Sumo et al., 2023). Moreover, as the epigraph at the beginning of this chapter illustrates, the future lives of used clothing donated to global second-hand economies have yet to receive significant research attention. To address this disconnect, this study examines the fate of the UK’s donated used clothing that is shipped to Nigeria. Theoretically, it answers the unaddressed question of transfer at the durable-rubbish interface of Thompson's (1979; 2017)Rubbish theory, i.e., where do objects in the durable category end up? It also uncovers the ritual dimensions that manifest through the use and disposal of the UK’s donated used clothing, which is shipped to Nigeria.
Three rubbish ritual performances are uncovered by following clothing items of rubbish value to their final destinations. These are deodourising, sanctifying and burning. Deodourising expands extant divestment rituals during the reacquisition of used clothing items. Deodourising is enacted to remove public meaning – i.e., the peculiar odour of second-handedness – and add private meanings – i.e., the consumers’ preferred fragrance. Deodourising helps them manage their identity and self-image and establish who they are. Sanctifying and burning are two novel divestment ritual dimensions used during the disposition of used clothing. Sanctifying represents a novel divestment ritual dimension enacted to ensure the safe transfer of meanings in used clothing without the detriment of reverse contagion. Sanctifying and burning reveals that previous users are gravely concerned about potential harm coming to them due to strangers accessing their essence that permeates their used possessions. The third novel divestment ritual that the study finds is burning. Although burning unwanted consumer objects is not new, burning used clothing to manage identity and prevent reverse contagion, as the current study finds, is a novel approach. Burning constitutes a divestment ritual with the intention of destroying rather than transferring meaning. Burning thus extends extant theorising on divestment rituals beyond its current
theorisation as meaning reconfiguration and transfer. Burning as a ritual performance also answers the unanswered question about the transfer at the durable-rubbish interface of Thompson’s rubbish theory. The findings in the current study evidence that the transfer at the durable-rubbish interface of the rubbish theory does occur. As a new permanent clothing disposition pathway, burning also extends extant taxonomy for clothing dispositio
Three essays on financial markets
Get PDFThe objective of this thesis is to investigate three distinct aspects of financial markets: (1) Credit Default Swaps and Bank Distress, (2) Deviations from Covered Interest Rate Parity for Sovereign Bonds and (3) Deviations from Covered Interest Rate Parity and Carry Trade.
It starts with the cross-country study which indicates how credit default swaps (CDS) predict bank distress for European banks. As bankruptcies in Europe are relatively rare, the paper introduces a new dataset that divides these banks into two categories (healthy and distressed banks) to examine the relationship between credit default swaps (CDS) and bank failure, together with bank information, market discipline and macro-economic indicators. Specifically, we define a future downgrade in financial condition as bank distress and we use four sets of variables: accounting indicators, market discipline, macroeconomic information and CDS to predict a future downgrade in bank’s financial condition. First, we conduct some logistic regresssions to investigate the explanatory power of credit default swap spreads on bank distress for European banks from 2005 to 2018. We conclude that after other variables are controlled for, CDS have strong and significant predictive power on future bank downgrade. In order to provide stronger evidence for such predictive power, we do some robustness tests: (1) short-term CDS on bank distress, (2) the impact of CDS on bank distress during crisis and out of crisis, (3) the explanatory power for small and large banks respectively. The result is that only out of financial crisis, CDS cannot explain much on bank distress. Therefore, we use data from 2005 to 2013 to examine a model for predicting bank failure in European banks using simulation after crisis. The key findings of this analysis are that CDS, together with bank-level and country-level indicators, improves the estimation model performance and generates more accurate out-of-sample predictions of bank distress.
