Mitochondrial respiratory chain defects are an important cause of inherited disorders affecting approximately 1 in 5000 people in the UK population. Collectively these disorders are termed ‘mitochondrial diseases’ and they result from either mitochondrial DNA mutations or defects in nuclear DNA. Although they are frequently multisystem disorders, neurological deficits are particularly common, wide‐ranging and disabling for patients. This review details the manifold neurological impairments associated with mitochondrial disease, and describes the efforts to understand how they arise and progressively worsen in patients with mitochondrial disease. We describe advances in our understanding of disease pathogenesis through detailed neuropathological studies and how this has spurred the development of cellular and animal models of disease. We underscore the importance of continued clinical, molecular genetic, neuropathological and animal model studies to fully characterize mitochondrial diseases and understand mechanisms of neurodegeneration. These studies are instrumental for the next phase of mitochondrial research that has a particular emphasis on finding novel ways to treat mitochondrial disease to improve patient care and quality of life. Mitochondria house the machinery necessary to perform oxidative phosphorylation (OXPHOS) within the inner mitochondrial membrane. This machinery comprises an electron transport chain (ETC) which is made up of four multisubunit complexes (complex I–IV) and two mobile electron carriers  and nuclear DNA (nDNA). mtDNA exists as a multiple copy circular double‐stranded 16.6 kb DNA molecule and encodes for 13 polypeptide proteins for the ETC and the necessary RNA machinery [2 ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs)] required for their synthesis within the mitochondria Leu, or large‐scale mtDNA rearrangements, including single large‐scale mtDNA deletions associated with Kearns–Sayre syndrome (KSS). MtDNA is strictly inherited through the maternal line Mitochondrial disorders represent a common group of human genetic diseases that result from a primary defect of mitochondrial OXPHOS. Impaired energy generation due to a failure of OXPHOS can therefore result from a genetic defect arising in either the mtDNA or nDNA. MtDNA mutations may either be in the form of point mutations, such as the most common mtDNA mutation m.3243A>G which affects mt‐tRNAMT‐TL1 mutation which was first described in relation to the classic mitochondrial encephalopathy with lactic acidosis and stroke‐like episodes (MELAS) syndrome The heterogeneous nature of mitochondrial disease means that patients may be affected at any age and with multisystem involvement that does not always correlate with genotype, and so this presents a major diagnostic and treatment challenge for patient management. Certain mtDNA mutations are associated with specific syndromes, however, a single mutation can cause several different phenotypes depending on the segregation of the mutation and heteroplasmy level. Perhaps the best example of this is the m.3243A>G POLG gene that encodes for the sole mtDNA polymerase γ and is responsible for replication of the mitochondrial genome. POLG mutations result in a range of different clinical phenotypes either with an early onset, such as in Alpers' syndrome, or late onset as seen in patients with CPEO, myoclonic epilepsy myopathy sensory ataxia (MEMSA) and ataxia neuropathy spectrum (ANS) and these are associated with either accumulation of multiple mtDNA deletions and/or depletion of mtDNA content within individual neurons The emergence of next generation sequencing has led to a rapid expansion in the number of nDNA mutations being identified Despite only weighing 2% of total body mass, the brain consumes 20% of oxygen and 50% glucose supplied through delivery from the vasculature and is used to drive aerobic respiration within mitochondria MT‐TL1 and MT‐TK and also single large‐scale mtDNA deletions. Cerebellar changes are also reported in patients harbouring nDNA mutations, including RARS2C10orf2POLG mutations POLG defects, ataxia may be reported as one of the prevailing neurological features and is frequently reported in patients with MEMSA Cerebellar ataxia is common in both adult and paediatric patients with mitochondrial disease MT‐TL1 show Purkinje cell vulnerability and a high frequency of microinfarcts (or ischaemic‐like lesions) affecting the cerebellar cortex. The aetiology of microinfarcts is not well understood, however, it might be the result of energy deficiency within neurons combined with microvascular abnormalities which lead to localized necrotic cell death MT‐TK and POLG mutations are very similar. Patients with these genetic defects also demonstrate ischaemic‐like lesions that histologically resemble those seen in MT‐TL1. Surviving neurons show a profound loss of complex I subunits indicative of complex I deficiency The major neuropathological findings include cerebellar atrophy, microinfarcts, Purkinje cell loss and morphological changes, including axonal torpedoes and abnormal dendritic arborisations, in remaining neurons POLG mutations. In 2004, Luoma and colleagues reported the first description of Parkinsonism in a patient with autosomal dominant PEO due to mutated POLGPOLG defect Extrapyramidal features, including dystonia, akathisia (motor restlessness), Parkinsonism and tardive dyskinesia, have been described in patients harbouring Leigh syndrome is a progressive neurodegenerative condition affecting infants owing to mutations affecting mtDNA, including mt‐mRNA and mt‐tRNA mutations, and nDNA defects POLG mutations that were very similar to those seen in iPD POLG and C10orf2 mutations showed neuronal loss without alpha‐synuclein or Lewy bodies, whereas remaining neurons demonstrated a preferential complex I deficiency POLG mutations demonstrated severe nigrostriatal degeneration with decreased mtDNA in remaining neurons In idiopathic Parkinson's disease (iPD), complex I deficiency and accumulation of mtDNA deletions have been detected in substantia nigra pars compacta (SNpc) neurons The neuropathological features of Leigh syndrome include symmetrical vasculo‐necrotic lesions affecting the substania nigra, putamen in the basal ganglia and thalamus or sub‐thalamic nuclei. These lesions are characterized by spongiform changes, and cytotoxic oedema and also increased capillary prominence POLG mutations where the neuropathy is mainly sensory with a loss of proprioception and vibration sense and touch and pinprick sensory changes with a varying degree of distal muscle weakness. Nerve conduction studies show decreased or absent sensory action potentials and varying motor involvement TYMP, the neuropathy is predominantly demyelinating with slowed conduction velocities and axonal degeneration and segmental demyelination in biopsied nerves MFN2, which encodes a protein involved in mitochondrial dynamics, and this leads to a progressive early onset axonal neuropathy Peripheral nerve involvement is frequent in mitochondrial disease, and might define the clinical picture in a number of patients with intergenomic signalling defects causing multiple mtDNA deletions and mtDNA depletion. This includes ANS due to POLG mutations, and confirmed a loss of sensory neurons and