An Excess of Risk-Increasing Low-Frequency Variants Can Be a Signal of Polygenic Inheritance in Complex Diseases

In most complex diseases, much of the heritability remains unaccounted for by common variants. It has been postulated that lower-frequency variants contribute to the remaining heritability. Here, we describe a method to test for polygenic inheritance from lower-frequency variants by using GWAS summary association statistics. We explored scenarios with many causal low-frequency variants and showed that there is more power to detect risk variants than to detect protective variants, resulting in an increase in the ratio of detected risk to protective variants (R/P ratio). Such an excess can also occur if risk variants are present and kept at lower frequencies because of negative selection. The R/P ratio can be falsely elevated because of reasons unrelated to polygenic inheritance, such as uneven sample sizes or asymmetric population stratification, so precautions to correct for these confounders are essential. We tested our method on published GWAS results and observed a strong signal in some diseases (schizophrenia and type 2 diabetes) but not others. We also explored the shared genetic component in overlapping phenotypes related to inflammatory bowel disease (Crohn disease [CD] and ulcerative colitis [UC]) and diabetic nephropathy (macroalbuminuria and end-stage renal disease [ESRD]). Although the signal was still present when both CD and UC were jointly analyzed, the signal was lost when macroalbuminuria and ESRD were jointly analyzed, suggesting that these phenotypes should best be studied separately. Thus, our method may also help guide the design of future genetic studies of various traits and diseases.

Small RNAs from plants, bacteria and fungi within the order Hypocreales are ubiquitous in human plasma

Background

The human microbiome plays a significant role in maintaining normal physiology. Changes in its composition have been associated with bowel disease, metabolic disorders and atherosclerosis. Sequences of microbial origin have been observed within small RNA sequencing data obtained from blood samples. The aim of this study was to characterise the microbiome from which these sequences are derived.

Abundant non-human small RNA sequences were identified in plasma and plasma exosomal samples. Assembly of these short sequences into longer contigs was the pivotal novel step in ascertaining their origin by BLAST searches. Most reads mapped to rRNA sequences. The taxonomic profiles of the microbes detected were very consistent between individuals but distinct from microbiomes reported at other sites. The majority of bacterial reads were from the phylum Proteobacteria, whilst for 5 of 6 individuals over 90% of the more abundant fungal reads were from the phylum Ascomycota; of these over 90% were from the order Hypocreales. Many contigs were from plants, presumably of dietary origin.  In addition, extremely abundant small RNAs derived from human Y RNAs were detected.

A characteristic profile of a subset of the human microbiome can be obtained by sequencing small RNAs present in the blood. The source and functions of these molecules remain to be determined, but the specific profiles are likely to reflect health status. The potential to provide biomarkers of diet and for the diagnosis and prognosis of human disease is immense.

Release of β-galactosidase from poloxamine/α-cyclodextrin hydrogels

All mammals lose their ability to produce lactase (β-galactosidase), the enzyme that cleaves lactose into galactose and glucose, after weaning. The prevalence of lactase deficiency (LD) spans from 2 to 15% among northern Europeans, to nearly 100% among Asians. Following lactose consumption, people with LD often experience gastrointestinal symptoms such as abdominal pain, bowel distension, cramps and flatulence, or even systemic problems such as headache, loss of concentration and muscle pain. These symptoms vary depending on the amount of lactose ingested, type of food and degree of intolerance. Although those affected can avoid the uptake of dairy products, in doing so, they lose a readily available source of calcium and protein. In this work, gels obtained by complexation of Tetronic 90R4 with α-cyclodextrin loaded with β-galactosidase are proposed as a way to administer the enzyme immediately before or with the lactose-containing meal. Both molecules are biocompatible, can form gels in situ, and show sustained erosion kinetics in aqueous media. The complex was characterized by FTIR that evidenced an inclusion complex between the polyethylene oxide block and α-cyclodextrin. The release profiles of β-galactosidase from two different matrices (gels and tablets) of the in situ hydrogels have been obtained. The influence of the percentage of Tetronic in media of different pH was evaluated. No differences were observed regarding the release rate from the gel matrices at pH 6 (t50 = 105 min). However, in the case of the tablets, the kinetics were faster and they released a greater amount of 90R4 (25%, t50 = 40–50 min). Also, the amount of enzyme released was higher for mixtures with 25% Tetronic. Using suitable mathematical models, the corresponding kinetic parameters have been calculated. In all cases, the release data fit quite well to the Peppas–Sahlin model equation, indicating that the release of β-galactosidase is governed by a combination of diffusion and erosion processes. It has been observed that the diffusion mechanism prevails over erosion during the first 50 minutes, followed by continued release of the enzyme due to the disintegration of the matrix.