For the second study, we examine deviations from covered interest parity (CIP) for sovereign bond market and three types of frictions that may cause CIP violation for bond pairs. In frictionless market, the no-arbitrage condition holds fairly well. However, arbitrage opportunities will exist after financial crisis due debt overhang. Therefore, from 2017 to 2019, we still find small CIP violations for sovereign bond markets due to bank regulation after financial crisis. The CIP violations are proxied by Basisbond. However, during Covid-19 crisis, we find the significant emergence of CIP violations for sovereign bond markets in three emerging markets (China, South Korea and Mexico). Besides, three different categories of frictions can help to explain large violations of sovereign bonds market especially during Covid-19 crisis. We choose bond pairs denominated in dollar and euro of China, South Korea and Mexico to study the impact of these frictions on bond price violations. We conclude that funding costs and macroeconomic conditions do influence CIP arbitrage opportunities for bond markets. In addition, we do some robustness tests to explore other possible determinants of the observed large basis for sovereign bonds during the COVID-19 shock: (1) the relationship of cash flow risk associated with bond characteristic and violation of defaultable sovereign bonds prices, (2) whether stock risk can explain CIP deviations for sovereign bonds, (3) the role of foreign exchange correlation risk and (4) the interaction of liquidity and economic conditions on CIP basis for bond pairs. The conclusion of robustness checks is that cash flow risk cannot explain bond price anomalies which means that we choose good bond pairs. Besides, stock risk, FX correlation risk and interply of liquidity and economic conditions cannot explain large CIP basis for sovereign bonds. Therefore, CIP arbitrage for bond markets can be only interpreted by increased secured funding cost and economic conditions.
For the third paper, we explore the relationship between deviations from the covered interest rate parity (CIP) and carry trade. Deviations from the covered interest rate parity (CIP) condition shows arbitrage opportunities in one of the largest asset markets. CIP violations could be explained by the constrained intermediaries after financial crisis. Large CIP deviations indicate that financial intermediaries are quite constrained, thus arbitragers could gain profits. During post-crisis period, large persistent deviations for major currencies are explained by debt overhang. The first section of this paper investigates the significant explanatory power of debt overhang on violations from covered interest parity after financial crisis. Then, the effect of quarter-end debt overhang on CIP deviations is examined. We conclude that tightened balance sheet constraints at week-ends translate into larger impact of debt overhang on CIP deviations in the post financial crisis period. Besides, we do an event study to examine this relationship especially during Covid-19 crisis. The finding is that as compared to the normal time, debt overhang during the Covid-19 crisis has a higher explanatory power. The second section of this paper is to adopt forward CIP trading strategy to compute excess return as a new indicator of CIP. After examining the impact of debt overhang on CIP deviations, we use cross-currency basis proxied by CIP violations to do carry trade by adopting forward CIP trading strategy that help identify the price of currency risk to do carry trade. We conclude that positive excess return of forward CIP trading strategy is associated with large deviations. In addition, we do some additional robustness tests: (1) we use return of forward CIP trading strategy as an alternative factor of CIP deviations, (2) we adopt a new indicator as a proxy of debt overhang and (3) We also consider the predictive power of 1-week debt overhang on 1-week CIP violations. The key findings of robustness tests are that there is there is a significant relationship between CIP deviations and debt overhang with the relationship being stronger for shorter maturities
Entrainment to speech rhythm from perception to production
Get PDFHuman speech comprehension requires a highly coordinated engagement of linguistic processes. Speech contains complex layers of information to be decoded and often acted on just-in-time. This thesis explores the possible role of speech rhythm in connecting the speech we hear to the speech we produce. Two methodological chapters are presented. The first reviews and evaluates different approaches to creating rhythmic speech stimuli. The second highlights the challenges of collecting precise and accurate auditory response times in web-based experiments. These methods are then applied to a series of three experiments, each building on the last. In a new experimental paradigm, participants responded verbally to simple maths sums where tempo and rhythm were manipulated. Both time-domain and frequency-domain analyses found effects of stimulus tempo on the timing of responses
The role of mothers’ non-transport pro-environmental behaviours in their children’s sustainable transport behaviours during adolescence and young adulthood
Get PDFPromoting sustainable transport behaviours (e.g. choosing public transport and active transport mode such as walking and cycling) among adolescents and young adults is critical for reducing transport-related greenhouse gas emissions. These sustainable transport behaviours fall under the category of pro-environmental behaviours which are defined as behaviours that reduce negative impacts or even positively impact the environment. Other pro-environmental behaviours include, for example, recycling, energy conservation, eco-friendly purchasing, and waste reduction. Previous studies have established the correlation between parents’ sustainable transport behaviours during children’s socialisation (e.g. during their children’s adolescence) and their children’s adoption of these sustainable transport behaviours during adolescence and young adulthood. However, the role of parents’ other pro-environmental behaviours, such as energy conservation and eco-friendly purchasing (referred to as Non-Transport Pro-Environmental Behaviours (NTPEB) in this thesis), in their children’ssustainable transport behaviours during adolescence and young adulthood has not been investigated. Exploring the role of these parental NTPEB is essential since these behaviours exhibit greater susceptibility to intervention measures and have higher participation rates than sustainable transport behaviours. This could create improved intervention opportunities for promoting sustainable transport behaviour among adolescents and young adults.
