Long term experience of robotic retroperitoneal partial nephrectomy as the default approach in the management of renal masses: should the paradigm shift?

Although retroperitoneal surgery has demonstrated a better quality of recovery compared to transperitoneal routes, Retroperitoneal Robot Assisted Partial Nephrectomy (RRAPN) remains proportionally infrequent. As the boundaries of what is achievable robotically continue to be pushed, we present our experience at a high-volume tertiary referral centre that specialises in retroperitoneal surgery, exploring its feasibility as standard of care in the management of small renal masses. A prospective database of 784 RAPNs (2009-2020) was reviewed and 721 RRAPNs (92%) were performed at our centre. In our practice, we utilise a four-port approach to RRAPN. Patient, tumour and operative characteristics were assessed and both oncological outcomes and trifecta and pentafecta achievements were determined. Pentafecta was defined as achieving trifecta (negative surgical margin, no post-operative complications and WIT of < 25 min) plus over 90% estimated GFR preservation and no CKD stage upgrading at 1 year. Multivariate analysis was conducted to predict peri-operative factors which may prevent achieving a trifecta/pentafecta outcome. From 784 cases, 112 RAPNs were performed for imperative reasons, whilst the remainder were elective. Mean BMI ± s.d amongst our cohort was 28.6 ± 5.7. Mean tumour size was 3.1 cm (range 0.8-10.5 cm) and 47% of cases were stratified as intermediate/high risk using R.E.N.A.L nephrometry scoring. Forty-six patients had lesions in a hilar location, and 31% were anterior. Median blood loss was 30mls, with an open conversion rate of 1% and transfusion rate of 1.6%. Median warm ischaemic time (WIT) was 21 min, positive surgical margins were found in 4% and our post-operative Clavien 3/ > complication rate was 2.6%. We had a 1-day median length of stay with a 30 day readmission rate of 2%. Of 631 patients (80%) with a definitive histological diagnosis of cancer, 23% had T1b/ > disease. Over a mean 15 month follow-up period (range 1-125 months), 2% of patients developed recurrences and our cohort demonstrated a 99% 5 year cancer specific survival. Trifecta was achieved in 67% of cases and pentafecta in 47%. Age (p = 0.05), operative time (p = 0.008), pT1b tumours (p = 0.03), R.E.N.A.L score and blood loss (p = 0.001) were found to statistically significantly influence achievement of trifecta. Pentafecta achievement was influenced by R.E.N.A.L score (p = 0.008), operative time (p = 0.001) and blood loss (p = 0.001). We demonstrate the retroperitoneal approach in RAPN is feasible and safe irrespective of lesion location and complexity. In the hands of high-volume centres that are skilled in the retroperitoneal approach the benefits of retroperitoneal surgery can be extended even to challenging cohorts of patients without compromising their oncological or functional outcomes.

A retrospective audit of the timescales involved in the diagnosis and management of suspected Achilles tendon ruptures at a single National Health Service trust: A quality service improvement and redesign project.

Introduction: The Achilles tendon is the most frequently ruptured tendon. Prompt diagnosis of this injury ensures optimal management decisions are instituted early ensuring the best outcome and patient experience, at minimal cost to the United Kingdom National Health Service. Despite this, regional and national variations to diagnosis and management exist, with anecdotal evidence of inefficiencies in the local patient pathway. To explore this further, a retrospective departmental audit of timescales from presentation to ultrasound diagnosis and definitive treatment decision was undertaken. Methods: All suspected Achilles tendon ruptures in 2018 were identified through electronic and written patient records, and information on timescales involved in the diagnosis and management of each compiled. Descriptive statistics were used to map each step of the pathway and timescales involved, with performance assessed against local departmental standards and the Swansea Morriston Achilles Rupture Treatment (SMART) protocol. Results: In total, 119 patients were identified, of which 113 received an ultrasound examination. Local departmental standards were met in the majority of cases, with 78% (n = 88) diagnosed by ultrasound within one week of the request and 83% (n = 91) given a treatment decision within two weeks of presentation. However, this was suboptimal when compared with timeframes utilised for developing the SMART protocol, with only 7% (n = 8) scanned within 48 hours of presentation. Conclusions: Key areas of the patient pathway were identified for quality service improvement and redesign, with multidisciplinary discussion resulting in the development of a revised patient pathway which expedites diagnosis and treatment for these injuries.