A population-based study of adverse physical effects following prostate cancer treatments: Results from the PiCTure (Prostate cancer treatment – your experience) study

Background:

Men and clinicians need reliable population based information when making decisions about investigation and treatment of prostate cancer. In the absence of clearly preferred treatments, differences in outcomes become more important.

Aim:

To investigate rates of adverse physical effects among prostate cancer survivors 2-15 years post diagnosis by treatment, and estimate population burden.

Methods:

A cross sectional, postal survey to 6,559 survivors (all ages) diagnosed with primary, invasive prostate cancer (ICD10-C61), identified in Northern Ireland and the Republic of Ireland via cancer registries. Questions included symptoms at diagnosis, treatments received and adverse physical effects (impotence, urinary incontinence, bowel problems, breast changes, libido loss, hot flashes, fatigue) experienced ‘ever’ and ‘current’ i.e. at questionnaire completion. Physical effect levels were weighted by age, country and time since diagnosis for all prostate cancer survivors. Bonferroni corrections were applied to account for multiple comparisons.

Results:

Adjusted response rate 54%, (n=3,348). 75% reported at least one current physical effect (90% ever), with 29% reporting at least three. These varied by treatment. Current impotence was reported by 76% post-prostatectomy, 64% post-external beam radiotherapy with hormone therapy, with average for all survivors of 57%. Urinary incontinence (overall current level: 16%) was highest post-prostatectomy (current 28%, ever 70%). 42% of brachytherapy patients reported no current adverse physical effects; however 43% reported current impotence and 8% current incontinence. Current hot flashes (41%), breast changes (18%) and fatigue (28%) were reported more commonly by patients on hormone therapy.

Conclusions:

This study provides evidence that adverse physical effects following prostate cancer represent a significant public health burden; an estimated 1.6% of men over 45 is a prostate cancer survivor with a current adverse physical effect. This information should facilitate investigation and treatment decision-making and follow-up care of patients.

Patient-reported 'ever had' and 'current' long term physical symptoms following prostate cancer treatments

OBJECTIVE: To document prostate cancer patient reported 'ever experienced' and 'current' prevalence of disease specific physical symptoms stratified by primary treatment received.
PATIENTS: 3,348 prostate cancer survivors 2-15 years post diagnosis.
METHODS: Cross-sectional, postal survey of 6,559 survivors diagnosed 2-15 years ago with primary, invasive PCa (ICD10-C61) identified via national, population based cancer registries in Northern Ireland and Republic of Ireland. Questions included symptoms at diagnosis, primary treatments and physical symptoms (impotence/urinary incontinence/bowel problems/breast changes/loss of libido/hot flashes/fatigue) experienced 'ever' and at questionnaire completion ("current"). Symptom proportions were weighted by age, country and time since diagnosis. Bonferroni corrections were applied for multiple comparisons.
RESULTS: Adjusted response rate 54%; 75% reported at least one 'current' physical symptom ('ever':90%), with 29% reporting at least three. Prevalence varied by treatment; overall 57% reported current impotence; this was highest following radical prostatectomy (RP)76% followed by external beam radiotherapy with concurrent hormone therapy (HT); 64%. Urinary incontinence (overall 'current' 16%) was highest following RP ('current'28%, 'ever'70%). While 42% of brachytherapy patients reported no 'current' symptoms; 43% reported 'current' impotence and 8% 'current' incontinence. 'Current' hot flashes (41%), breast changes (18%) and fatigue (28%) were reported more often by patients on HT.
CONCLUSION: Symptoms following prostate cancer are common, often multiple, persist long-term and vary by treatment. They represent a significant health burden. An estimated 1.6% of men over 45 is a prostate cancer survivor currently experiencing an adverse physical symptom. Recognition and treatment of physical symptoms should be prioritised in patient follow-up. This information should facilitate men and clinicians when deciding about treatment as differences in survival between radical treatments is minimal.

Long-term health-related quality of life of prostate cancer survivors varies by primary treatment. Results from the PiCTure (Prostate Cancer Treatment, your experience) study

PURPOSE: Men are living longer with prostate cancer. In a two-country study, we investigated the health-related quality of life (HRQoL) of prostate cancer survivors up to 18 years post-diagnosis.

METHODS: Postal questionnaires were administered in 2012 to 6559 prostate cancer (ICD10 C61) survivors 2-18 years post-diagnosis, identified through population-based cancer registries in Ireland. HRQoL was measured using QLQ-C30 and QLQ-PR25. HRQoL, functional and symptom scores were compared by primary treatment(s) using multiple linear regression.