Given that mothers have a more substantial influence than fathers in shaping their children’s education, behaviours, and attitudes, this study primarily investigated mothers’NTPEB in shaping their children’s sustainable transport behaviours during adolescence and young adulthood. This U.K.-focused thesis empirically examined four interconnected research questions to achieve this aim.
The first research question investigated the relationship between mothers’ NTPEB during their children’s adolescence (ages 10–15 years) and their children’s choice of sustainable transport modes (e.g. active transport like walking and cycling and public transport like buses and subways) for their journeys to school during this period. This relationship was investigated via multinomial logistic regression using data from the fourth wave of the UK Household Longitudinal Study (UKHLS). The findings indicated a positive relationship between the frequency of mothers’ NTPEB and the likelihood of their adolescent children choosing public transport to school. Importantly, more easily observable mothers’ NTPEB hold a stronger strength of correlation with the likelihood of adolescents’ use of public transport to school compared to maternal psychological factors like pro-environmental attitudes.
The second and third research questions separately analysed the role of mothers’ NTPEB during their children’s adolescence in their children’s frequency of sustainable transport behaviours (encompassing all travel purposes) and the choice of sustainable transport methods for commuting to work in young adulthood. The second research question was explored through structural equation models, which used data from Waves 4 and 10 of the UKHLS. The findings revealed an indirectly but no directly positive influence of the frequency of maternal NTPEB on children’s frequency of sustainable transport behaviours as young adults. This indirectly positive influence was mediated by children’s pro-environmental attitudes as young adults. The third research question, which employed an integrated choice and latent variable model, identified a similar indirect correlation between the frequency of maternal NTPEB during their children’s adolescence and the likelihood of children’s sustainable transport choice for travelling to work as young adults.
The final research question in this thesis validated the hypothesis of an association between mothers’ NTPEB during their children’s adolescence and the persistent adoption of sustainable transport choices by their children from adolescence through young adulthood. Data from Waves 4 and 10 of the UKHLS were analysed using the integrated choice and latent variable model to validate this hypothesis. Therefore, this thesis’s findings provide a new perspective for understanding the determinants of sustainable transport behaviours among adolescents and young adults and reveal pathways of intergenerational transmission of pro-environmental behaviours from mother to children. In addition, this thesis includes implications for developing interventions to promote sustainable transport behaviour
The interplay between the gut metabolome and immune system and their role on the efficacy of neoadjuvant chemotherapy in early breast cancer
Get PDFPromising results have identified the gut microbiome and immune system as important modulators of response to cancer therapies. This provided a rationale for the current study to explore their combined roles on influencing response to neoadjuvant chemotherapy (NACT) in early-breast cancer patients enrolled in the NEO-MICROBE BREAST clinical study. This study aimed to characterise the composition of metabolites within the gut by conducting LCMS analysis on stool samples from cancer patients. A second aim was to start the process of immunophenotyping peripheral blood mononuclear cells through optimisation of a novel 10-colour flow cytometry panel.
Untargeted and targeted metabolomics data analysis of the stool samples profiled the gut metabolic environment of cancer patients and healthy volunteers highlighting several metabolites indicative of NACT response: elucidating alpha-ketoglutarate (aKG) and citrate as potential biomarkers for achievement of pathological complete response, associating guanine and uridine with non-response to NACT and uridine-5’-monophosphate (UMP) potentially linked to cancer status. In combination with metabolomic analysis of blood samples from the same cohort; glutamate demonstrated a correlation between higher stool- and blood- derived levels in TNBC patients, demonstrating potential direct involvement of glutamate in the response to NACT.
