Economic evaluations of a pharmacogenomics test for Statin-induced myopathy in secondary cardiovascular prevention

Les statines constituent la pierre angulaire du traitement des dyslipidémies. Les myopathies secondaires aux statines seraient l’une des principales causes d’abandon. Le diagnostic de myopathie repose sur la comparaison du taux de créatine kinase (CK) avec des valeurs de référence normales. Or, des études ont révélé que ces valeurs ne sont pas représentatives de l’ensemble de la population. Le test du taux de CK n’a donc qu’une utilité diagnostique restreinte. Un test pharmacogénomique (PGx) pour le diagnostic des myopathies chez les patients qui affichent une hausse légère ou modérée du taux de CK après l’amorce d’un traitement par une statine est en développement. Nous avons évalué l’impact économique de ce test PGx hypothétique grâce à deux techniques de modélisation : un modèle de Markov et un modèle de simulation par événement discret (SED). Nous avons examiné les modèles avec la perspective d’un payeur canadien, avec un horizon temporel de la vie entière, pour les patients à risque cardiovasculaire (CV) élevé initiant une statine en prévention secondaire. La détermination des taux de faux positifs (TFP) et de faux négatifs (TFN) du test revêt encore plus d’importance que le choix de la technique de modélisation. Dans cette thèse, nous avons opté pour une interprétation globale des résultats des tests, afin que les décisions des médecins et des patients s’apparentent à des erreurs de test. Cette définition permet de mesurer l’utilité clinique du test à influencer les décisions de prescription des médecins et, surtout, la volonté des patients de poursuivre le traitement. Ce dernier aspect s’applique particulièrement aux médicaments prescrits à titre préventif dont les bienfaits à long terme dépendent de l’adhésion du patient au traitement. Les articles I et II présentent les résultats des modèles de Markov et SED. Les résultats concordent sur le plan qualitatif. Au Canada, un test PGx pour le dépistage des myopathies secondaires aux statines serait rentable avec une faible disposition à payer. Selon les analyses de sensibilité probabilistes, les modèles de Markov et SED donnaient des résultats favorables dans au moins 90 % des simulations assorties d’une disposition à payer de seulement 6150 $et 12000$ par année de vie pondérée par la qualité. L’article III poursuit la réflexion des modèles présentés dans les articles I et II. Ceux-ci ont permis de constater qu’un test PGx complètement erroné (TFP = TFN = 100 %) se traduirait par un avantage différentiel monétaire net positif pour les payeurs. Ce résultat s’explique par le déséquilibre du risque entre les bienfaits d’une réduction des manifestations CV chez les patients atteints d’une myopathie légère ou modérée et le risque extrêmement faible de rhabdomyolyse. Cependant, ce résultat n’est pas plausible lorsque qu’on prend en considération les décisions à long terme des médecins et des patients, notamment le haut niveau de non-adhésion aux statines. Dans l’ensemble, cette thèse souligne l’importance d’évaluer l’impact économique des erreurs de test. Cette démarche ne doit pas se limiter à une supposition a priori des paramètres de rendement du test. Il convient d’examiner la fourchette complète des TFP et des TFN pour bien cerner l’incidence économique des tests diagnostiques, surtout lorsque le résultat du test influence la prescription d’un médicament préventif administré à long terme.Statins are the mainstay of treatment for dyslipidemia. Statin-induced myopathies are thought to be a major cause of patients discontinuing statin treatment. Myopathy diagnoses are based on creatine kinase (CK) elevation, which is compared to age-gender specific CK upper limit of normal values. Studies have shown, however, reference CK values are not representative of all population subgroups. Thus, CK tests have limited diagnostic capacity due to poor internal validity and limited external validity. A pharmacogenomics (PGx) test for statin-induced myopathies is in development for patients who have initiated statin therapy and who have mild to moderate CK elevation. We conducted economic evaluations of this hypothetical PGx test using two modelling techniques: a Markov health state model and a discrete event simulation (DES) model. We evaluated the economic models with a lifetime horizon from the Canadian payer perspective for high cardiovascular (CV) risk patients initiating a statin in secondary prevention. We found that even more important than the choice of modelling technique when evaluating the economic value of diagnostic tools, was the assessment of the diagnostic test false-positive and false-negative results. In this thesis, we have proposed an approach for interpreting diagnostic test results broadly such that physician and patient behaviours are akin to test errors. This definition addresses the clinical utility of the test in influencing physician prescribing recommendations and, importantly, patient decisions to adhere to therapy. This point is especially true for preventive medications, such as statins where the long-term benefits of therapy depend on patient adherence. Articles I and II present the model results from the Markov health state model and the DES model. We found that, although the Markov and DES model results differed slightly, the qualitative model results were in agreement. A PGx test for statin-induced myopathy was cost-effective at a relatively low willingness-to-pay (WTP). In the probabilistic sensitivity analyses, the Markov and DES strategies were favoured in at least 90% of the model simulations with a payer WTP as low as $6,150 and$12,000 per quality-adjusted life year, respectively. Article III was a reflection on the implications of model results presented in Articles I and II. Articles I and II highlighted that a totally inaccurate PGx test (i.e., false-positive rate [FPR] = false-negative rate [FNR] = 100%) would yield a positive incremental net monetary benefit for the payers. This result is explained by the risk imbalance between the benefit in reduction of CV events for patients suffering from mild to moderate myopathy compared to the extremely low risk of rhabdomyolysis. Although the totally inaccurate test result helped us understand the consequences of test errors, we recognize that a PGx test that is completely inaccurate, is not a plausible solution. The PGx test must be clinically valid and account for long-term physician and patient behavioural responses to the test results. As we have argued, the economic value of the PGx test for statin-induced myopathy in high CV risk patients depends on its ability to influence lifetime adherence to statin therapy. Overall, this thesis highlights the importance of assessing the economic consequences of test errors. The assessment of test errors should not be limited to an a priori supposition of test performance parameters. The complete range of FPR and FNR test values should be investigated to fully understand the economic consequences of diagnostic tests. This is even more important when the diagnostic test is used to prescribe a long-term preventive medication