respiratory chain deficiency in remaining cells in the dorsal root ganglia. In this patient, respiratory chain deficiency was associated with lowered mtDNA content in remaining neurons Relatively few studies have explored neuropathological features associated with peripheral neuropathy, however, a recent electrophysiological and neuropathological study provided evidence of a sensory neuronopathy in patients with MT‐TL1 mutation will develop epilepsy and of these 17.5% also develop stroke‐like episodes. In these patients, epilepsy may be classified as focal motor seizures with or without a loss of consciousness. While in patients harbouring MT‐TK, epilepsy affects 92% of patients and is usually progressive myoclonus and generalized tonic clonic seizures Epilepsy may be a presenting feature, such as in myoclonic epilepsy ragged red fibres (MERRF) or MEMSA, or emerge on the background of multiple neurological impairments, such as in MELAS, and seizures may occur in any seismology or classification. A recent study identified that approximately 23.1% of 182 adult patients with genetically‐defined mitochondrial disease in a UK cohort develop epilepsy, and that approximately 34.9% of patients with vs. secondary changes. Often seizures associated with stroke‐like episodes reveal foci of necrosis affecting the cerebral cortex, and these will be discussed in further detail under ‘seizure‐associated stroke‐like episodes’. The importance of neuronal energy depletion in epilepsy is underscored by the high prevalence of epilepsy in mitochondrial disease. A vulnerability of cortical inhibitory interneurons has recently been shown in post‐mortem tissues from patients with mitochondrial disease with evidence of combined complex I and IV defects and reduced interneuron densities  as T2‐weighted hyperintensities which are typically in posterior brain regions though not associated with any major vascular territories. Recently there have been a number of radiological studies to determine the mechanisms contributing to the onset of a stroke‐like episode and also to monitor its progression as they can migrate to other regions of the brain. There is evidence that during preclinical or acute onset of a stroke‐like episode, focal hyperperfusion can be detected by either arterial spin labelling or SPECT and can manifest before any structural abnormalities might be seen on MRI l‐arginine therapy in the acute phase and during the interictal phases of stroke‐like episodes to prevent or decrease the severity of these episodes in patients with MELAS l‐arginine is to allow the conversion of l‐arginine into nitric oxide (NO) in the vascular endothelium. NO is a potent mediator of vascular smooth muscle relaxation to improve vasodilation and blood flow in the cerebrovasculature. Recent studies have shown that serum arginine and NO levels are depleted in patients with MELAS and that administration of l‐arginine may be beneficial The treatment of seizure‐associated stroke‐like episodes involves the urgent control of seizures in the acute phase and then continued anticonvulsants for the prevention of further seizures and development of refractory status epilepticus, a widely recognized complication of mitochondrial disease l‐arginine in conjunction with serial neuroimaging to provide insights into the evolution of lesions to the brain and influence the implementation of neuroprotective therapies to prevent the irreversible loss of brain function.There is a clear need for standardized, serial neuroimaging studies of patients with stroke‐like episodes in order to establish specific imaging criteria to accurately detect and monitor stroke‐like episodes, especially when considering therapeutic trials for these patients where accurate and measurable outcomes are crucial for determining drug efficacy. Furthermore, there is an urgent need for effective evidence‐based therapeutic strategies using randomized open‐label, multicentre studies to confirm the efficacy of anticonvulsant drugs and The most common neuropathological findings in patients with stroke‐like episodes are the presence of multiple foci of neuronal necrosis  affecting the posterior cerebral cortex, basal ganglia and cerebellum. These areas of chronic necrosis are ischaemic‐like in appearance; exhibiting neuronal cell loss, destruction of the neuropil and subcortical white matter accompanied by proliferation of astrocytes and inflammatory cells Figure , but thec oxidase (COX) activity, whereas others suggest COX activity is lost and is associated with high mutant load in microvessels l‐arginine as discussed previously While the pathological mechanisms underpinning stroke‐like episodes are not clearly defined, unaffected areas of the brain provide clues with evidence of neuronal respiratory chain defects and angiopathic changes. There are a number of hypotheses to explain mechanisms underpinning neurodegeneration occurring during and after a stroke‐like event, and these include: (i) Mitochondrial cytopathic theory, (ii) Mitochondrial angiopathic theory and finally and (iii) Neuronal hyperexcitability theory. The mitochondrial cytopathic theory suggests that respiratory chain defects and therefore compromised energy production in neurons or glial cells or a combination of both are sufficient to cause focal necrosis Cognitive impairment and dementia have been frequently in case reports of patients with mitochondrial disease due to mtDNA mutations, however, there are very few large‐scale longitudinal studies and standardised criteria to define cognitive impairments. A neuropsychological study conducted on 16 adult patients with mitochondrial disease  revealed nonverbal cognitive impairments and verbal short‐term memory deficits, associated with working memory, with hypometabolism in the temporal lobes on neuroradiological imaging There is a paucity of studies correlating neuropathological changes with cognitive impairments in mitochondrial disease. Although it is likely that deterioration in cognition might be attributed to the presence of necrotic foci which impinge on multiple circuits involved in cognitive processing, certainly cognitive decline has been observed in patients without stroke‐like episodes implying that the frontal domains are affected. Neuropathological studies detect changes in neuronal populations in patients affected by either mtDNA or nDNA mutations which could contribute to cognitive dysfunction in mitochondrial disease. A loss of calbindin expression in hippocampal neurons without neuronal loss has been described, and also loss of cortical inhibitory interneurons and respiratory chain deficiencies which could certainly contribute to impaired network activity in the brain Clinical, molecular genetic and neuropathological studies have given important insights into the disease pathogenesis. The application of the knowledge gained from these studies is now driving the development of cell and animal model systems to test hypotheses and adopt a functional approach to understanding mechanisms and evaluate the efficacy of treatment.Modelling mtDNA disease has been impeded by the inability to generate stable mtDNA point mutations in mice without undergoing a bottleneck effect and loss of the mutation through successive generations of mice TFAM which is a nuclear encoded transcriptional