A 10-colour panel was generated and optimised via flow cytometry analysis of PBMCs from healthy blood donors and its ability to successfully identify T cell subsets associated with breast cancer was validated. Upon further validation to allow for optimal marker detection, this panel provides the foundation for future PBMC immunophenotyping of this cohort. Overall, this study strengthens the evidence that NACT efficacy may be influenced by the involvement of gut-derived metabolites and systemic modulation; and highlights the importance of the immune-profiling of breast cancer to allow for a comprehensive approach to improve NACT response via personalised treatment
CD180 in KMT2A-rearranged paediatric acute myeloid leukaemia: A novel biomarker for chemoresistance and relapse
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Validation of submaximal heart rate recovery as a perioperative risk measure
Get PDFThe number and complexity of patients presenting for surgery is increasing, with postoperative morbidity placing considerable burden on the health service, as well as negatively impacting patients’ quality and length of life. Effective preoperative risk stratification assesses the likelihood of poor postoperative outcomes so appropriate perioperative strategies can be implemented to reduce the incidence and severity of complications. Current risk stratification modalities include risk scores, biomarkers and assessment of cardiorespiratory fitness via exercise testing. The predictive value of these modalities however is variable. Preoperative risk scores involve a degree of subjectivity, particularly in the assessment of functional capacity. Cardiorespiratory fitness as measured by cardiopulmonary exercise testing (CPET) is an objective measure and associated with postoperative outcome. However, CPET is resource-intensive and not appropriate for all patients.
The aim of this thesis was to assess the utility of heart rate recovery (HRR) after submaximal exercise as a preoperative risk measure. Heart rate recovery is a marker of cardiac vagal tone and is prognostic for mortality and cardiovascular events in patients with cardiovascular disease and the general population. Systematic review performed as part of this thesis demonstrated that impaired HRR is associated with poor postoperative outcomes in individual studies, although evidence is limited (Chapter 2). Subsequently it was hypothesised that submaximal HRR could provide an objective preoperative risk prediction measure with broad applicability.
The validity of submaximal HRR in the perioperative population was investigated. The study was performed in three hospitals in the West of Scotland. Eighty-four patients (aged over 50 years) performed a submaximal step test in pre-assessment clinic or the ward prior to elective noncardiac surgery, with continuous electrocardiography for determination of HRR parameters. Perioperative data was collected, including cardiac troponins for the primary outcome of postoperative myocardial injury (PMI). Criterion, predictive, face, construct and concurrent validity were assessed in a series of investigations.
The first investigation of this thesis (Chapter 6) explored the predictive value of submaximal HRR in a cohort of 64 patients who underwent the step test and surgery, with PMI data for analysis. A range of different HRR parameters were assessed for predictive value for PMI, including absolute values, area under the heart rate recovery versus time curve and effort-corrected values, to both proportion of age-predicted maximum HR and proportion of predicted maximum power output reached. Six of the parameters demonstrated predictive value for PMI (area under the receiver operator curve (AUROC) > 0.64 for all), comparable to preoperative risk prediction measures currently in use. Submaximal HRR measured one minute after exercise cessation (HRR1) demonstrated fair predictive value for PMI (AUROC 0.69, 95% confidence interval 0.55 – 0.82). Furthermore, addition of submaximal HRR1 improved the predictive performance of a selection of preoperative risk scores in current use.
Secondary analyses (Chapter 7) explored the face validity of submaximal HRR in 72 patients who underwent both the step test and surgery. Submaximal HRR1 was associated with renal complications and intensive care admission, indicating face validity. However, there was no association between other secondary outcomes and HRR parameters.
The third investigation (Chapter 8) explored construct validity of submaximal HRR in 81 patents who underwent the step test and NT-ProBNP measurement, DASI, SORT, RCRI and POSSUM risk calculation. Submaximal HRR1 demonstrated construct validity via significant association with SORT mortality; ACS NSQIP SRC risk of any postoperative complication and length of hospital stay; DASI; RCRI and POSSUM mortality and morbidity risk.
The fourth investigation (Chapter 9) explored both criterion and concurrent validity of submaximal HRR in 12 patients who underwent the submaximal step test and CPET. Submaximal HRR did not demonstrate association with anaerobic threshold (AT), peak oxygen consumption or the ventilatory equivalent of carbon dioxide at AT and so criterion validity was not demonstrated. Concurrent validity was not reliably demonstrated, which may reflect the different aspects of cardiorespiratory fitness measured by HRR and CPET. Patients tolerated both exercise tests well but found the step test more comfortable and acceptable to perform (Chapter 10).
The work within this thesis confirms that submaximal HRR is a well-tolerated, feasible and valid measure in the perioperative population. From the range of HRR parameters measured, submaximal HRR1 consistently performed well, demonstrating predictive, face and construct validity. Future work may focus on the incorporation of submaximal HRR1 into preoperative risk assessment models; HRR measurement in the community; and integration of submaximal HRR into prehabilitation programmes
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