RESULTS: Fifty-four percent responded (n = 3348). After controlling for socio-demographic and clinical factors, global HRQoL varied significantly by primary treatment (p < 0.001); compared to radical prostatectomy (RP), survivors who received androgen deprivation therapy alone (ADT; p < 0.001) or external beam radiotherapy (EBRT) without concurrent ADT (p = 0.001) had significantly lower global HRQoL. The global HRQoL of men who received brachytherapy (p = 0.157), EBRT with concurrent ADT (p = 0.940) or active surveillance/watchful waiting (p = 0.388) was not significantly different from men treated with RP. There were statistically and clinically significant differences in general (fatigue, pain, dyspnoea, appetite loss, constipation, diarrhoea, financial difficulties) and disease-specific symptoms (sexual, urinary, bowel, ADT) by primary treatment. Fatigue and insomnia scores were high for survivors in all treatment groups.

CONCLUSIONS: Prostate cancer survivors' long-term HRQoL varied with primary treatment.

IMPLICATIONS OF CANCER SURVIVORS: Population-based information regarding statistically and clinically significant treatment effects on long-term global HRQoL, symptom burden and functionality should be provided during treatment decision-making. Screening for symptoms and utilising interventions during long-term follow-up may improve survivors' HRQoL.

FOXP3+ regulatory T-cell counts correlate with histological response in Crohn's colitis treated with infliximab

Crohn's disease is a chronic inflammatory bowel disease of unknown aetiology. Mucosal inflammatory dysregulation is likely important, with increased production of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNFα). The chimeric monoclonal antibody, infliximab, inhibits TNFα and promotes intestinal mucosal healing. Despite this, many patients still require surgical intervention. Patients who have undergone colonic resection post-infliximab therapy, show markedly variable morphological response to treatment. FOXP3+ CD4+ regulatory T-cells have been shown to have a protective role in autoimmune/inflammatory diseases and their sequestration to the bowel is found in those treated with infliximab. We examined the immunohistochemical profile of lymphoid aggregates in tissue sections from post-infliximab Crohn's colitis resection specimens, classified as morphological responders or non-responders, defined in relation to the absence/presence of mucosal ulceration and active inflammation, and a control group. Results indicated no significant diffences in CD68-positive cell counts but increased FOXP3-positive (P = 0.02) and CD4-positive (P = 0.05) cell counts in responders versus non-responders. Untreated control scores were similar to non-responders. Although based on small study numbers, our results suggest an association between upregulation of FOXP3+/CD4+ regulatory T-cells and morphological response to infliximab therapy. This represents a possible quantitative methodology for monitoring therapeutic response to infliximab therapy, based on immunohistochemical evaluation of endoscopic biopsy specimens.

Sector analysis provides additional spatial information on the permanent prostate brachytherapy learning curve

PURPOSE: To evaluate the permanent prostate brachytherapy (PPB) learning curve using postimplant multisector dosimetric analysis and to assess the correlation between sector -specific dosimetry and patient-reported outcome measures (PROMs).

METHODS AND METHODS: First 200 patients treated with (125)I PPB monotherapy (145 Gy) at a single institution were assessed. Postimplant dosimetry (PID) using CT was evaluated for whole prostate (global) and 12 sectors, assessing minimum dose to 90% of prostate (D90) and dose to 0.1 cm(3) of rectum (D0.1cc). Global and sector PID results were evaluated to investigate changes in D90 with case number. Urinary and bowel PROMs were assessed using the International Prostate Symptom Score and the Expanded Prostate Cancer Index Composite questionnaire. The correlation between global and individual sector PID and urinary/bowel PROMs was also evaluated.

RESULTS: Linear regression confirmed a significant improvement in global D90 with case number (r(2) = 0.20; p = 0.001) at a rate of 0.11 Gy/case. Postimplant D90 of base sectors increased at a rate of 0.11-0.15 Gy/case (p = 0.0001) and matched global improvement. The regression lines of midgland and apex sectors were significantly different from global D90 (p = 0.01). Posterior midgland sectors showed a significant reduction in D90 with case number at a rate of 0.13-0.19 Gy/case (p = 0.01). Dose to posterior midgland sectors correlated with rectal D0.1cc dose but not bowel PROMs. Dose to posterior midgland sectors correlated with urinary International Prostate Symptom Score change, which was not apparent when global D90 alone was considered.

CONCLUSIONS: Sector analysis provided increased spatial information regarding the PPB learning curve. Furthermore, sector analysis correlated with urinary PROMs and rectal dose.

Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

BACKGROUND: Patient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial.

METHODS: The CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b-T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer-generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923.