The Effects of Finasteride on Parity in Female Drosophila Melanogaster

Finasteride has been used to treat male pattern baldness and benign prostate hyperplasia and could potentially treat female pattern baldness and polycystic ovary syndrome. The impact on reproduction in female patients who are taking or have taken finasteride is unknown. Using drosophila melanogaster as a model, this study was designed to investigate the impact of finasteride on female fly reproduction and their offspring. The female flies in this study will be fed dosage equivalents of 0.5 mg, 1 mg, and 5 mg of finasteride, along with a control group of females who consume no finasteride. The flies will be allowed to mate after consuming their respective dose of the drug and the viable offspring will be counted over the next three days. If there are viable male offspring, they will be allowed to mate with female flies as well to determine if they are impacted by the drug. This study predicts the results will indicate the finasteride, especially at higher doses, will impact the reproductive ability of the females and their male offspring. These results will further the database that could lead to determining if finasteride could be used to treat the previously stated conditions in human females

The effects of Finasteride on parity in female drosophila melanogaster

Finasteride has been used to treat male pattern baldness and benign prostate hyperplasia, and could potentially treat female pattern baldness and polycystic ovary syndrome. The effects that finasteride ingestion has on reproduction in female patients is still inconclusive. Using Drosophila melanogaster as a model, this study was designed to investigate the impact of finasteride on female fly reproduction and their offspring. The female flies in this study will be fed dosage equivalents of 0.5 mg, 1 mg, and 5 mg of finasteride, with a control group of females who consume no finasteride. The flies will be allowed to mate after consuming their respective dose of the drug and the viable offspring will be counted over the next three days. Additionally, viable male offspring will be allowed to mate with female flies to determine if they are impacted by the drug. This study predicts the results will indicate that finasteride will impact the reproductive ability of the females and their male offspring. We will support these results by using an RNA sequencer to investigate their genome. These results will further the database that could lead to determining if finasteride could be used to treat the disorders in human females

Impact of mineral and bone disorder on healthcare resource use and associated costs in the European Fresenius medical care dialysis population: a retrospective cohort study

BACKGROUND: Secondary hyperparathyroidism (SHPT) is associated with mortality in patients with chronic kidney disease (CKD), but the economic consequences of SHPT have not been adequately studied in the European population. We assessed the relationship between SHPT parameters (intact parathyroid hormone [iPTH], calcium, and phosphate) and hospitalisations, medication use, and associated costs among CKD patients in Europe. METHODS: The analysis of this retrospective cohort study used records of randomly selected patients who underwent haemodialysis between January 1, 2005 and December 31, 2006 at participating European Fresenius Medical Care facilities in 10 countries. Patients had ≥ 1 iPTH value recorded, and ≥ 1 month of follow-up after a 3-month baseline period during which SHPT parameters were assessed. Time at risk was post-baseline until death, successful renal transplantation, loss to follow-up, or the end of follow-up. Outcomes included cost per patient-month, rates of hospitalisations (cardiovascular disease [CVD], fractures, and parathyroidectomy [PTX]), and use of SHPT-, diabetes-, and CVD-related medications. National costs were applied to hospitalisations and medication use. Generalised linear models compared costs across strata of iPTH, total calcium, and phosphate, adjusting for baseline covariates. RESULTS: There were 6369 patients included in the analysis. Mean ± SD person-time at risk was 13.1 ± 6.4 months. Patients with iPTH > 600 pg/mL had a higher hospitalisation rate than those with lower iPTH. Hospitalisation rates varied little across calcium and phosphate levels. SHPT-related medication use varied with iPTH, calcium, and phosphate. After adjusting for demographic and clinical variables, patients with baseline iPTH > 600 pg/mL had 41% (95% CI: 25%, 59%) higher monthly total healthcare costs compared with those with iPTH in the K/DOQI target range (150–300 pg/mL). Patients with baseline phosphate and total calcium levels above target ranges (1.13–1.78 mmol/L and 2.10–2.37 mmol/L, respectively) had 38% (95% CI: 27%, 50%) and 8% (95% CI: 0%, 17%) higher adjusted monthly costs, respectively. Adjusted costs were 25% (95% CI: 18%, 32%) lower among patients with baseline phosphate levels below the target range. Results were consistent in sensitivity analyses. CONCLUSIONS: These data suggest that elevated SHPT parameters increase the economic burden of CKD in Europe