Symptomatic trochanteric non-union following total hip replacement treated with reattachment combined with two-stage revision surgery of the femoral stem.

We present a case of symptomatic trochanteric non-union following total hip replacement treated initially with a Dall-Miles grip plate. After failure of this treatment, the patient had a two-stage revision. Trochanteric non-union is one of the well-described complications after total hip replacement. It is frequently difficult to treat, while potentially causing weakness, altered gait and instability of the artificial joint. We believe that reattachment of the trochanter combined with a staged revision of the femoral stem using a posterior approach for the second stage could be a valuable technique to be added to the orthopaedic armamentarium for recurrent and symptomatic trochanteric non-unions after primary total hip replacement, particularly after failure to treat with all the other techniques described in literature.

Difference in trochanteric thickness between well-aligned and malaligned polished collarless stem.

BACKGROUND: Surgical techniques and instruments are continuously evolving to improve placement of components in ideal position. We investigated if there is difference in greater trochanter thickness between the stems in satisfactory position and stems in malposition and to assess the ideal thickness of trochanter for femoral stem placement in neutral position as under reaming of trochanter can result in stem malposition. METHODS: Measurement of greater trochanteric thickness in 95 hip replacements (posterior approach) was performed by a junior doctor and two hip fellows using the trauma CAD/PACS software. The stem was considered neutral if the central axis of femur passes through the distal tip of stem in AP and in varus if the tip of stem was lateral to the femoral shaft axis. RESULTS: 79 patients had stem in satisfactory position and 16 patients in varus malposition. Mean trochanteric thickness was 12.6 mm (+/-0.56 mm 95%CI, Median 12.5 mm, SD 2.5 mm) in neutral stems while mean thickness in the varus stem was 18.4 mm (+/-1.01 mm 95%CI, Median 17.8 mm, SD 2 mm). There was statistical significant difference between both groups with p< 0.0001 with intra-observer correlation at 99% between the senior personal while correlation was at 80% between the senior personnel and junior doctor. No statistically significant difference was noted in measurements between the senior personal. CONCLUSIONS: The study confirms the significant difference in greater trochanteric thickness between the well aligned and misaligned femoral components. The study raises the possibility that trochanteric thickness can be used as an accessory surgical aid to check if sufficient broaching has been done laterally to allow the stem to be seated in neutral position with an ideal remnant thickness of 12.5 mm. A surgical instrument can be developed to measure the intraoperative thickness of the trochanter which can be a useful tool for young hip surgeons for better placement of components.

Irradiation and prolonged storage of red cells are associated with increased adverse events.

BACKGROUND: Red blood cell (RBC) transfusion is associated with the most transfusion-related adverse events (AE). Recent clinical studies showed no significant difference in transfusion-associated mortality between fresh and older RBCs. However, the impact of storage duration as well as irradiation on nonfatal yet much more common complications has not been fully investigated. MATERIALS/METHODS: In this retrospective study of RBC transfusion-associated AEs, a total of 188,562 units of leucocyte-reduced RBCs were transfused in approximately 5·5 years. After excluding washed, deglycerolized, autologous or directed RBCs and RBCs transfused during a massive transfusion protocol, 149,052 units were analysed. Attributes of RBCs including storage time, collection method, CMV serological status and gamma irradiation, as well as the recipient's gender, were analysed. A total of 358 RBC transfusion AEs were categorized into allergic and non-allergic reactions and analysed. RESULTS: Univariate and multivariate logistic analyses showed that irradiated RBCs were associated with a significantly increased frequency of non-allergic reactions (OR (95% CI): 1·89 (1·52, 2·35); P < 0·001). There was a significant association between the frequency of non-allergic reactions and the storage time of irradiated RBCs (OR (95% CI): 1·024 (1·001, 1·048); P = 0·042). In contrast, there was no association between the frequency of allergic reactions and the storage time of irradiated RBCs or between the age of non-irradiated RBCs and the frequency of non-allergic reactions. CONCLUSIONS: Prolonged storage of irradiated RBCs was associated with a significant increase in non-allergic transfusion reactions. Overall, the irradiated RBCs appeared to cause more non-allergic reactions compared with non-irradiated RBCs.