FINDINGS: 2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50·0 months (IQR 38·4-64·2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0·59). We saw no differences between treatment groups in change of bowel bother score from baseline or pre-radiotherapy to 24 months.

INTERPRETATION: The incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy. If efficacy outcomes from CHHiP show non-inferiority for hypofractionated treatments, these findings will add to the growing evidence for moderately hypofractionated radiotherapy schedules becoming the standard treatment for localised prostate cancer.

FUNDING: Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

A comparison of endoscopy versus pathology sizing of colorectal adenomas and potential implications for surveillance colonoscopy

Background and AimsTo compare endoscopy and pathology sizing in a large population-based series of colorectal adenomas and to evaluate the implications for patient stratification into surveillance colonoscopy.MethodsEndoscopy and pathology sizes available from intact adenomas removed at colonoscopies performed as part of the Northern Ireland Bowel Cancer Screening Programme, from 2010 to 2015, were included in this study. Chi-squared tests were applied to compare size categories in relation to clinicopathological parameters and colonoscopy surveillance strata according to current American Gastroenterology Association and British Society of Gastroenterology guidelines.ResultsA total of 2521 adenomas from 1467 individuals were included. There was a trend toward larger endoscopy than pathology sizing in 4 of the 5 study centers, but overall sizing concordance was good. Significantly greater clustering with sizing to the nearest 5 mm was evident in endoscopy versus pathology sizing (30% vs 19%, p<0.001), which may result in lower accuracy. Applying a 10-mm cut-off relevant to guidelines on risk stratification, 7.3% of all adenomas and 28.3% of those 8 to 12 mm in size had discordant endoscopy and pathology size categorization. Depending upon which guidelines are applied, 4.8% to 9.1% of individuals had differing risk stratification for surveillance recommendations, with the use of pathology sizing resulting in marginally fewer recommended surveillance colonoscopies.ConclusionsChoice of pathology or endoscopy approaches to determine adenoma size will potentially influence surveillance colonoscopy follow-up in 4.8% to 9.1% of individuals. Pathology sizing appears more accurate than endoscopy sizing, and preferential use of pathology size would result in a small, but clinically important, decreased burden on surveillance colonoscopy demand. Careful endoscopy sizing is required for adenomas removed piecemeal.

Development of a Parent Version of the Manchester-Minneapolis Quality of Life Survey for use by Parents and Crers of UK Children: MMQL-UK (PF).

Background Although it is now widely endorsed that children should as far as possible rate their own health related quality of life (HRQL), there are situations where proxy information on child HRQL may be useful, especially where a child is too ill or young to provide their own HRQL assessment. There is limited availability of generic HRQL scales that have a parallel child and parent version and that are reliable, valid, brief, comprehensible and suitable for use in UK populations. The aims of this study were therefore to develop and validate a parent version of the anglicised Manchester-Minneapolis Quality of Life child form (MMQL-UK (CF)) and to determine the level of association between the child and parent versions of this form. Methods This study was undertaken concurrently with the anglicisation and validation of the MMQL, a measure of HRQL developed for use with children in North America. At that time, no parent version existed, so the MMQL form for children (MMQL-UK (CF)) was used as the basis for the development of the MMQL-UK parent form (PF). The sample included a control group of healthy children and their parents and five exemplar groups; children diagnosed with asthma, diabetes or inflammatory bowel disease and their parents, children in remission from cancer and their parents and children in public care and their carers. Consistency of the MMQL-UK (PF) components were assessed by calculating Cronbach's alpha. Validation of the parent questionnaire was undertaken by comparing MMQL-UK (PF) component scores with comparable components on the proxy PedsQL™ quality of life scales, comparing MMQL-UK (PF) component scores between parents of healthy and chronic disease children and by comparison of component scores from children and their parents or carers. Reproducibility and responsiveness were assessed by retesting parents by follow-up questionnaires. Results A total of 874 children (completing MMQL-UK (CF)) and 572 parents or carers (completing MMQL-UK (PF)) took part in the study. The internal consistency of all the MMQL-UK (PF) components exceeding the accepted criterion of 0.70 and the construct validity was good with moderate correlations being evident between comparable components of the MMQL-UK (PF) and the proxy PedsQL™. Discriminant validity was demonstrated with significant differences being identified between parents of healthy children and those with chronic conditions. Intra-class correlations exceeded 0.65 for all MMQL-UK (PF) components demonstrating good reproducibility. Weak to moderate levels of responsiveness were demonstrated for all but social functioning. The MMQL-UK (PF) showed moderate parent-child correlation with the MMQL-UK (CF) for all components. The best correlations were seen for those components measuring the same construct (Pearson's r ranged from 0.31 to 0.61, p < 0.01 for equivalent components). Conclusion The MMQL-UK (PF) showed moderate to good correlations with the MMQL-UK (CF) component scores. The MMQL-UK (PF) will be of use when comparing child and parent/carer perception of the impact of a child's condition on their HRQL or where the child is too ill or young to provide their own report.