activator which has a number of roles within the mitochondrion including binding to the mtDNA promotor to activate mitochondrial transcription, provides RNA primers to facilitate mtDNA replication and also plays a histone‐like role by coating the mtDNA TFAM, including forebrain neurons using a CaMKIIα‐Cre [Mitochondrial Late Onset Neurodegeneration (MILON) mice] and dopaminergic neurons using a DAT‐Cre (MitoPark mice) which lead mtDNA depletion in the targeted neurons. The MILON mice show a reduction in mtDNA copy number in neocortex at 2 months of age and develop a phenotype at age 5–6 months whereby they severely deteriorate and die within 2–3 weeks after onset Here, we provide a brief overview and examples of models associated with defects in; (i) mtDNA maintenance and (ii) OXPHOS in certain neuronal populations. A number of mouse models have been generated by targeting TFAM and develop a progressive Parkinson‐like phenotype at 12 weeks of age with motor deficits, dopamine depletion and SNpc degeneration The MitoPark mice harbour dopaminergic neuron‐specific KO of NDUFS4 (NADH:ubiquinone oxidoreductase subunit S4), which encodes for a nuclear‐encoded accessory subunit of complex I, has been generated. This mouse shows rapidly progressive gait impairments, breathing difficulties and death by 7 weeks of age and therefore resembles Leigh syndrome. Neuropathological features include complex I deficiency and progressive degeneration in the form of spongiosis and lesions within the olfactory bulb, cerebellum and vestibular nuclei accompanied by progressive glial activation and inflammation NDUFS4 KO mice were exposed to chronic hypoxia (11% oxygen) environment showed extended lifespan with improved motor coordination and reduced neuroinflammation upon neurohistopathological assessment The second group of transgenic mouse models we discuss are those associated with defects in OXPHOS either due to abolished complex subunit or assembly unit expression. There are a number of model which target subunits associated with complex I as complex I deficiencies are frequently detected in mitochondrial disease. A neuronal and glial‐specific KO (using a nestin‐Cre) of NDUFA5 (NADH:ubiquinone oxidoreductase subunit A5) KO, a nuclear‐encoded structural subunit of complex I, in forebrain neurons (using CaMKIIα‐Cre) were healthy until 10–11 months of age when they became lethargic, demonstrated a loss of motor coordination and hindlimb clasping. These mice showed only a mild encephalopathy with evidence of complex I deficient neurons without evidence of neurodegeneration which the authors suggest might be related to compensatory processes Mice harbouring RISP  and COX10 (encoding an accessory protein involved in assembly of COX) have been created to understand more about the selective brain involvement in mitochondrial disease. These studies revealed that the RISP‐KO mice developed a rapid phenotype aged 2 months with poor rotarod performance with a rapid disease progression and died aged 3–3.5 months. Evaluation of CNS tissues confirmed complex III deficiency and high levels of oxidative stress in remaining neurons, particularly affecting the piriform cortex. While in the COX10‐KO mice, rotarod performance was poor aged 3 months but they survived until aged 8–12 months with a vulnerability of the cingulate cortex and oxidative stress in remaining neurons Recently, forebrain neuron‐specific (using CaMKIIα‐Cre) KOs for in vitro disease modelling, drug screening and cell‐replacement therapies. iPSCs constitute cells which are capable of self‐renewal and can differentiate into any cell type and are generated by reprogramming patient fibroblasts with pluriopotency associated transcription factors. In recent years, a number of studies have utilized patient‐derived iPSC to understand mechanisms of mitochondrial disease exploiting the main advantages of (i) maintaining the nuclear genetic background of the patient, and (ii) differentiation into disease‐specific tissue‐ or cell‐type, e.g. postmitotic neurons. There are some caveats associated with the study of iPSCs including the acquisition of genome instability during culture Induced pluripotent stem cells (iPSC) hold the potential for Induced pluripotent stem cells have been derived from fibroblasts from patients with MELAS due to the m.3243A>G mutation and two cell lines were generated; one harbouring high heteroplasmy levels (>80%) and the other which was low heteroplasmy levels (undetectable). Following differentiation into neurons, the high heteroplasmy line showed downregulation of complex I and an increase in mitophagy Unlike other neurodegenerative diseases, brains from patients with mitochondrial disease show atrophy and severe neuronal cell loss that this is not associated with any extra‐ or intracellular accumulation of misfolded proteins. The salient neuropathological features are the decrease or absence of mitochondrial respiratory chain subunits, particularly involving subunits comprising complex I, and high ratio mutated mtDNA to wild type mtDNA in surviving neurons. The future of mitochondrial research should aim to prevent the irreversible brain loss and neurological disability in these patients. Post‐mortem human brain studies are invaluable for characterizing the chronic neurodegenerative changes, and new techniques, such as CLARITY


Simultaneous measurements with an ionization chamber array (ICA) and EPID were performed to separate beam and detector response characteristics. Three different pixel calibration methods were demonstrated and compared for an example ‘clinical IMRT field’. The dose response with the Elekta EPID for ‘simple’ segmented IMRT fields versus static fields agreed to within 2.5% for monitor unit (MU)≥2. The dose response for the Siemens systems was difficult to interpret due to the poor reproducibility for segmented delivery, at MU≤5, which was not observed with the standalone research EPID nor ICA on the same machine. The dose response measured under different acquisition settings and different linac/EPID combinations matched closely (≤1%), except for the Siemens EPID. Clinical IMRT EPID dosimetry implemented with the different pixel‐to‐dose calibration methods indicated that calibration at 20 MU provides equivalent results to implementing a ghosting correction model. The nonlinear dose response was consistent across both clinical EPIDs and the standalone research EPID, with the exception of the poor reproducibility seen with Siemens EPID images of IMRT fields. The nonlinear dose response was relatively insensitive to acquisition settings and appears to be primarily due to gain ghosting effects. No additional ghosting correction factor is necessary when the pixel‐to‐dose calibration factor at small MU calibration method is used.The purpose of this study was to investigate the dose response of amorphous silicon (a‐Si) electronic portal imaging devices (EPIDs) under different acquisition settings for both open jaw defined fields and segmented intensity‐modulated radiation therapy (IMRT) fields. Four different EPIDs were used. Two Siemens and one Elekta plus a standalone Perkin Elmer research EPID. Each was operated with different acquisition systems and settings. Dose response linearity was measured for open static jaw defined fields and ‘simple’ segmented IMRT fields for a range of equipment and system settings. Six ‘simple’ segmented IMRT fields were used. The segments of each IMRT field were fixed at PACS numbers: 87.53.Bn, 87.55.Qr, 87.56.Fc, 87.57.uq I.All medical linear accelerator (linac) vendors currently provide amorphous silicon (a‐Si) electronic portal imaging devices (EPIDs) as a standard option. EPIDs are used routinely in radiotherapy for image verification of patient position. However, it has been demonstrated previously that a‐Si EPIDs also have great potential for dosimetry applications.Despite many studies demonstrating the potential of a‐Si EPIDs for dosimetry, there remain some technical challenges to be overcome in order to realize their full potential in routine clinical practice. There are issues related to the non‐water equivalence of the EPIDImage lag measured from the relative residual signal in image frames acquired immediately after an exposure has been reported as 2%–10%, depending upon incident exposure and EPID model.The above review summarizes some of the key studies of EPID dose response, highlighting the inconsistent interpretation of EPID dose response characteristics. Despite the apparent successful and increasingly widespread clinical implementation of EPID dosimetry, fundamental dose response issues remain unresolved. These issues came to light during the development of an EPID dosimetry program in our department and were the motivation for this work. The specific issues we aim to address in this work include: i) the inconsistencies in the literature about the underlying causes of nonlinear dose response of EPIDs; ii) the EPIDs nonlinear behavior is widely reported based on static open beam exposures, with little or no consideration for how accurately this behavior translates to segmented IMRT; iii) the management of these effects on a multivendor EPID dosimetry program, with particular regard to the relative importance of the EPID detector design, the linac, and the image acquisition and processing methods implemented across different systems; and iv) unexpected EPID dose response behavior observed on Siemens EPIDs. This work will contribute to a more consistent understanding and implementation of pixel‐to‐dose calibration methods for EPID‐based IMRT dosimetry.II.A.Different combinations of linacs, EPIDs, and acquisition software were investigated in an attempt to isolate the source and relative contributions to EPID dose response behavior. Each experimental setup is described in Table A.1* the number of frames (Nframes) acquired per segment or beam is determined by the following relation:Details of EPID construction, acquisition software, and image processing implemented on the Siemens equipment  can be found in previous study.Rt denotes the EPID frame average pixel value for the ith segment , and Ni denotes the number of frames (Nframes) for the ith segment. Nframes is reported in the DICOM file header. All images were exported in DICOM format and analyzed with in‐house code using MATLAB (MathWorks Inc version 7.12.0.635(R2011a); MathWorks, Natick, MA). The ‘Port during’ imaging option used for IMRT operates in ‘free running mode’. Based on personal communications† with other research groups and the vendor, the image acquisition is thought to be triggered by a beam‐on and beam‐off signal from secondary Siemens software. There is no beam pulse synchronization in ‘free running mode’.The integrated pixel value (IPV) for IMRT fields with N segments is given by Eq. A.2PSF is the pixel scaling factor. The PSF for each segment of an IMRT field is reported by the iViewGT software. The integrated EPID image was obtained by manually adding the IPV of each segment determined using Eq. 1/Nframes from Eq. ‡Details of EPID construction, acquisition software, and image processing implemented on the Elekta equipment  can be found in previous studies.The measurements with the XIS application   positioned beneath the EPID to acquire simultaneous reference measurements. This ICA has been previously shown to display linear dose response behavior in both ‘movie’ mode and integrating mode.All the measurements discussed below in Material & Methods sections B and C were conducted with all three equipment combinations summarized in Table B.10×10cm2 field size, each field having a total of 20 MU. Field 1 consisted of 20 segments at 1 MU per segment, field 2 consisted of 10 segments at 2 MU per segment, and fields 3, 4, 5, and 6 consisted of 5, 4, 2, and 1 segments of 4, 5, 10, and 20 MU per segment, respectively. The 20 MU per segment ‘simple’ IMRT field was analogous to a standard static open beam delivery of 20 MU. The total integrated EPID response for each IMRT field was obtained from the sum of the average of the central 20×20 pixels per frame. The integrated pixel value per segment and in total for each IMRT field was compared with integrated pixel value from a static open beam with the corresponding MUs. For the remainder of this study we refer to the IMRT fields used in this experiment as ‘simple’ IMRT fields.The linearity of EPID response with dose was measured with static open fields for varying MU exposures (1–100 MUs). The open beam experiment provided a baseline for comparison with EPID dose response linearity with IMRT delivery. Six IMRT fields were created specifically for this experiment. The segments of each IMRT field were fixed at The average integrated measured values for each experiment was analyzed in the following manner to derive linearity plots: i) ICA measurements  for each segment and/or field were normalized to the ICA measured value for 100 MU static open beam exposure; ii) the EPID measurements  for each segment and/or field were normalized to the EPID‐measured value for 100 MU static open beam exposure; iii) the EPID data from step ii) was again normalized against the corresponding measured ICA data from step i). Step iii) removes any nonlinearity in dose per MU delivery at small MUs from the EPID analysis. All ICA and EPID measurements were conducted simultaneously, as described earlier, to further minimize the impact of any inter‐beam linac output fluctuations on the EPID experiments. The relative EPID response as a function of dose for single static open fields and segmented IMRT fields was compared to assess whether the underresponse seen in static fields persists with segmented IMRT delivery.C.To evaluate intersegment variations in clinical EPID response during segmented delivery, the ‘simple IMRT fields’ described above were delivered five times consecutively . The ‘clinical IMRT fields’ consist of 20 IMRT segments. Ten repeat measurements for ‘clinical IMRT fields’ were performed simultaneously on both Siemens and Elekta clinical EPID along with ICA n is the integrated pixel value for the nth segment, CF(100MU) and CF(20MU) is a pixel‐to‐dose calibration factor determined at 100 MU and 20 MU, respectively, trad is radiation beam‐on time, and G(trad) is a ghosting correction factor determined from the function of EPID dose response linearity measured with open static fields for linac 1 and linac 3  on clinical dosimetry. A gamma evaluation, with 2% and 3% dose difference  and 2 and 3 mm distance‐to‐agreement criterion with 10% dose threshold, is performed to quantify the difference between the integrated