Value Homophily Benefits Cooperation but Motivates Employing Incorrect Social Information

Individuals often judge others based on third-party gossip, rather than their own experience, despite the fact that gossip is error-prone. Rather than judging others on their merits, even when such knowledge is free, we judge based on the opinions of third parties. Here we seek to understand this observation in the context of the evolution of cooperation. If individuals are being judged on noisy social reputations rather than on merit, then agents might exploit this, eroding the sustainability of cooperation. We employ a version of the Prisoner’s Dilemma, the Donation game, which has been used to simulate the evolution of cooperation through indirect reciprocity. First, we validate the proposition that adding homophily (the propensity to interact with others of similar beliefs) into a society increases the sustainability of cooperation. However, this creates an evolutionary conflict between the accurate signalling of ingroup status versus the veridical report of the behaviour of other agents. We find that conditions exist where signalling ingroup status outweighs honesty as the best method to ultimately spread cooperation

Improvement of editorial quality of journals indexed in DOAJ: a data analysis

In 2013, Directory of Open Access Journals (DOAJ) expanded and updated its inclusion criteria and its journal evaluation process, ultimately removing a large number of journals that failed to submit an updated application. The present study examined the results of the new process and its capability to improve the quality of the directory and the reliability of the information contained in it. A dataset of 12.595 journals included in DOAJ, since its launch in 2003 until May 15th 2016, was examined and compared to other data. The number of journals deleted from DOAJ during this period is 3776; the majority of them (2851 journals) were excluded because publishers failed to complete the reapplication on time; 490 had ceased publication or were otherwise inactive; 375 were excluded for ethical issues; 53 because they were no longer open access or the content was embargoed, the final 7 were removed for other reasons. The top five countries in terms of the percentage of journals removed are: Japan (74% of journals removed); Pakistan (60%); Canada (51%); United States (50%); and Mexico (49%). Our study has shown that 158 of the removed journals are included in Beall’s lists; 1130 journals indexed in DOAJ are included in Scopus and/or JCR. Our analysis demonstrates that, thanks to the new acceptance criteria, to the improved screening process performed by national groups under the direction of the new management, there is a noticeable quality improvement of the journals indexed in DOAJ

On the reliability of unreliable information:Gossip as cultural memory

Abstract When individuals learn from what others tell them, the information is subject to transmission error that does not arise in learning from direct experience. Yet evidence shows that humans consistently prefer this apparently more unreliable source of information. We examine the effect this preference has in cases where the information concerns a judgment on others’ behaviour and is used to establish cooperation in a society. We present a spatial model confirming that cooperation can be sustained by gossip containing a high degree of uncertainty. Accuracy alone does not predict the value of information in evolutionary terms; relevance, the impact of information on behavioural outcomes, must also be considered. We then show that once relevance is incorporated as a criterion, second-hand information can no longer be discounted on the basis of its poor fidelity alone. Finally we show that the relative importance of accuracy and relevance depends on factors of life history and demography.</jats:p

Miniature biplanar coils for alkali-metal-vapor magnetometry

Atomic spin sensors offer precision measurements using compact, microfabricated packages, placing them in a competitive position for both market and research applications. Performance of these sensors such as dynamic range may be enhanced through magnetic field control. In this work, we discuss the design of miniature coils for three-dimensional, localized field control by direct placement around the sensor, as a flexible and compact alternative to global approaches used previously. Coils are designed on biplanar surfaces using a stream-function approach and then fabricated using standard printed-circuit techniques. Application to a laboratory-scale optically pumped magnetometer of sensitivity $\sim$20 fT/Hz$^{1/2}$ is shown. We also demonstrate the performance of a coil set measuring $7 \times 17 \times 17$ mm$^3$ that is optimized specifically for magnetoencephalography, where multiple sensors are operated in proximity to one another. Characterization of the field profile using $^{87}$Rb free-induction spectroscopy and other techniques show $>$96% field homogeneity over the target volume of a MEMS vapor cell and a compact stray field contour of $\sim$1% at 20 mm from the center of the cell