Computational Identification of Recessive Mutations in Cancers using High Throughput SNP-arrays

This thesis presents a highly sensitive genome wide search method for recessive mutations. The method is suitable for distantly related samples that are divided into phenotype positives and negatives. High throughput genotype arrays are used to identify and compare homozygous regions between the cohorts. The method is demonstrated by comparing colorectal cancer patients against unaffected references. The objective is to find homozygous regions and alleles that are more common in cancer patients. We have designed and implemented software tools to automate the data analysis from genotypes to lists of candidate genes and to their properties. The programs have been designed in respect to a pipeline architecture that allows their integration to other programs such as biological databases and copy number analysis tools. The integration of the tools is crucial as the genome wide analysis of the cohort differences produces many candidate regions not related to the studied phenotype. CohortComparator is a genotype comparison tool that detects homozygous regions and compares their loci and allele constitutions between two sets of samples. The data is visualised in chromosome specific graphs illustrating the homozygous regions and alleles of each sample. The genomic regions that may harbour recessive mutations are emphasised with different colours and a scoring scheme is given for these regions. The detection of homozygous regions, cohort comparisons and result annotations are all subjected to presumptions many of which have been parameterized in our programs. The effect of these parameters and the suitable scope of the methods have been evaluated. Samples with different resolutions can be balanced with the genotype estimates of their haplotypes and they can be used within the same study.

Search for a Light Higgs Boson in Central Exclusive Diffraction: Method and Detectors

By detecting leading protons produced in the Central Exclusive Diffractive process, p+p → p+X+p, one can measure the missing mass, and scan for possible new particle states such as the Higgs boson. This process augments - in a model independent way - the standard methods for new particle searches at the Large Hadron Collider (LHC) and will allow detailed analyses of the produced central system, such as the spin-parity properties of the Higgs boson. The exclusive central diffractive process makes possible precision studies of gluons at the LHC and complements the physics scenarios foreseen at the next e+e− linear collider. This thesis first presents the conclusions of the first systematic analysis of the expected precision measurement of the leading proton momentum and the accuracy of the reconstructed missing mass. In this initial analysis, the scattered protons are tracked along the LHC beam line and the uncertainties expected in beam transport and detection of the scattered leading protons are accounted for. The main focus of the thesis is in developing the necessary radiation hard precision detector technology for coping with the extremely demanding experimental environment of the LHC. This will be achieved by using a 3D silicon detector design, which in addition to the radiation hardness of up to 5×10^15 neutrons/cm2, offers properties such as a high signal-to- noise ratio, fast signal response to radiation and sensitivity close to the very edge of the detector. This work reports on the development of a novel semi-3D detector design that simplifies the 3D fabrication process, but conserves the necessary properties of the 3D detector design required in the LHC and in other imaging applications.

Search for the Higgs boson produced in association with Z→ℓ+ℓ- using the matrix element method at CDF II

We present a search for associated production of the standard model (SM) Higgs boson and a $Z$ boson where the $Z$ boson decays to two leptons and the Higgs decays to a pair of $b$ quarks in $p\bar{p}$ collisions at the Fermilab Tevatron. We use event probabilities based on SM matrix elements to construct a likelihood function of the Higgs content of the data sample. In a CDF data sample corresponding to an integrated luminosity of 2.7 fb$^{-1}$ we see no evidence of a Higgs boson with a mass between 100 GeV$/c^2$ and 150 GeV$/c^2$. We set 95% confidence level (C.L.) upper limits on the cross-section for $ZH$ production as a function of the Higgs boson mass $m_H$; the limit is 8.2 times the SM prediction at $m_H = 115$ GeV$/c^2$.

Visual search and eye movements: Studies of perceptual span

In visual search one tries to find the currently relevant item among other, irrelevant items. In the present study, visual search performance for complex objects (characters, faces, computer icons and words) was investigated, and the contribution of different stimulus properties, such as luminance contrast between characters and background, set size, stimulus size, colour contrast, spatial frequency, and stimulus layout were investigated. Subjects were required to search for a target object among distracter objects in two-dimensional stimulus arrays. The outcome measure was threshold search time, that is, the presentation duration of the stimulus array required by the subject to find the target with a certain probability. It reflects the time used for visual processing separated from the time used for decision making and manual reactions. The duration of stimulus presentation was controlled by an adaptive staircase method. The number and duration of eye fixations, saccade amplitude, and perceptual span, i.e., the number of items that can be processed during a single fixation, were measured. It was found that search performance was correlated with the number of fixations needed to find the target. Search time and the number of fixations increased with increasing stimulus set size. On the other hand, several complex objects could be processed during a single fixation, i.e., within the perceptual span. Search time and the number of fixations depended on object type as well as luminance contrast. The size of the perceptual span was smaller for more complex objects, and decreased with decreasing luminance contrast within object type, especially for very low contrasts. In addition, the size and shape of perceptual span explained the changes in search performance for different stimulus layouts in word search. Perceptual span was scale invariant for a 16-fold range of stimulus sizes, i.e., the number of items processed during a single fixation was independent of retinal stimulus size or viewing distance. It is suggested that saccadic visual search consists of both serial (eye movements) and parallel (processing within perceptual span) components, and that the size of the perceptual span may explain the effectiveness of saccadic search in different stimulus conditions. Further, low-level visual factors, such as the anatomical structure of the retina, peripheral stimulus visibility and resolution requirements for the identification of different object types are proposed to constrain the size of the perceptual span, and thus, limit visual search performance. Similar methods were used in a clinical study to characterise the visual search performance and eye movements of neurological patients with chronic solvent-induced encephalopathy (CSE). In addition, the data about the effects of different stimulus properties on visual search in normal subjects were presented as simple practical guidelines, so that the limits of human visual perception could be taken into account in the design of user interfaces.