EPID dose map calculated from calibration methods 1, 2, and 3 using the same EPID data. Field size correction factors and other detector scatter corrections were ignored for the EPID dose computation, since they remain constant irrespective of calibration methods being investigated here.III.A.MU≥2 for 0, 3, and 10 PostBeamOff frames with renormalization setting 40,000 plus renormalization value set to zero. However, for Siemens EPID, the agreement in dose response for ‘simple’ IMRT fields versus static fields was difficult to interpret due to the poor reproducibility for segmented delivery, particularly at MU≤5. Both Siemens (for static open jaw defined fields) underresponded by 9%, while Elekta clinical EPIDs underresponded by 8% relative to ICA for 1 MU per segment (or field). At 2 MU and above, the agreement between Elekta clinical EPID and ICA was within 2.5%. No significant difference was observed in dose response for the Elekta clinical EPID when measured under different acquisition setting, as described in the Methods & Materials section A, and agreed within 1%. The renormalization for each of the three different PostBeamOff frame Elekta datasets was set to 40,000 . The reproducibility of the ICA data remained within 0.3% in all cases.The EPID dose response as a function of MU for static and ‘simple’ IMRT fields for all EPIDs are shown in Figs. 00 Figs. . At 2 MU00 Figs. , while fMU≥2. The research EPID underresponded by 6% and 5% relative to ICA for 1 MU per segment for Siemens and Elekta linacs, respectively. At 4 MU and above, the agreement between research EPID and ICA response was within 3% for both linacs. The dose response measured with the clinical Siemens EPID agreed closest with the dose response measured with the research EPID with no PostBeamOff frame setting for static open fields. The research EPID did not show the poor reproducibility seen at small MU with the Siemens EPID  and 2MU(≤2%–3%) per segment, similar to static open. The underresponse was seen for all three PostBeamOff frame settings.The EPID dose response as a function of MU for static and ‘simple’ IMRT fields for the research EPID are shown in Figs. B.B.1±20%. The simultaneously measured ICA did not indicate any variation in beam delivery. The Elekta EPID response per segment was within 1%. Further investigation for the Siemens EPID images found inconsistencies in the value of Nframes. The frequency of this EPID dose response phenomenon varied depending on the MU per segment. Intersegment reproducibility was worst at MU per segment ≤5MU; at 10 MU per segment and above the phenomena was not observed at all and reproducibility was within 1%. The same variation in Nframes was not present for the measurements taken with the same linac, EPID, and software for open static beam (nonsegmented) delivery at any MU settings.Figure B.2The off–axis profiles for each IMRT segment (frame average image) along the central row (cross‐plane) and central column (in‐plane) of the Siemens EPID panel and ICA were compared for the ‘simple’ IMRT fields. Some EPID cross‐plane profiles were tapered at the field edge, while the in‐plane profiles did not display this effect. By comparison, the profiles in both planes , described in the Material & Method section E and implemented in calibration method 1 (Eq. G(trad) for Elekta EPID was used based on EPID dose response data acquired with the renormalization value set to 0. The function fit was accurate within 0.5% to measured data for beam‐on time (down to 2 MU). Table To determine the ghosting correction factor, od 1 Eq. , a curveod 1 Eq.  as a funIV.The dose response linearity experiments conducted in this work confirm that the nonlinear dose response measured with static open beams at small MU persists in segmented IMRT delivery based on the MU per segment. This validates the pixel‐to‐dose calibration methods incorporating a ghosting correction on a segment‐by‐segment basis for IMRT dosimetry using corrections determined from open static beam exposures. The existence of gain ghosting was confirmed as being present and consistent across different EPIDs and linear accelerators at small MU exposure. Gain ghosting is associated with variations in the quantity of trapped charge with exposure to radiation. The rate of the accumulation of trapped charge and the rate of signal from the discharge of trapped charge slowly approaches equilibrium with increasing dose. The close agreement between segmental IMRT and static open beam delivery, and the fact that the static open beam fields had substantially longer time periods between subsequent exposures, supports the finding that gain ghosting affects dominate over image lag signal from previous exposures in terms of the EPIDs nonlinear response behavior at small MU. The nonlinearity at small MUs was relatively insensitive to acquisition settings. We have not investigated the impact of pulse repetition frequency (PRF). A method of simultaneous measurements with an ICA and EPID was demonstrated to reliably separate out the EPID dose response from beam delivery characteristics. This methodology demonstrated an irregularity in the Siemens implementation, which resulted in poor measurement reproducibility of IMRT fields at small MU per segment. It was also demonstrated that the ghosting correction is not required if the EPID is calibrated at an appropriately small MU exposure.≤1%) was observed in dose response for both the static and ‘simple’ IMRT fields measured with the clinical Elekta EPID under different PostBeamOff frame acquisition settings. This demonstrates that nonlinearity at small MUs was relatively insensitive to acquisition settings and across different EPID detectors. The poor reproducibility for the Siemens EPID in the case of ‘simple’ IMRT fields was not observed either with simultaneous measurement conducted, neither with ICA nor with the standalone research EPID (Fig. ≤5MU for Siemens EPIDs and occurs in a nondeterministic manner. This was attributed to an inconsistent number of frames per segment being recorded in the image header file. The vendor documentation indicates that the frame number is derived using Eq. ≥1MU. Winkler et al.The magnitude of underdose response reported in the present work is smaller than some previously reported studies. This may be partly due to the fact we normalized the dose response relative to 100 MU rather than 1000 MU used in other studies.PID Fig. . There wThe ghosting correction suggested by McDermott et al.V.The EPID dose response behavior for step and shoot IMRT fields delivered by Siemens and Elekta linacs was investigated. The nonlinear EPID dose response as a function of MU measured for single open beam exposures was found to be consistent with dose response for segmented IMRT delivery. The nonlinear dose response was consistent across both clinical EPIDs and the standalone research EPID, with the exception of the poor reproducibility seen with Siemens EPID images of IMRT fields. The nonlinear dose response was relatively insensitive to acquisition settings and appears to be primarily due to gain ghosting affects in the a‐Si photodiodes. When the pixel‐to‐dose calibration factor was determined at 20 MU, no additional ghosting correction factor is necessary for the accurate determination of dose for clinical IMRT fields.