Socioeconomic deprivation and the burden of head and neck cancer-Regional variations of incidence and mortality in Merseyside and Cheshire, North West, England.

OBJECTIVES: The aim of this longitudinal study was to examine the distribution of head and neck cancer (HANC) disease burden across the region comparing it to national trends. DESIGN: We undertook a retrospective study of routine data combining it with indicators of deprivation and lifestyle at small geographical areas within the 9 Local Authorities (LAs) of Merseyside and Cheshire Network (MCCN) for head and neck cancers. Data from the North West of England and England were used as comparator regions. SETTING: This research was undertaken by the Cheshire and Merseyside Public Health Collaborative, UK. PARTICIPANTS: The Merseyside and Cheshire region serves a population of 2.2 million. Routine data allowed us to identify HANC patients diagnosed with cancers coded ICD C00-C14 and C30-C32 within 3 cohorts 1998-2000, 2008-2010 and 2009-2011 for our analysis. MAIN OUTCOME MEASURES: Directly age-standardised incidence rates and directly age-standardised mortality rates in the LAs and comparator regions were measured. Lifestyle and deprivation indicators were plotted against them and measured by Pearson's correlation coefficients. RESULTS: The incidence of head and neck cancer has increased across the region from 1998-2000 to 2008-2010 with a peak incidence for Liverpool males at 35/100 000 population. Certain Middle Super Output Areas contribute disproportionately to the significant effect of incidence and mortality within LAs. Income deprivation had the strongest correlation with incidence (r = .59) and mortality (r = .53) of head and neck cancer. CONCLUSION: Our study emphasises notable geographical variations within the region which need to be addressed through public health measures.

History matching of a complex epidemiological model of human immunodeficiency virus transmission by using variance emulation.

Complex stochastic models are commonplace in epidemiology, but their utility depends on their calibration to empirical data. History matching is a (pre)calibration method that has been applied successfully to complex deterministic models. In this work, we adapt history matching to stochastic models, by emulating the variance in the model outputs, and therefore accounting for its dependence on the model's input values. The method proposed is applied to a real complex epidemiological model of human immunodeficiency virus in Uganda with 22 inputs and 18 outputs, and is found to increase the efficiency of history matching, requiring 70% of the time and 43% fewer simulator evaluations compared with a previous variant of the method. The insight gained into the structure of the human immunodeficiency virus model, and the constraints placed on it, are then discussed.

Optical coherence tomography segmentation analysis in relapsing remitting versus progressive multiple sclerosis.