Celiac disease diagnosis and gluten-free food analytical control

Celiac disease (CD) is an autoimmune enteropathy, characterized by an inappropriate T-cell-mediated immune response to the ingestion of certain dietary cereal proteins in genetically susceptible individuals. This disorder presents environmental, genetic, and immunological components. CD presents a prevalence of up to 1% in populations of European ancestry, yet a high percentage of cases remain underdiagnosed. The diagnosis and treatment should be made early since untreated disease causes growth retardation and atypical symptoms, like infertility or neurological disorders. The diagnostic criteria for CD, which requires endoscopy with small bowel biopsy, have been changing over the last few decades, especially due to the advent of serological tests with higher sensitivity and specificity. The use of serological markers can be very useful to rule out clinical suspicious cases and also to help monitor the patients, after adherence to a gluten-free diet. Since the current treatment consists of a life-long glutenfree diet, which leads to significant clinical and histological improvement, the standardization of an assay to assess in an unequivocal way gluten in gluten-free foodstuff is of major importance.

Anti-Tumor Necrosis Factor Alpha-Induced Drug Eruptions: One Patient, More Than a Pattern

Background: Tumor necrosis factor alpha (TNFα) antagonists are effective in treating several immune-inflammatory diseases, including psoriasis and inflammatory bowel disease. The paradoxical and unpredictable induction of psoriasis and psoriasiform skin lesions is a recognized adverse event, although of unclear aetiology. However, histological analysis of these eruptions remains insufficient, yet suggesting that some might constitute a new pattern of adverse drug reaction, rather than true psoriasis. Case report: The authors report the case of a 43-year-old woman with severe recalcitrant Crohn disease who started treatment with infliximab. There was also a personal history of mild plaque psoriasis without clinical expression for the past eight years. She developed a heterogeneous cutaneous eruption of psoriasiform morphology with pustules and crusts after the third infliximab infusion. The histopathological diagnosis was of a Sweet-like dermatosis. The patient was successfully treated with cyclosporine in association with both topical corticosteroid and vitamin D3 analogue. Three weeks after switching to adalimumab a new psoriasiform eruption was observed, histologically compatible with a psoriasiform drug eruption. Despite this, and considering the beneficial effect on the inflammatory bowel disease, it was decided to maintain treatment with adalimumab and to treat through with topicals, with progressive control of skin disease. Discussion: Not much is known about the pathogenesis of psoriasiform eruptions induced by biological therapies, but genetic predisposition and Koebner phenomenon may contribute to it. Histopathology can add new facets to the comprehension of psoriasiform reactions. In fact, histopathologic patterns of such skin lesions appear to be varied, in a clear asymmetry with clinical findings. Conclusion: The sequential identification in the same patient of two clinical and histopathologic patterns of drug reaction to TNFα antagonists is rare. Additionally, to the authors’ knowledge, there is only one other description in literature of a TNFα antagonist-induced Sweet-like dermatosis, emphasizing the singularity of this case report.

Osmolality of Elemental and Semi-Elemental Formulas Supplemented with Nonprotein Energy Supplements

Elemental and semi-elemental formulas are used to feed infants with short bowel syndrome, who may not be able to tolerate feeds of more than 310 mOsm kg(-1). The present study aimed to measure the osmolality of elemental and semi-elemental formulas at different concentrations, with and without the addition of nonprotein energy supplements.

Essays in health economics: Volume-Outcome Effect, upcoding behaviour and the evaluation of a short-term intervention program

Evidence in the literature suggests a negative relationship between volume of medical procedures and mortality rates in the health care sector. In general, high-volume hospitals appear to achieve lower mortality rates, although considerable variation exists. However, most studies focus on US hospitals, which face different incentives than hospitals in a National Health Service (NHS). In order to add to the literature, this study aims to understand what happens in a NHS. Results reveal a statistically significant correlation between volume of procedures and better outcomes for the following medical procedures: cerebral infarction, respiratory infections, circulatory disorders with AMI, bowel procedures, cirrhosis, and hip and femur procedures. The effect is explained with the practice-makes-perfect hypothesis through static effects of scale with little evidence of learning-by-doing. The centralization of those medical procedures is recommended given that this policy would save a considerable number of lives (reduction of 12% in deaths for cerebral infarction).