Empirical results presented in this paper suggest that parents’ marginal willingness to pay (MWTP) for a reduction in morbidity risk from heart disease is inversely related to baseline risk  both for themselves and for their children. For instance, a 40% reduction from the mean of baseline risk results in an increase in MWTP by 70% or more. Thus, estimates of monetary benefits of public programs to reduce heart disease risk would be understated if the standard practice is followed of evaluating MWTP at initial risk levels and then multiplying this value by the number of cases avoided. Estimates are supported by: (1) unique quantitative information on perceptions of the risk of getting heart disease that allow baseline risk to be defined at an individual level and (2) improved econometric procedures to control for well-known difficulties associated with stated preference data.The online version of this article (10.1007/s11166-017-9267-x) contains supplementary material, which is available to authorized users. Estimation of monetary benefits of reductions in risk to human health is central to analysis of policies affecting the environment, transportation, and workplace safety because: (1) protection of human health is emphasized in both the statutory and regulatory framework of the U.S. and other countries and (2) benefit-cost analysis is commonly used as an evaluation tool when considering policy changes. As illustrated in recent analyses of more stringent diesel fuel standards  that necessarily holds if risk is endogenous, but does not necessarily hold if risk is exogenous. Further advantages of distinguishing parents from children in the analysis are: (1) children often are singled out for special treatment in policy analyses Clinton , 2) hou hou2Data utilized in the empirical analysis are drawn from a nationally representative stated preference survey conducted in the U.S. on the risk of getting heart disease. Four features of these data and the empirical methods are particularly important. First, an advantage of the data is that they include unique quantitative information on perceptions of the risk of getting heart disease that allow baseline risk to be defined at an individual level both for parents and their children. This approach avoids the concern expressed by Viscusi , p. 764 The main empirical finding suggests that parents’ MWTP for a reduction in heart disease risk increases as baseline risk declines both for themselves and for their children. For instance, a 40% reduction from the mean of baseline heart disease risk results in an increase in MWTP by 70% or more for both parents and children. Taken by itself, this finding could be consistent with either the exogenous risk or endogenous risk formulation of the conceptual model, but in either case calls into question the conventional practice in policy analysis of obtaining total health benefit estimates by multiplying an estimate of MWTP for health risk reduction by the number of cases avoided. Additionally, the inclusion of children in the analysis yields two further insights. First, estimates suggest that parents are willing to pay the same amount at the margin for given absolute or proportionate risk reductions in heart disease risk for themselves and for their children, an outcome that is consistent with the endogenous risk model. Second, this finding, together with the inverse relationship found between MWTP for heart disease risk reduction and baseline risk of this disease, is consistent with the notion that the marginal utility of income may be greater in the healthy state than in the sick state.p) that makes decisions for herself and one child (k). The models: (1) contrast the determination of MWTP to reduce morbidity risk and its relationship to baseline risk when risk is treated as exogenous or as endogenous  and (2) represent simple extensions of work by Pratt and Zeckhauser  or sick (S).EU) is In the case where morbidity risk is exogenously determined, the parent’s Uij refers to the parent’s utility in health state ij where i indicates the parent’s health state  and j denotes the child’s health state  , and Rp and Rk denote probabilities that the parent and child are sick possibly as a result of exposure to toxins at home, at work, or while commuting.I); thus Uij = Uij(I) and In Eq. , Uij reEquation  can be sEUH· = (1 − Rk)UHH + RkUHS denotes expected utility of the parent if healthy given that the child is either healthy or sick and EUS· = (1 − Rk)USH + RkUSS denotes expected utility of the parent if sick given that the child is either healthy or sick. Expected utility if sick could be positive, however EUH· is assumed to be greater than EUS· (EUH· − EUS· > 0) at all levels of income.In Eq. , EUH· =MWTPp) by a small amount at unchanged expected utility isFor a given morbidity risk to the child, the parent’s MWTP to reduce her own morbidity risk (MWTPp > 0).In Eq. , the numMWTPp increases with an increase in Rp . This outcome might be referred to as the “sick anyway” effect because higher values of Rp  boost the probability that the payment would come from the sick health state S in which the parent has a smaller marginal utility of income. The “sick anyway” effect is directly analogous to the “dead anyway” effect described in detail by Pratt and Zeckhauser (MWTPp decreases with an increase in baseline risk (∂2I/∂Rp∂Rp < 0). Viscusi and Evans  and (EUH· − EUS·) are unknown.Notation and discussion pertaining to Eq.  parallelThe expected utility model just considered can be reformulated to make health risk endogenous )UHH + RkUHS denotes expected utility of the parent if healthy given that the child is either healthy or sick and EUS· = )USH + RkUSS denotes expected utility of the parent if sick given that the child is either healthy or sick. Additionally, X = Xp + Xk denotes household (private) expenditures on health risk reduction for the benefit of the parent or child (assumed to be ubiquitously available at unit cost), and G represents expenditures on health risk reduction (perhaps by the public sector) that are exogenous to the household.In Eq. , EUH· =I − X); thus, Uij = Uij(I − X), and U′(I − X) > 0,  U″(I − X) ≤ 0. Expenditures on X and G reduce the parent’s and child’s probability of illness and exhibit diminishing marginal productivity ). Additionally, G makes X less productive in reducing risk ))\documenk∗ (Eqs.  and 4)))\documenMWTP∗ with respect to G as shown in Eq.  Xi.The numerator on the right hand side of Eq.  is compoG reduces the productivity of X in reducing risk ∂MWTP∗/∂G > 0 and because Consider the case in which an increase in Third, the endogenous risk model restricts the relative magnitudes of the parent’s marginal values of risk reduction between family members via an optimality condition; in contrast, the exogenous risk model imposes no corresponding requirement. In the endogenous risk model, first order conditions require thatXp and Xk result in equal absolute reductions in morbidity risk for the parent and the child: X is the same for the parent and the child. Thus, the parent is willing to pay an equal amount of money at the margin for equal reductions in morbidity risk to each person. A similar argument establishes that if one unit changes in Xp and Xk result in equal proportionate morbidity risk reductions for parent and child, then the parent equates MWTP for equal proportionate risk reductions for herself and for her child. In this case, however, the parent’s MWTP per unit of morbidity risk reduction for herself and for her child will depend on the initial level of risk  faced by each as shown in Eq.   8) \docuX result in equal proportionate risk reductions, then Eq.  completed the questionnaire and, of those, 3155 (73%) had the desired characteristics and completed at least a portion of the survey.n = 2211.The total sample was divided into three subsamples: (1) 505 parents included in the pretest of the survey instrument, (2) 434 matched pairs of spouses (868 parents) living together in the same household, and (3) 1782 parents living in different households. This study is based on data from the subsample of unmatched parents plus the first randomly recruited parent for each of the matched pairs. One observation from the matched parents