INTRODUCTION: Optical coherence tomography (OCT) with retinal segmentation analysis is a valuable tool in assessing axonal loss and neuro-degeneration in multiple sclerosis (MS) by in-vivo imaging, delineation and quantification of retinal layers. There is evidence of deep retinal involvement in MS beyond the inner retinal layers. The ultra-structural retinal changes in MS in different MS phenotypes can reflect differences in the pathophysiologic mechanisms. There is limited data on the pattern of deeper retinal layer involvement in progressive MS (PMS) versus relapsing remitting MS (RRMS). We have compared the OCT segmentation analysis in patients with relapsing-remitting MS and progressive MS. METHODS: Cross-sectional study of 113 MS patients (226 eyes) (29 PMS, 84 RRMS) and 38 healthy controls (72 eyes). Spectral domain OCT (SDOCT) using the macular cube acquisition protocol (Cirrus HDOCT 5000; Carl Zeiss Meditec) and segmentation of the retinal layers for quantifying the thicknesses of the retinal layers. Segmentation of the retinal layers was carried out utilizing Orion software (Voxeleron, USA) for quantifying the thicknesses of individual retinal layers. RESULTS: The retinal nerve finer layer (RNFL) (p = 0.023), the ganglion-cell/inner plexiform layer (GCIPL) (p = 0.006) and the outer plexiform layer (OPL) (p = 0.033) were significantly thinner in PMS compared to RRMS. There was significant negative correlation between the outer nuclear layer (ONL) and EDSS (r = -0.554, p = 0.02) in PMS patients. In RRMS patients with prior optic neuritis, the GCIPL correlated negatively (r = -0.317; p = 0.046), while the photoreceptor layer (PR) correlated positively with EDSS (r = 0.478; p = 0.003). CONCLUSIONS: Patients with PMS exhibit more atrophy of both the inner and outer retinal layers than RRMS. The ONL in PMS and the GCIPL and PR in RRMS can serve as potential surrogate of disease burden and progression (EDSS). The specific retinal layer predilection and its correlation with disability may reflect different pathophysiologic mechanisms and various stages of progression in MS.

Bayesian sensitivity analysis of a model of the aortic valve.

Understanding the mechanics of the aortic valve has been a focus of attention for many years in the biomechanics literature, with the aim of improving the longevity of prosthetic replacements. Finite element models have been extensively used to investigate stresses and deformations in the valve in considerable detail. However, the effect of uncertainties in loading, material properties and model dimensions has remained uninvestigated. This paper presents a formal statistical consideration of a selected set of uncertainties on a fluid-driven finite element model of the aortic valve and examines the magnitudes of the resulting output uncertainties. Furthermore, the importance of each parameter is investigated by means of a global sensitivity analysis. To reduce computational cost, a Bayesian emulator-based approach is adopted whereby a Gaussian process is fitted to a small set of training data and then used to infer detailed sensitivity analysis information. From the set of uncertain parameters considered, it was found that output standard deviations were as high as 44% of the mean. It was also found that the material properties of the sinus and aorta were considerably more important in determining leaflet stress than the material properties of the leaflets themselves.

Do atmospheric pressure changes influence seizure occurrence in the epilepsy monitoring unit?

In a prior study of epilepsy and atmospheric pressure, we were able to show a small association between changes in atmospheric pressure and increased seizure frequency in consecutive patients with epilepsy undergoing video telemetry. In this study, we used a larger data set of similar patients undergoing telemetry at another Seattle institution, and examined the possible impact of atmospheric pressure (AP) changes on seizure onset in subtypes of seizures (focal, generalized, and nonepileptic). Comparisons were made between AP score at time of seizure onset and AP score at selected time ranges prior to the event (hour of seizure and 3, 6, and 24 hours prior) and a random sample of AP scores collected over similar time frames using nonparametric testing with correction for multiple comparisons. We could find no evidence to suggest atmospheric pressure changes made seizure occurrence more likely in any of the seizure groups across any of the time periods.

Survey of the initial management and imaging protocols for occult scaphoid fractures in UK hospitals.

