Cost-effectiveness of medically assisted reproduction or expectant management for unexplained subfertility:when to start treatment?

STUDY QUESTION Over a time period of 3 years, which order of expectant management (EM), IUI with ovarian stimulation (IUI-OS) and IVF is the most cost-effective for couples with unexplained subfertility with the female age below 38 years? SUMMARY ANSWER If a live birth is considered worth Euro32 000 or less, 2 years of EM followed by IVF was the most cost-effective, whereas above Euro32 000 this was 1 year of EM, 1 year of IUI-OS and then 1 year of IVF. WHAT IS KNOWN ALREADY IUI-OS and IVF are commonly used fertility treatments for unexplained subfertility although many couples can conceive naturally, as no identifiable barrier to conception could be found by definition. Few countries have guidelines on when to proceed with medically assisted reproduction (MAR), mostly based on the expected probability of live birth after treatment, but there is a lack of evidence to support the strategies proposed by these guidelines. The increased uptake of IUI-OS and IVF over the past decades and costs related to reimbursement of these treatments are pressing concerns to health service providers. For MAR to remain affordable, sustainable and a responsible use of public funds, guidance is needed on the cost-effectiveness of treatment strategies for unexplained subfertility, including EM. STUDY DESIGN, SIZE, DURATION We developed a decision analytic Markov model that follows couples with unexplained subfertility of which the woman is under 38 years of age for a time period of 3 years from completion of the fertility workup onwards. We divided the time axis of 3 years into three separate periods, each comprising 1 year. The model was based on contemporary evidence, most notably the dynamic prediction model for natural conception, which was combined with MAR treatment effects from a network meta-analysis on randomized controlled trials. We changed the order of options for managing unexplained subfertility for the 1 year periods to yield five different treatment policies in total: IVF-EM-EM (immediate IVF), EM-IVF-EM (delayed IVF), EM-EM-IVF (postponed IVF), IUIOS-IVF-EM (immediate IUI-OS) and EM-IUIOS-IVF (delayed IUI-OS). PARTICIPANTS/MATERIALS, SETTING, METHODS The main outcomes per policy over the 3-year period were the probability of live birth, the average treatment and delivery costs, the probability of multiple pregnancy, the incremental cost-effectiveness ratio (ICER) and finally, which policy yields the highest net benefit in which costs for a policy were deducted from the health effects, i.e. live births gained. We chose the Dutch societal perspective, but the model can be easily modified for other locations or other perspectives. The probability of live birth after EM was taken from the dynamic prediction model for natural conception and updated for Years 2 and 3. The relative effects of IUI-OS and IVF in terms of odds ratios, taken from the network meta-analysis, were applied to the probability of live birth after EM. We applied standard discounting procedures for economic analyses for Years 2 and 3. The uncertainty around effectiveness, costs and other parameters was assessed by probabilistic sensitivity analysis in which we drew values from distributions and repeated this procedure 20 000 times. In addition, we changed model assumptions to assess their influence on our results. MAIN RESULTS AND THE ROLE OF CHANCE From IVF-EM-EM to EM-IUIOS-IVF, the probability of live birth varied from approximately 54-64% and the average costs from approximately Euro4000 to Euro9000. The policies IVF-EM-EM and EM-IVF-EM were dominated by EM-EM-IVF as the latter yielded a higher cumulative probability of live birth at a lower cost. The policy IUIOS-IVF-EM was dominated by EM-IUIOS-IVF as the latter yielded a higher cumulative probability of live birth at a lower cost. After removal of policies that were dominated, the ICER for EM-IUIOS-IVF was approximately Euro31 000 compared to EM-EM-IVF. The range of ICER values between the lowest 25% and highest 75% of simulation replications was broad. The net benefit curve showed that when we assume a live birth to be worth approximately Euro20 000 or less, the policy EM-EM-IVF had the highest probability to achieve the highest net benefit. Between Euro20 000 and Euro50 000 monetary value per live birth, it was uncertain whether EM-EM-IVF was better than EM-IUIOS-IVF, with the turning point of Euro32 000. When we assume a monetary value per live birth over Euro50 000, the policy with the highest probability to achieve the highest net benefit was EM-IUIOS-IVF. Results for subgroups with different baseline prognoses showed the same policies dominated and the same two policies that were the most likely to achieve the highest net benefit but at different threshold values for the assumed monetary value per live birth. LIMITATIONS, REASONS FOR CAUTION Our model focused on population level and was thus based on average costs for the average number of cycles conducted. We also based the model on a number of key assumptions. We changed model assumptions to assess the influence of these assumptions on our results. The change in relative effectiveness of IVF over time was found to be highly influential on results and their interpretation. WIDER IMPLICATIONS OF THE FINDINGS EM-EM-IVF and EM-IUIOS-IVF followed by IVF were the most cost-effective policies. The choice depends on the monetary value assigned to a live birth. The results of our study can be used in discussions between clinicians, couples and policy makers to decide on a sustainable treatment protocol based on the probability of live birth, the costs and the limitations of MAR treatment. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the ZonMw Doelmatigheidsonderzoek (80-85200-98-91072). The funder had no role in the design, conduct or reporting of this work. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research support from ObsEva, Merck and Guerbet. TRIAL REGISTRATION NUMBER N/A

