A tool for helping operations research

This paper describes an integrated environment in which a student can acquire and test knowledge about Operations Research techniques. In this environment all the interactions with the users are performed by means of an appropriated graphical interface related to the problem and the algorithm chosen to solve it During a step-by-step problem solving session, the user makes the decisions and lets the system process the necessary computations. Moreover, this environment is able: (i) to check the correctness of the user's replies, (ii) to display warnings every time a wrong decision is taken, and (iii) to return to any previous step in order to give more flexibility to the teacher's exposition. The system is designed to include: Primal Simplex, Dual Simplex, Revised Simplex, Stepping-Stone Method for Transportation Problems, Hungarian Method for Assignment Problems, and Sensitivity Analysis

Applying sequential mixed-methods approaches when working with businesses: insights from longitudinal research into the influence of business on sustainable lifestyles

Working with businesses can be complex and equally demanding requiring flexible and rigorous research approaches to ensure sufficient data is captured to fully answer the respective research questions. Sequential mixed-methods approaches allow to combine quantitative and qualitative methods in ways that allow for exploration and explanation. While often multifaceted and resource-intense, sequential designs such as sequential exploratory and sequential explanatory approaches utilize a wide breadth of data in an attempt to capture the real world in its entirety. The application of both types of sequential mixed-methods designs is presented by drawing on a longitudinal behavior change study with IKEA UK & Ireland, a leading multi-national home furniture retailer. A variety of qualitative data mining techniques were used to collect data including qualitative data from in-depth semi-structured interviews and blog posts, among others. Quantitative data were collected following a pre-post survey design. The case example demonstrates the potential of sequential designs, addressing advantages and potential challenges. It also highlights the need to stay flexible throughout the research process to adapt to changes while applying a rigorous approach to data collection and analysis

A family tree of Markov models in systems biology

Motivated by applications in systems biology, we seek a probabilistic framework based on Markov processes to represent intracellular processes. We review the formal relationships between different stochastic models referred to in the systems biology literature. As part of this review, we present a novel derivation of the differential Chapman-Kolmogorov equation for a general multidimensional Markov process made up of both continuous and jump processes. We start with the definition of a time-derivative for a probability density but place no restrictions on the probability distribution, in particular, we do not assume it to be confined to a region that has a surface (on which the probability is zero). In our derivation, the master equation gives the jump part of the Markov process while the Fokker-Planck equation gives the continuous part. We thereby sketch a {}``family tree'' for stochastic models in systems biology, providing explicit derivations of their formal relationship and clarifying assumptions involved.Comment: 18 pages, 2 figure

Uuden molekulaarisen menetelmän soveltaminen syöpädiagnostiikkaan : AR-V7 mRNA:n detektio