OBJECTIVE: The aim of this research was to survey how occult fractures of the scaphoid bone are both imaged and managed initially. MATERIALS AND METHODS: A total of 832 questionnaires were sent via e-mail to active associate members of the British Orthopaedic Association. Included was a series of questions regarding the timing of initial and subsequent orthopaedic review of this group of patients and the use of serial radiographs and second-line imaging techniques. RESULTS: Nearly half of the UK's acute NHS trusts were represented (45%). The response rate was 16% (130 out of 832). Only 16% of respondents were aware of a local imaging protocol for the investigation of suspected fractures of the scaphoid. Ninety-four percent of respondents performed a second radiograph at first fracture clinic review. Fifty-eight percent used magnetic resonance imaging (MRI) as a second-line investigation; with computed tomography scan and radionuclide isotope bone scan being performed by 26% and 16% respondents, respectively. CONCLUSIONS: The survey revealed a wide variation in the management of occult fractures of the scaphoid. MRI has been shown to be both sensitive and specific in diagnosing occult carpal bone fractures. There is a need to standardise the management of these injuries to ensure early diagnosis and limit unnecessary wrist immobilisation.

The surgeon and his tools-the case for a focused orthopaedic theatre induction programme.

BACKGROUND: Induction programme for trainee doctors in the UK generally do not focus on the surgical aspects of their jobs. In this context we decided to conduct a telephonic survey among the hospitals belonging to three orthopaedic training regions in the UK from the point of view of the diversity of instrumentations and implants used for index procedures. RESULTS: We chose four index trauma & orthopaedic procedures (Total hip replacement, total knee replacement, intramedullary nailing and external fixator systems for long bone fractures). A telephonic survey was done in six NHS trust hospitals which were part of an orthopaedic training rotation (2 from England, 2 from Wales and 2 from Scotland). In total there were 39 different instrumentation systems for these 4 index procedures in the 6 trusts (see table 1). These comprise 12 Total hip replacement (THR) systems, 14 total knee replacement (TKR) systems, 9 intra-medullary nailing systems, and 4 external fixator systems. The number of different systems for each trust ranged from 7 to 19. There is a vast array of implants and instrumentation systems in each trust, as highlighted by our survey. The surgical tools are not the same in each hospitals. This situation is more complicated when trainees move to new hospitals as part of training rotations. CONCLUSION: In view of this we feel that more focused theatre based induction programmes for higher surgical trainees is advocated in each hospital trust so trainees can familiarise themselves with the tools available to them. This could include discussion with the consultants and senior theatre staff along with representatives from the companies supplying the implants and instrumentation systems.

Osteoprotegerin Lys3Asn polymorphism and the risk of fracture in older women.

CONTEXT: Osteoprotegerin (OPG) is a soluble decoy receptor for receptor activator nuclear factor kappa-beta that blocks osteoclastic bone resorption. OBJECTIVE: We investigated the association between a Lys3Asn polymorphism in the OPG gene and bone mineral density (BMD), and the risk of fracture in 6695 women aged 65 yr and older participating in the Study of Osteoporotic Fractures. DESIGN: BMD was measured using either single-photon absorptiometry (Osteon Osteoanalyzer; Dove Medical Group, Los Angeles, CA) or dual-energy x-ray absorptiometry (Hologic QDR 1000; Hologic, Inc., Bedford, MA). Incident fractures were confirmed by physician adjudication of radiology reports. Genotyping was performed using an immobilized probe-based assay. RESULTS: Women who were homozygous for the minor G (Lys) allele had significantly lower BMD at the intertrochanter, distal radius, lumbar spine, and calcaneus than those with the C (Asn) allele. There were 701 incident hip fractures during 13.6-yr follow-up (91,249 person-years), including 362 femoral neck and 333 intertrochanteric hip fractures. Women with the C/C (Asn-Asn) genotype had a 51% higher risk of femoral neck fracture (95% confidence interval, 1.13-2.02) and 26% higher risk of hip fracture (95% confidence interval, 1.02-1.54) than those with the G/G (Lys-Lys) genotype. These associations were independent of BMD. Intertrochanteric fractures were not associated with the Lys3Asn polymorphism. CONCLUSION: These results require confirmation but suggest a role for the OPG Lys3Asn polymorphism in the genetic susceptibility to hip fractures among older white women.