An evolutionary stage model of outsourcing and competence destruction : a Triad comparison of the consumer electronics industry

Outsourcing has gained much prominence in managerial practice and academic discussions in the last two decades or so. Yet, we still do not understand the full implications of outsourcing strategy for corporate performance. Traditionally outsourcing across borders is explained as a cost-cutting exercise, but more recently the core competency argument states that outsourcing also leads to an increased focus, thereby improving effectiveness. However, no general explanation has so far been provided for how outsourcing could lead to deterioration in a firm‟s competence base. We longitudinally analyze three cases of major consumer electronics manufacturers, Emerson Radio from the U.S., Japan‟s Sony and Philips from the Netherlands to understand the dynamic process related to their sourcing strategies. We develop an evolutionary stage model that relates outsourcing to competence development inside the firm and shows that a vicious cycle may emerge. Thus it is appropriate to look not only at how outsourcing is influenced by an organization‟s current set of competences, but also how it alters that set over time. The four stages of the model are offshore sourcing, phasing out, increasing dependence on foreign suppliers, and finally industry exit or outsourcing reduction. The evolutionary stage model helps managers understand for which activities and under which conditions outsourcing across borders is not a viable option. Results suggest that each of these firms had faced a loss of manufacturing competitiveness in its home country, to which it responded by offshoring and then outsourcing production. When a loss of competences occurred, some outsourcing decisions were reversed

The early diagenetic and PETROphysical behaviour of recent cold-water CARbonate mounds in Deep Environments (PETROCARDE)

Sub-recent cold-water carbonate mounds localized in deeper slope settings on the Atlantic continental margins cannot be any longer neglected in the study of carbonate systems. They clearly play a major role in the dynamics of mixed siliciclastic-carbonate and/or carbonate-dominated continental slopes. Carbonate accumulation rates of cold-water carbonate mounds are about 4 to 12 % of the carbonate accumulation rates of tropical shallow-water reefs but exceed the carbonate accumulation rates of their slope settings by a factor of 4 to 12 (Titschack et al.,2009). These findings emphasize the importance of these carbonate factories as carbonate niches on the continental margins. The primary environmental architecture of such carbonate bodies is well-characterized. However, despite proven evidences of early diagenesis overprinting the primary environmental record (e.g. aragonite dissolution) (Foubert & Henriet, 2009), the extent of early diagenetic and biogeochemical processes shaping the petrophysical nature of mounds is until now not yet fully understood.Understanding (1) the functioning of a carbonate mound as biogeochemical reactor triggering early diagenetic processes and (2) the impact of early diagenesis on the petrophysical behaviour of a carbonate mound in space and through time are necessary (vital) for the reliable prediction of potential late diagenetic processes. Approaching the fossil carbonate mound record, through a profound study of recent carbonate bodies is innovative and will help to better understand processes observed in the fossil mound world (such as cementation, brecciation, fracturing, etc. . . ).In this study, the 155-m high Challenger mound (Porcupine Seabight, SW of Ireland), drilled during IODP Expedition 307 aboard the R/V Joides Resolution (Foubert & Henriet, 2009), and mounds from the Gulf of Cadiz (Moroccan margin) will be discussed in terms of early diagenetic processes and petrophysical behaviour. Early differential diagenesis overprints the primary environmental signals in Challenger mound, with extensive coral dissolution and the genesis of small-scaled semi-lithified layers in the Ca-rich intervals. The low cementation rates compared to the extensive dissolution patterns can be explained by an open-system diagenetic model. Moreover, Pirlet et al. (2009) emphasizes the occurrence of gypsum and dolomite in another mound system (Mound Perseverance) in Porcupine Seabight, which might be also related with fluid oxidation events in a semi-open diagenetic system. Along the Moroccan margins, fluid seepage and fluxes in pore water transport affect the development of mound structures, enhancing extensive cold-water coral dissolution and precipitation of diagenetic minerals such as dolomite, calcite, pyrite, etc. (Foubert et al., 2008). Recent carbonate mounds provide indeed an excellent opportunity to study early diagenetic processes in carbonate systems without the complications of burial and/or later meteoric diagenesis

Big data in economics: evolution or revolution?