Cone beam computed tomography in oral radiology

In dentistry, basic imaging techniques such as intraoral and panoramic radiography are in most cases the only imaging techniques required for the detection of pathology. Conventional intraoral radiographs provide images with sufficient information for most dental radiographic needs. Panoramic radiography produces a single image of both jaws, giving an excellent overview of oral hard tissues. Regardless of the technique, plain radiography has only a limited capability in the evaluation of three-dimensional (3D) relationships. Technological advances in radiological imaging have moved from two-dimensional (2D) projection radiography towards digital, 3D and interactive imaging applications. This has been achieved first by the use of conventional computed tomography (CT) and more recently by cone beam CT (CBCT). CBCT is a radiographic imaging method that allows accurate 3D imaging of hard tissues. CBCT has been used for dental and maxillofacial imaging for more than ten years and its availability and use are increasing continuously. However, at present, only best practice guidelines are available for its use, and the need for evidence-based guidelines on the use of CBCT in dentistry is widely recognized. We evaluated (i) retrospectively the use of CBCT in a dental practice, (ii) the accuracy and reproducibility of pre-implant linear measurements in CBCT and multislice CT (MSCT) in a cadaver study, (iii) prospectively the clinical reliability of CBCT as a preoperative imaging method for complicated impacted lower third molars, and (iv) the tissue and effective radiation doses and image quality of dental CBCT scanners in comparison with MSCT scanners in a phantom study. Using CBCT, subjective identification of anatomy and pathology relevant in dental practice can be readily achieved, but dental restorations may cause disturbing artefacts. CBCT examination offered additional radiographic information when compared with intraoral and panoramic radiographs. In terms of the accuracy and reliability of linear measurements in the posterior mandible, CBCT is comparable to MSCT. CBCT is a reliable means of determining the location of the inferior alveolar canal and its relationship to the roots of the lower third molar. CBCT scanners provided adequate image quality for dental and maxillofacial imaging while delivering considerably smaller effective doses to the patient than MSCT. The observed variations in patient dose and image quality emphasize the importance of optimizing the imaging parameters in both CBCT and MSCT.

Accuracy of absorbed dose in external photon beam radiotherapy : what level is sufficient and how to approach it?

Radiation therapy (RT) plays currently significant role in curative treatments of several cancers. External beam RT is carried out mostly by using megavoltage beams of linear accelerators. Tumor eradication and normal tissue complications correlate to dose absorbed in tissues. Normally this dependence is steep and it is crucial that actual dose within patient accurately correspond to the planned dose. All factors in a RT procedure contain uncertainties requiring strict quality assurance. From hospital physicist´s point of a view, technical quality control (QC), dose calculations and methods for verification of correct treatment location are the most important subjects. Most important factor in technical QC is the verification that radiation production of an accelerator, called output, is within narrow acceptable limits. The output measurements are carried out according to a locally chosen dosimetric QC program defining measurement time interval and action levels. Dose calculation algorithms need to be configured for the accelerators by using measured beam data. The uncertainty of such data sets limits for best achievable calculation accuracy. All these dosimetric measurements require good experience, are workful, take up resources needed for treatments and are prone to several random and systematic sources of errors. Appropriate verification of treatment location is more important in intensity modulated radiation therapy (IMRT) than in conventional RT. This is due to steep dose gradients produced within or close to healthy tissues locating only a few millimetres from the targeted volume. The thesis was concentrated in investigation of the quality of dosimetric measurements, the efficacy of dosimetric QC programs, the verification of measured beam data and the effect of positional errors on the dose received by the major salivary glands in head and neck IMRT. A method was developed for the estimation of the effect of the use of different dosimetric QC programs on the overall uncertainty of dose. Data were provided to facilitate the choice of a sufficient QC program. The method takes into account local output stability and reproducibility of the dosimetric QC measurements. A method based on the model fitting of the results of the QC measurements was proposed for the estimation of both of these factors. The reduction of random measurement errors and optimization of QC procedure were also investigated. A method and suggestions were presented for these purposes. The accuracy of beam data was evaluated in Finnish RT centres. Sufficient accuracy level was estimated for the beam data. A method based on the use of reference beam data was developed for the QC of beam data. Dosimetric and geometric accuracy requirements were evaluated for head and neck IMRT when function of the major salivary glands is intended to be spared. These criteria are based on the dose response obtained for the glands. Random measurement errors could be reduced enabling lowering of action levels and prolongation of measurement time interval from 1 month to even 6 months simultaneously maintaining dose accuracy. The combined effect of the proposed methods, suggestions and criteria was found to facilitate the avoidance of maximal dose errors of up to even about 8 %. In addition, their use may make the strictest recommended overall dose accuracy level of 3 % (1SD) achievable.