Factors affecting the cohesion of impaction bone graft.

The role of bone-graft extenders in impaction revision surgery is becoming increasingly important. Tricalcium phosphate and hydroxyapatite have been shown to be both biocompatible and osteoconductive, yet many surgeons remain reluctant to use them. The difficulty in handling bone-graft extenders can be partly alleviated by using porous particles and adding clotted blood. In an in vitro model we measured the cohesive properties of various impaction graft mixes. Several factors were evaluated including the use of pure bone graft compared with mixes with extender, washing the bone and the addition of clotted blood. Our findings showed that pure allograft bone particles had significantly higher cohesion than when mixed with extender (p < 0.001). Washing had no effect on cohesion. The addition of clotted blood significantly increased the cohesion of both pure bone (p < 0.019) and mixes with pure bone and with porous graft extender (p < 0.044).

Practical virtue ethics: healthcare whistleblowing and portable digital technology.

Medical school curricula and postgraduate education programmes expend considerable resources teaching medical ethics. Simultaneously, whistleblowers' agitation continues, at great personal cost, to prompt major intrainstitutional and public inquiries that reveal problems with the application of medical ethics at particular clinical "coalfaces". Virtue ethics, emphasising techniques promoting an agent's character and instructing their conscience, has become a significant mode of discourse in modern medical ethics. Healthcare whistleblowers, whose complaints are reasonable, made in good faith, in the public interest, and not vexatious, we argue, are practising those obligations of professional conscience foundational to virtue based medical ethics. Yet, little extant virtue ethics scholarship seriously considers the theoretical foundations of healthcare whistleblowing. The authors examine whether healthcare whistleblowing should be considered central to any medical ethics emphasising professional virtues and conscience. They consider possible causes for the paucity of professional or academic interest in this area and examine the counterinfluence of a continuing historical tradition of guild mentality professionalism that routinely places relationships with colleagues ahead of patient safety.Finally, it is proposed that a virtue based ethos of medical professionalism, exhibiting transparency and sincerity with regard to achieving uniform quality and safety of health care, may be facilitated by introducing a technological imperative using portable computing devices. Their use by trainees, focused on ethical competence, provides the practical face of virtue ethics in medical education and practice. Indeed, it assists in transforming the professional conscience of whistleblowing into a practical, virtue based culture of self reporting and personal development.

A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis.