subsample and four observations from the unmatched parents subsample were excluded because respondents failed to complete the entire survey, so the number of observations available is For the 74% of parents with two or more children living at home, one child was randomly selected and designated as the sample child. The decision to focus the empirical analysis on a single child is consistent with the conceptual framework in Section Parents provided estimates of risk of being diagnosed with coronary artery disease before age 75 years using a computer-based interactive grid scale similar to those used by Corso et al. , and VisParents’ initial assessments of heart disease risks for themselves and for their child are summarized in Table Parents had the opportunity to revise their initial risk estimates after considering information about heart disease. Parents were told that the average person has about 27 chances in 100 of being diagnosed with coronary artery disease before age 75. This average risk was illustrated using a risk scale showing the 27% risk level next to the risk scales that parents had marked for themselves and their children. Parents then were told that they and their children probably would not have the same risk as the average person, because chances of getting heart disease depend on six risk factors that are different for everyone: gender, smoking, current health status, family history, exercise, and diet. The survey elicited information from parents about each of these risk factors while also providing information about how the factors influence risk. For example, parents’ smoking status was assessed and respondents were advised that coronary artery disease risks are higher for the average smoker than for the average non-smoker. Risk levels for smokers and non-smokers were illustrated using risk scales.After reviewing the risk factors, parents were shown their initial risk assessments using the risk scales and were allowed to revise their assessments if desired. Revised risk assessments are shown in Table X in the endogenous risk model) and are introduced to operationalize Eqs.   X in thep = 0.1 or Δp = 0.7 were assigned to parents and proportionate risk reductions of either Δk = 0.2 or Δk = 0.8 were assigned to their children. Thus, marginal products of the vaccines in reducing risk can be expressed as ΔiRi, where Ri now denotes parents’ revised perceived risk for themselves and for their children. Proportions were assigned so that the value for the child always exceeded the value for the parent. Parents were told that risk reductions: (1) would materialize only for those who continued to receive the vaccinations annually through age 75 and (2) are larger for children because the vaccination program would be initiated earlier in life.Two characteristics of the vaccines, marginal product of risk reduction  and price, were varied randomly across respondents. Proportionate risk reductions of either ΔQ = $10, $20, $40, $80, $160) selected on the basis of focus group input and pretest results. Prices varied only across households: the prices of the vaccines presented to parents for their own vaccine and for their child’s vaccine were the same. The idea behind the willingness to pay questions was to ask each parent if she would pay $ Q for a risk reduction of ΔkRk for the child and $ Q for a risk reduction of ΔpRp for herself.Vaccine prices assigned to parents were randomly drawn from among five values ($ iRi) and (2) the amount of (revised) risk that would remain if the vaccine was purchased. After examining the new risk scales, parents were provided a budget constraint reminder, told that the vaccination program would continue in future years, and were asked about their intentions to purchase the vaccines for themselves and for their children .The purchase scenario was introduced by: (1) reminding parents about symptoms of heart disease and the need for medical treatment and (2) presenting individualized hazard functions for themselves and their children to show how cumulative heart disease risk would be expected to increase between the present and age 75. Each parent then read the description of each vaccine and examined new risk scales for herself and for her child that showed: (1) the marginal product of the vaccine in reducing risk calculated on the basis of parent revised risk estimates  for herself only if she planned to continue purchasing it in the future and (2) for her child only if she believed that the child would continue to purchase vaccinations as an adult. This assumption is consistent with parents being told that the risk reductions assigned in the survey would materialize only for those who continue to receive the vaccinations annually through age 75. Then the decision to purchase the vaccine in the first period represents a continuing commitment to purchase the vaccine in the future, and the percentage risk reductions assigned represent the risk reductions resulting from this decision. Although baseline risk, age and other demographics may affect the choice, the percentage risk reductions are assigned independently of those factors.The overall validity of the survey instrument might be assessed from three perspectives: (1) incentive compatibility and consequentiality of the stated preference question about intentions to purchase the vaccine, (2) practices followed in designing the survey instrument, and (3) whether data collected on intentions to purchase the vaccine are at least broadly consistent with rational behavior. As to the first point, the main finding of recent literature is that stated preference instruments may be consequential under certain conditions  rather than the marginal valuation of components of a good. In this study, the total value of the vaccine is of little interest; instead, attention is focused on the change in value for a change in risk reduction. Carson and Groves  discuss Second, the survey approach adopted here includes many if not most of the elements outlined in the recent stated preference guidelines paper by Johnston et al. . These gThird, Table This section begins by describing econometric methods used to estimate the relationship between MWTP for the vaccine and the proportionate reduction in heart disease risk that it offers. These methods build on those developed by Adamowicz et al.  and are Wi denotes the parent’s true (unobserved) willingness to pay (the parent index is suppressed to economize on notation) for the vaccine to reduce risks of heart disease for the parent (p) or the child (k), and, as discussed in Section i denotes the experimentally assigned percentage reduction  in heart disease risk offered by the vaccine. Thus, γi/100 is interpreted as the parent’s annual MWTP for a one percentage point reduction in heart disease risk.In this equation, αi).Empirical methods applied build three additional features into Eq. . First, αi is included to reflect systematic tendencies to misstate true willingness to pay. The disturbance νi = σiεi, assumed to be normally distributed with zero mean and variance of εi has mean of zero and variance of unity), reflects the influence of household characteristics and unobserved heterogeneity among parents in determining stated willingness to pay for the vaccines.The constant Q) from both sides of Eq. . The new constant term (ci/σi) is the mean of Mean-centering eliminates the original constant term . This feature supports consistent estimation of γi and σi.Estimates of Eq.  minimizeγi by Ri where Ri denotes the level of (revised) perceived risk (expressed as chances in 100). An alternative approach is to begin the derivation of Eq. (i in Eq. (iRi. This variable indicates the absolute reduction in heart disease risk (in chances in 100) that would be achieved by using the vaccine. The equation estimated then is Eq.  