Huolimatta viimeaikaisista edistysaskelista syöpädiagnostiikan ja syöpähoitojen saralla, on tämä kompleksi ja monitahoinen tauti yhä yksi maailman yleisimmistä kuolinsyistä. Uusia ja nopeita diagnostisia menetelmiä tarvitaan syöpätautien tunnistamiseen niiden aikaisessa kehitysvaiheessa, jotta tautien aiempi prognoosi, parempi riskienhallinta ja tehokkaampi hoito olisivat mahdollisia. Kiinnostus spesifisiin molekulaarisiin biomerkkiaineisiin, jotka toimivat syövän tunnusmerkkeinä, on vähitellen kasvamassa. Näiden merkkiaineiden tunnistaminen nestemäisistä näytemateriaaleista kehittyneiden molekulaaristen diagnostiikkamenetelmien avulla tarjoaa huomattavia etuja perinteisiin onkologiassa käytettäviin kuvantamismenetelmiin verrattuna. Tämän tutkielman tavoite oli tutkia uuden molekulaarisen menetelmän, SIBA®:n (Strand Invasion Based Amplification), soveltuvuutta syöpämerkkiaineiden tunnistamiseen, sekä kehittää testi androgeenireseptorin silmukointivariantti 7 (AR-V7) mRNA:n tunnistamiseen. AR-V7:ä on esitetty hoitovaste-biomerkkiaineeksi potilaissa, joilla on metastaattinen kastraatioresistentti eturauhassyöpä (mCRPC). Tämän variantin ekspressio voi ilmaista kehittynyttä resistenssiä edistyneen eturauhassyövän hoitoon käytetyille hormonaalisille hoidoille. Eturauhassyöpä on maailmanlaajuisesti toiseksi yleisin miehillä esiintyvä syöpä keuhkosyövän jälkeen, ja se voi vähitellen kehittyä pitkälle edenneeksi kuolettavaksi metastaattiseksi kastraatioresistentiksi eturauhassyöväksi, johon androgeeni-deprivaatiohoito ei enää toimi. Positiivisen AR-V7-statuksen on esitetty edustavan tämän pitkälle edenneen eturauhassyövän fenotyyppiä, ja sen tunnistaminen voi auttaa sopivan hoitomuodon valinnassa mCRPC-potilaille. SIBA on uusi isotermaalinen menetelmä nukleiinihappojen monistamiseen ja tunnistamiseen. Teknologia tarjoaa merkittäviä etuja perinteiseen molekulaariseen tunnistusmenetelmään, polymeraasiketjureaktioon (PCR) verrattuna, sillä SIBA-monistus tapahtuu vakiolämpötilassa eikä vaadi lämpösykliseen monistamiseen tarvittavaa hienostunutta laboratoriovälineistöä. Käänteistranskriptio-SIBA (RT-SIBA) mahdollistaa RNA:n käänteistranskription cDNA:ksi samanaikaisesti cDNA:n monistuksen ja tunnistuksen kanssa yksivaiheisessa reaktiossa ja isotermaalisissa olosuhteissa. Menetelmä on osoittanut korkeaa analyyttistä herkkyyttä sekä spesifisyyttä kohdenukleiinihapoille. RT-SIBA-teknologiaa ei ole aiemmin sovellettu ihmisperäisen DNA:n tai RNA:n tunnistamiseen. Tämän tutkielman tärkein havainto oli, että RT-SIBA-teknologiaa voidaan soveltaa molekulaaristen syöpämerkkiaineiden, kuten AR-V7 mRNA:n, nopeaan ja spesifiseen tunnistamiseen. Tässä tutkimuksessa kehitettiin ja optimoitiin kaksi RT-SIBA-testiä, jotka kohdistuivat täyspitkän androgeenireseptori (AR-FL) mRNA:n sekä androgeenireseptorin silmukointivariantti 7 (AR-V7) mRNA:n tunnistamiseen. Näiden testien suorituskykyä arvioitiin testaamalla RNA:ta, joka oli eristetty AR-V7 positiivisista sekä negatiivisista eturauhassyöpäsoluista. Reaktiossa oli samanaikaisesti läsnä myös nestemäistä näytemateriaalia; kokoverta tai plasmaa. Kehitetyt RT-SIBA-testit olivat analyyttisesti erittäin spesifisiä ja herkkiä: ne monistivat alhaisia kopiomääriä kohde-mRNA:ta alle 20 minuutissa ilman epäspesifisten amplikonien muodostumista. Tulokset osoittavat, että RT-SIBA-teknologiaa voidaan hyödyntää AR-V7 ja AR-FL mRNA:n helppoon ja nopeaan tunnistukseen suoraan nestemäisestä näytemateriaalista ilman aikaa vievää näytteenkäsittelyä. Jatkokokeet todellisilla AR-V7-positiivisilla mCRPC-potilaiden kliinisillä näytteillä ovat tarpeellisia, jotta kehitetyt testit voidaan validoida luotettavasti.Despite recent advances in understanding, diagnosis and treatment of cancer, this complex and versatile disease remains one of the leading causes of death worldwide. New and rapid diagnostic methods are needed to detect cancers at their early stages of development, thus enabling earlier prognosis, better risk assessment and more efficient treatment of the disease. There has been an increasing interest in specific molecular biomarkers as the hallmark for cancer research, and the detection of these markers from liquid biopsies using advanced molecular diagnostics methods provides major advantages over the conventional imaging methods currently used in oncology. The aims of this thesis were to examine the applicability of a novel molecular method, SIBA® (Strand Invasion Based Amplification), for the detection of cancer biomarkers, and to develop an assay targeting androgen receptor splice variant 7 (AR-V7) mRNA. The AR-V7 is proposed as a treatment-response biomarker in patients with castration-resistant metastatic prostate cancer (mCRPC). The expression of this variant can indicate resistance to hormonal therapies used for the treatment of advanced prostate cancer. Prostate cancer is the most common cancer after lung cancer in men worldwide and can gradually develop into a highly advanced lethal form, mCRPC, that is not responsive to androgen deprivation therapies. Positive AR-V7 status is suggested to represent the phenotype of this advanced stage of prostate cancer, and its detection can assist in treatment selection for the mCRPC patients. SIBA is a novel isothermal method for the amplification and detection of nucleic acids. The technology offers significant advantages over the more conventional molecular detection method, polymerase chain reaction (PCR), since the amplification reaction occurs at constant temperature and does not require sophisticated laboratory equipment for the thermal cycling. Reverse transcription SIBA (RT-SIBA) enables reverse transcription of RNA to cDNA as well as the simultaneous amplification and detection of the cDNA in one-step reaction under isothermal conditions. The method displays both high analytical sensitivity and specificity to the target nucleic acids. The RT-SIBA technology has not formerly been applied for the detection of human DNA or RNA. The main finding of this thesis was, that the RT-SIBA technology can be applied for rapid detection of specific molecular cancer biomarkers such as the AR-V7 mRNA. In this study, two RT-SIBA assays targeting the full-length androgen receptor (AR-FL) mRNA and the AR splice variant 7 mRNA were developed and optimized. Performance of the assays were evaluated by testing RNA isolates from AR-V7 positive and negative prostate cancer cell lines in the presence of human whole blood and plasma in the reaction. The developed RT-SIBA assays provided high analytical sensitivity and specificity: low copies of the target mRNA were amplified within 20 minutes without the production of non-intended amplicons. The results suggest that the RT-SIBA technology can be utilized for easy and rapid detection of AR-V7 and AR-FL mRNA directly from liquid sample material without a need for time-consuming sample treatment. Further performance evaluation using real AR-V7 positive clinical samples from mCRPC patients is necessary for the reliable validation of the developed assays