OBJECTIVES: To establish the clinical effectiveness and cost-effectiveness of selective oestrogen receptor modulators, bisphosphonates and parathyroid hormone (subject to licensing) for the prevention and treatment of osteoporosis and the prevention of osteoporotic fractures in postmenopausal women. DATA SOURCES: Electronic databases. REVIEW METHODS: Studies that met the review's entry criteria were eligible for inclusion in the meta-analyses provided that they reported fracture incidence in terms of the number of patients suffering fractures. Meta-analysis was carried out using the random-effects model. A model was constructed to estimate the cost-effectiveness of osteoporosis interventions. The model calculated the number of fractures that occurred and provided the costs associated with osteoporotic fractures, and the quality-adjusted life-years (QALYs). In addition, the conditions of breast cancer and coronary heart disease (CHD) were modelled, as some interventions have been shown to affect the risk of these conditions. RESULTS: Ninety randomised controlled trials (RCTs) met the inclusion criteria. They related to the five interventions (alendronate, etidronate, risedronate, raloxifene and teriparatide) and to five comparators (calcium, calcium plus vitamin D, calcitriol, hormone replacement therapy and exercise), as well as placebo or no treatment. All five interventions have been shown to reduce the risk of vertebral fracture in women with severe osteoporosis with adequate calcium intakes. However, none of these drugs has been demonstrated, by direct comparison, to be significantly more effective than either each other or the other active interventions reviewed in this report. The intervention costs of treating all osteoporotic women, for a period of 5 years, were in the region of pound 900-1500 million for alendronate, etidronate, risedronate and raloxifene. The cost per QALY ratios fell dramatically with age. Assuming the risks of a woman with severe osteoporosis at the threshold of osteoporosis, no treatment had a cost per QALY below pound 35,000 at 50 years of age. At 60 years of age, the cost per QALY of raloxifene was pound 26,000 assuming no impact on hip fractures, and pound 31,000 assuming an adverse effect. However, these results are driven by the effect on breast cancer and the assumptions made regarding this disease state. No other intervention had a cost per QALY below pound 35,000. When analyses were conducted assuming that the fracture risk is doubled at each site, alendronate and risedronate had cost per QALY ratios below pound 30,000 at all ages. For women at the threshold of osteoporosis, without a prior fracture and aged 70 years, the cost per QALY of the three bisphosphonates ranged from pound 34,000 to pound 41,000. Raloxifene had a cost per QALY of pound 23,000, assuming no effect on hip fracture, given assumptions regarding breast cancer. At 80 years of age, the cost per QALY of alendronate and risedronate was below pound 20,000. This was true for etidronate when incorporating observational data, but the value rose to pound 69,000 when only RCT data were used. No other intervention had a cost per QALY below pound 35,000. It was assumed that doubling the risk of fracture for women without a prior fracture would give results similar to patients at the threshold of osteoporosis with a prior fracture. CONCLUSIONS: Of the five interventions, only raloxifene appeared to reduce the risk of vertebral fracture in postmenopausal women unselected for low bone mineral density (BMD). However, as the full data have not been made public, there is some uncertainty regarding this result. None of the five interventions has been shown to reduce the risk of non-vertebral fracture in women unselected for low BMD. All of the proposed interventions provided gains in QALYs compared with no treatment in women with sufficient calcium and vitamin D intakes. The size of the QALY gain for each intervention was strongly related to the age of the patient. The estimated costs varied widely for the interventions. These net costs were markedly different by age, with some interventions becoming cost-saving at higher age ranges in patients with a prior fracture. Areas for future research include: the evidence base for the efficacy of fracture prevention in the very elderly, reanalysis of raloxifene using a dedicated breast cancer and CHD model, and more trials considering the cost-effectiveness of teriparatide.

Tumor necrosis factor-alpha polymorphism, bone strength phenotypes, and the risk of fracture in older women.

TNFalpha is a proinflammatory cytokine that promotes osteoclastic bone resorption. We evaluated the association between a G-308A polymorphism (rs1800629) at the TNFA locus and osteoporosis phenotypes in 4306 older women participating in the Study of Osteoporotic Fractures. Femoral neck bone mineral density (BMD) and structural geometry were measured using dual-energy x-ray absorptiometry and hip structural analysis. Incident fractures were confirmed by physician adjudication of radiology reports. Despite similar femoral neck BMD, women with the A/A genotype had greater subperiosteal width (P = 0.01) and endocortical diameter (P = 0.03) than those with the G/G genotype. The net result of these structural differences was that there was a greater distribution of bone mass away from the neutral axis of the femoral neck in women with the A/A genotype, resulting in greater indices of bone bending strength (cross-sectional moment of inertia: P = 0.004; section modulus: P = 0.003). Among 376 incident hip fractures during 12.1 yr of follow-up, a 22% decrease in the risk of hip fracture was seen per copy of the A allele (relative risk 0.78; 95% confidence interval 0.63, 0.96), which was not influenced by adjustments for potential confounding factors, BMD, or bone strength indices. The G-308A polymorphism was not associated with a reduced risk of other fractures. These results suggest a potential role of genetic variation in TNFalpha in the etiology of osteoporosis.

Methods for expected value of information analysis in complex health economic models: developments on the health economics of interferon-beta and glatiramer acetate for multiple sclerosis.