Patient doses in ct, dental cone beam ct and projection radiography in Finland, with emphasis on paediatric patients

Diagnostic radiology represents the largest man-made contribution to population radiation doses in Europe. To be able to keep the diagnostic benefit versus radiation risk ratio as high as possible, it is important to understand the quantitative relationship between the patient radiation dose and the various factors which affect the dose, such as the scan parameters, scan mode, and patient size. Paediatric patients have a higher probability for late radiation effects, since longer life expectancy is combined with the higher radiation sensitivity of the developing organs. The experience with particular paediatric examinations may be very limited and paediatric acquisition protocols may not be optimised. The purpose of this thesis was to enhance and compare different dosimetric protocols, to promote the establishment of the paediatric diagnostic reference levels (DRLs), and to provide new data on patient doses for optimisation purposes in computed tomography (with new applications for dental imaging) and in paediatric radiography. Large variations in radiation exposure in paediatric skull, sinus, chest, pelvic and abdominal radiography examinations were discovered in patient dose surveys. There were variations between different hospitals and examination rooms, between different sized patients, and between imaging techniques; emphasising the need for harmonisation of the examination protocols. For computed tomography, a correction coefficient, which takes individual patient size into account in patient dosimetry, was created. The presented patient size correction method can be used for both adult and paediatric purposes. Dental cone beam CT scanners provided adequate image quality for dentomaxillofacial examinations while delivering considerably smaller effective doses to patient compared to the multi slice CT. However, large dose differences between cone beam CT scanners were not explained by differences in image quality, which indicated the lack of optimisation. For paediatric radiography, a graphical method was created for setting the diagnostic reference levels in chest examinations, and the DRLs were given as a function of patient projection thickness. Paediatric DRLs were also given for sinus radiography. The detailed information about the patient data, exposure parameters and procedures provided tools for reducing the patient doses in paediatric radiography. The mean tissue doses presented for paediatric radiography enabled future risk assessments to be done. The calculated effective doses can be used for comparing different diagnostic procedures, as well as for comparing the use of similar technologies and procedures in different hospitals and countries.

Search for new physics in the μμ+e/μ+E̸T channel with a low-pT lepton threshold at the Collider Detector at Fermilab

A search for new physics using three-lepton (trilepton) data collected with the CDF II detector and corresponding to an integrated luminosity of 976 pb-1 is presented. The standard model predicts a low rate of trilepton events, which makes some supersymmetric processes, such as chargino-neutralino production, measurable in this channel. The mu+mu+l signature is investigated, where l is an electron or a muon, with the additional requirement of large missing transverse energy. In this analysis, the lepton transverse momenta with respect to the beam direction (pT) are as low as 5 GeV/c, a selection that improves the sensitivity to particles which are light as well as to ones which result in leptonically decaying tau leptons. At the same time, this low-p_T selection presents additional challenges due to the non-negligible heavy-quark background at low lepton momenta. This background is measured with an innovative technique using experimental data. Several dimuon and trilepton control regions are investigated, and good agreement between experimental results and standard-model predictions is observed. In the signal region, we observe one three-muon event and expect 0.4+/-0.1 mu+mu+l events

Search for standard model Higgs boson production in association with a W boson using a neural network discriminant at CDF

We present a search for standard model Higgs boson production in association with a W boson in proton-antiproton collisions at a center of mass energy of 1.96 TeV. The search employs data collected with the CDF II detector that correspond to an integrated luminosity of approximately 1.9 inverse fb. We select events consistent with a signature of a single charged lepton, missing transverse energy, and two jets. Jets corresponding to bottom quarks are identified with a secondary vertex tagging method, a jet probability tagging method, and a neural network filter. We use kinematic information in an artificial neural network to improve discrimination between signal and background compared to previous analyses. The observed number of events and the neural network output distributions are consistent with the standard model background expectations, and we set 95% confidence level upper limits on the production cross section times branching fraction ranging from 1.2 to 1.1 pb or 7.5 to 102 times the standard model expectation for Higgs boson masses from 110 to $150 GeV/c^2, respectively.