Clinical probability assessment and biochemical markers in the diagnosis of deep vein thrombosis

The combination of pre-test clinical probability assessment and D-dimer test is now widely applied in the diagnostic process of DVT. The general objective of the present investigation was to validate these results in a Swedish routine emergency setting were the prevalence of the disease is high and were the clinical probability assessment was handled by many junior physicians. Furthermore, our aims were to evaluate our D-dimer method and to make comparisons with other D-dimer methods as with a new marker of coagulation, the APC-PCI complex. In addition, a cost effectiveness analysis was made of this diagnostic strategy. Material and methods: 357 outpatients with clinical suspicion of DVT were included in the clinical management study. The diagnostic workup included estimation of pre-test probability, D-dimer determination, objective imaging as well as 3 month clinical follow up of negative patients (Paper I). 350 plasma samples from the management study was used for comparison between two well established D-dimer methods and the APC-PCI complex (Paper II) and 311 plasma samples for the evaluation of two new D-dimer methods (Paper III). Direct and indirect costs were calculated for the tested diagnostic strategy and for two hypothetical strategies. A decision analysis was performed (Paper IV). Results and conclusions: One out of 110 patients categorized as having a low clinical probability in combination with a negative D-dimer test was diagnosed with DVT during follow up. About 30% of the patients do not need further investigation for DVT. The APC-PCI complex perform inferior to the D-dimer methods for the exclusion of DVT but slightly superior when indicating its presence. The AxSYM® and Innovance™ D-dimer assays perform well and in good agreement with the two well established assays with NPV´s of > 98% in the low clinical probability estimate (CP). Objective imaging in all patients was the least cost effective (€581) strategy, D-dimer screening of all patients before CP (€421) and CP in combination with D-Dimer testing only in patients with low CP (€406). Conclusion: the investigated diagnostic strategy is safe, result in more convenient and cost-effective care for patients