OBJECTIVES: To develop methods for performing expected value of perfect information (EVPI) analysis in computationally expensive models and to report on the developments on the health economics of interferon-beta and glatiramer acetate in the management of multiple sclerosis (MS) using this methodological framework. DATA SOURCES: Electronic databases and Internet resources, reference lists of relevant articles. REVIEW METHODS: A methodological framework was developed for undertaking EVPI analysis for complex models. The framework identifies conditions whereby EVPI may be calculated numerically, where the one-level algorithm sufficiently approximates the two-level algorithm, and whereby metamodelling techniques may accurately approximate the original simulation model. Metamodelling techniques, including linear regression, neural networks and Gaussian processes (GP), were systematically reviewed and critically appraised. Linear regression metamodelling, GP metamodelling and the one-level EVPI approximation were used to estimate partial EVPIs using the ScHARR MS cost-effectiveness model. RESULTS: The review of metamodelling approaches suggested that in general the simpler techniques such as linear regression may be easier to implement, as they require little specialist expertise although may provide only limited predictive accuracy. More complex methods such as Gaussian process metamodelling and neural networks tend to use less-restrictive assumptions concerning the relationship between the model inputs and net benefits, and therefore may permit greater accuracy in estimating EVPIs. Assuming independent treatment efficacy, the 'per patient' EVPI for all uncertainty parameters within the ScHARR MS model is 8855 British pounds. This leads to a population EVPI of 86,208,936 British pounds, which represents the upper estimate for the overall EVPI over 10 years. Assuming all treatment efficacies are perfectly correlated, the overall per patient EVPI is 4271 British pounds. This leads to a population EVPI of 41,581,273 British pounds, which represents the lower estimate for the overall EVPI over 10 years. The partial EVPI analysis, undertaken using both the linear regression metamodel and Gaussian process metamodel clearly, suggests that further research is indicated on the long-term impact of these therapies on disease progression, the proportion of patients dropping off therapy and the relationship between the EDSS, quality of life and costs of care. CONCLUSIONS: The applied methodology points towards using more sophisticated metamodelling approaches in order to obtain greater accuracy in EVPI estimation. Programming requirements, software availability and statistical accuracy should be considered when choosing between metamodelling techniques. Simpler, more accessible techniques are open to greater predictive error, whilst sophisticated methodologies may enhance accuracy within non-linear models, but are considerably more difficult to implement and may require specialist expertise. These techniques have been applied in only a limited number of cases hence their suitability for use in EVPI analysis has not yet been demonstrated. A number of areas requiring further research have been highlighted. Further clinical research is required concerning the relationship between the EDSS, costs of care and health outcomes, the rates at which patients drop off therapy and in particular the impact of disease-modifying therapies on the progression of MS. Further methodological research is indicated concerning the inclusion of epidemiological population parameters within the sensitivity analysis; the development of criteria for selecting a metamodelling approach; the application of metamodelling techniques within health economic models and in the specific application to EVI analyses; and the use of metamodelling for EVSI and ENBS analysis.

Gaussian process modeling in conjunction with individual patient simulation modeling: a case study describing the calculation of cost-effectiveness ratios for the treatment of established osteoporosis.

Individual patient-level models can simulate more complex disease processes than cohort-based approaches. However, large numbers of patients need to be simulated to reduce 1st-order uncertainty, increasing the computational time required and often resulting in the inability to perform extensive sensitivity analyses. A solution, employing Gaussian process techniques, is presented using a case study, evaluating the cost-effectiveness of a sample of treatments for established osteoporosis. The Gaussian process model accurately formulated a statistical relationship between the inputs to the individual patient model and its outputs. This model reduced the time required for future runs from 150 min to virtually-instantaneous, allowing probabilistic sensitivity analyses-to be undertaken. This reduction in computational time was achieved with minimal loss in accuracy. The authors believe that this case study demonstrates the value of this technique in handling 1st- and 2nd-order uncertainty in the context of health economic modeling, particularly when more widely used techniques are computationally expensive or are unable to accurately model patient histories.