The Big Data Era creates a lot of exciting opportunities for new developments in economics and econometrics. At the same time, however, the analysis of large datasets poses difficult methodological problems that should be addressed appropriately and are the subject of the present chapter

So you call that research? : mending methodological biases in strategy and organization departments of top business schools

We believe that all strategy and organization (SO) scholars should be able to decide for themselves whether to specialize in certain parts of the knowledge cycle or adopt a broader, multi-method view on the scientific process. In a situation of ―methodological pluralism‖, individuals might choose to contribute to the construction of new administrative theories by means of qualitative works like case studies, ethnographies, biographies, or grounded theory studies (e.g., see Denzin and Lincoln, 2000). Others could then specialize in testing these theories by means of experiments, surveys, or longitudinal econometric studies (e.g., see Lewis-Beck, 1987-2004). Again others could combine both approaches in Herculean attempts to conduct high-impact, integrative research with the potential to change the way we understand the field as a whole

Aspects of Cooling at the TRIμ\muP Facility

The Tri$\mu$P facility at KVI is dedicated to provide short lived radioactive isotopes at low kinetic energies to users. It comprised different cooling schemes for a variety of energy ranges, from GeV down to the neV scale. The isotopes are produced using beam of the AGOR cyclotron at KVI. They are separated from the primary beam by a magnetic separator. A crucial part of such a facility is the ability to stop and extract isotopes into a low energy beamline which guides them to the experiment. In particular we are investigating stopping in matter and buffer gases. After the extraction the isotopes can be stored in neutral atoms or ion traps for experiments. Our research includes precision studies of nuclear $\beta$-decay through $\beta$-$\nu$ momentum correlations as well as searches for permanent electric dipole moments in heavy atomic systems like radium. Such experiments offer a large potential for discovering new physics.Comment: COOL05 Workshop, Galena, Il, USA, 18-23. Sept. 2005, 5 pages, 3 figure

Thyroid cancer in a patient with a germline MSH2 mutation. Case report and review of the Lynch syndrome expanding tumour spectrum

Lynch syndrome (HNPCC) is a dominantly inherited disorder characterized by germline defects in DNA mismatch repair (MMR) genes and the development of a variety of cancers, predominantly colorectal and endometrial. We present a 44-year-old woman who was shown to carry the truncating MSH2 gene mutation that had previously been identified in her family. Recently, she had been diagnosed with an undifferentiated carcinoma of the thyroid and an adenoma of her coecum. Although the thyroid carcinoma was not MSI-high (1 out of 5 microsatellites instable), it did show complete loss of immunohistochemical expression for the MSH2 protein, suggesting that this tumour was not coincidental. Although the risks for some tumour types, including breast cancer, soft tissue sarcoma and prostate cancer, are not significantly increased in Lynch syndrome, MMR deficiency in the presence of a corresponding germline defect has been demonstrated in incidental cases of a growing range of tumour types, which is reviewed in this paper. Interestingly, the MSH2-associated tumour spectrum appears to be wider than that of MLH1 and generally the risk for most extra-colonic cancers appears to be higher for MSH2 than for MLH1 mutation carriers. Together with a previously reported case, our findings show that anaplastic thyroid carcinoma can develop in the setting of Lynch syndrome. Uncommon Lynch syndrome-associated tumour types might be useful in the genetic analysis of a Lynch syndrome suspected family if samples from typical Lynch syndrome tumours are unavailable

A Review of the Dose Justification of Phase 3 Trials to Regulatory Authorities for Drugs Intended for the Treatment of Type 2 Diabetes in Europe

Aims: Cardiovascular outcome trials with anti-diabetic drugs suggest that additional cardiovascular benefit can be achieved independent of improving glycaemic control. Nonetheless, dose selection of anti-diabetic drugs is typically based solely on glycaemic effects. We evaluated whether off-target drug effects are currently considered for dose justification to regulatory agencies. Methods: In the European Union, anti-diabetic drugs are registered by the European Medicines Agency. We extracted available information regarding dose selection from public assessment reports and marketing application dossiers. Descriptive statistics were used to summarise the extracted information. Results: In total, 14 drugs of three drug classes were included; sodium-glucose co-transporter-2 inhibitors (n = 4), dipeptidyl peptidase-4 inhibitors (n = 4) and glucagon-like peptide-1 receptor agonists (n = 6). For these drugs, 21 dose-finding trials were submitted including results of multiple off-target effects, of which body weight (n = 18) and low-density lipoprotein cholesterol (n = 14) were most frequently reported. Dose-response curves for off-target effects appeared to be different compared to the glycaemic dose-response curve. Glycated hemoglobin (100%) and fasting plasma glucose (42.9%), were used most frequently for the dose justification, but generally off-target effects (<25%) were not. Conclusions: Dose justification to regulatory authorities was mainly based on glycaemic effects. The dose-response relationship for the off-target effects did not necessarily follow the dose-response relationship of the on-target effects suggesting that selection of the optimal anti-diabetic dose could benefit from including off-target effects in the dose selection process as well