MWTP for a proportionate change in heart disease risk is independent of baseline risk and (2) MWTP for an absolute change in baseline risk is independent of baseline risk. Estimates presented in the second subsection relax these restrictions. The third subsection considers how the relationship between MWTP and baseline risk is affected by changes in income and family size. The fourth subsection illustrates implications of the foregoing results for computing estimates of total morbidity benefits for a representative parent and child.n = 2211 sample described in Section Columns 2 and 3 of Table γi/σi) are positive and significantly different from zero at the 1% level and (2) estimates of coefficients of price are negative and significantly different from zero at the 1% level.In the columns 2 and 3 estimates, the estimated correlation between disturbances is about 0.89, which differs significantly from zero at the 1% level and indicates that the use of bivariate probit yields an efficiency gain over separately estimating the parent and child equations using binomial probit. Additionally, in both child and parent equations: (1) estimates of the normalized coefficients of proportionate risk reduction .Coefficients of the normalized proportionate risk reduction variables can be divided by 100 and then multiplied by the negative of the reciprocal of the respective coefficients of price to yield point estimates of the parents’ annual MWTP to reduce heart disease risk by one percentage point. The resulting un-normalized estimates, which do not depend on the level of baseline risk, are $2.29 in the case of parents’ own risk and $2.00 in the case of their children’s risk. Based on these estimates, the null hypothesis that parents’ MWTP for a one percentage point reduction in heart disease risk for themselves is equal to their MWTP for a one percentage point reduction in heart disease risk for their children is not rejected at conventional significance levels under a Wald test ) when evaluated at parents’ mean revised risk of ωi, the mean-centered absolute risk change. All coefficient estimates in these equations are statistically different from zero at conventional levels. Un-normalized coefficient estimates suggest that at the margin parents are willing to pay $5.40 annually to reduce their own heart disease risk by 1 chance in 100 and $5.95 annually to reduce their children’s heart disease risk by this same absolute amount. These values are about 20–25% lower than those implied by the columns 2 and 3 regressions when evaluated at mean levels of heart disease risk for parents and their children.Columns 4 and 5 of Table The null hypothesis that parents’ MWTP to reduce their own heart disease risk by 1 chance in 100 is equal to their MWTP to reduce their children’s risk of heart disease by this same amount is not rejected under a Wald test . The columns 4 and 5 estimates say little about the health state dependence of the marginal expected utility of income. In the case where MWTP to reduce baseline risk is constant in the face of changes in baseline risk, marginal expected utility of income when healthy may be greater than or less than marginal utility of income when sick in both the endogenous risk and exogenous risk models.δi and the vaccine price q.δi) and vaccine price (q) are randomly assigned, so their coefficients are consistently estimated. As demonstrated in the electronic supplementary material, coefficients of the interaction variables are consistently estimated as well. Coefficients of the indicator variables for revised perceived risk may not be consistently estimated in view of the probable non-zero correlation between these variables and the disturbance term. The possible inconsistency of these coefficients, however, is of little consequence because these constant term shifters play no role in subsequent analyses.The relationship between MWTP for heart disease risk reduction and the baseline risk of this disease is further assessed by estimating alternative specifications to those shown in Table δi) and vaccine price (q) differ significantly from zero at the 1% level in both the parent and child equations and are virtually identical numerically to those in columns 2 and 3 of Table Estimates in Table ωi) and price (q) are interacted with indicators of baseline risk. These indicators also are entered as constant term shifters. The pattern of estimated coefficients of interaction variables between ωi and the level of perceived risk indicates that parents’ MWTP to reduce heart disease risk by 1 chance in 100 is highest at the lowest levels of risk for both parents and children. In the piecewise linear estimates, effects of absolute risk reduction also are nonlinear in baseline risk, with larger effects at lower risk. In both the step function and piecewise linear estimates, MWTP for risk reduction rises more gradually with declines in baseline risk than in the rectangular hyperbola estimates, particularly at the lowest risk levels.Two alternative specifications of the regressions presented in Table Table δi/100 to the negative of the estimated coefficient of q) and their MWTP to reduce their own risk of heart disease is $2.33. Estimates of MWTP at lower levels of risk are calculated by multiplying these values by 100/ Ri. For instance, parents’ MWTP to reduce their own risk of heart disease by 1 chance in 100 evaluated at the mean of parents’ own perceived risk  in the step-function estimates, the representative parent’s MWTP for reductions in heart disease risk by 1 chance in 100 is $14.20 for themselves and $14.07 for their children , then estimated total willingness to pay based on the rectangular hyperbola would be about 2.2 times greater than when based on the assumption that MWTP to reduce risk is independent of baseline risk ($282.30 vs. $127.39), and (3) estimates of total willingness to pay for reduced risk of heart disease for children follow similar patterns to those just described for parents.Further comparisons show that: (1) Estimates of total willingness to pay developed from the step function estimates  to reduce morbidity risk from heart disease and baseline risk of this illness using unique data on parents’ perceptions of the risk of getting heart disease both for themselves and for their children. The main finding is that MWTP declines as baseline risk rises. A possible explanation for this result is that people engage in risk reducing efforts up to the point at which MWTP equates to marginal cost and marginal cost rises as more risk is eliminated. In any event, this outcome calls into question the standard practice in policy analysis of computing total benefits of health risk reduction based on the assumption that MWTP is independent of baseline risk. An example based on the empirical estimates shows that a 40% reduction in heart disease risk from the mean baseline risk for both parents and children results in a nearly 70% increase in MWTP.Empirical results are supported by an expected utility model of parental decision-making in which health risk is treated either as exogenous or endogenous . Results suggest that parents are willing to pay an equal amount at the margin for equal absolute and proportionate risk reductions for themselves and their children. This outcome is consistent with optimizing behavior in the endogenous risk model, but may or may not be consistent with a similar model formulated with exogenous health risk. Empirical findings are thus consistent with the ideas that: (1) morbidity risk is endogenous, (2) marginal utility of consumption falls with the onset of illness , and (3) parents adjust behavior to at least partly offset public policies aiming to reduce risk.Results presented in this paper should be interpreted cautiously as additional research is needed to more conclusively establish the relationship between MWTP for health risk reduction and baseline risk. Future research might look at: (1) mortality rather than morbidity risk, (2) illnesses other than heart disease, (3) experimental methods, rather than stated preference methods, for estimating MWTP for health risk reduction, and (4) the shape of the relationship between MWTP and baseline risk at lower levels of risk than the present study is able to consider.ESM 1(PDF 287 kb)


G68e or respiratory‐averaged CT based attenuation correction and good patient cooperation, approximately 21% of perfusion studies exhibit artifacts arising from misalignment that cannot be corrected by manipulating the attenuation acquisition protocol. This misalignment, termed cardiac drift, is caused by slow‐moving abdominal cavity contents that reposition the heart in the thorax and appear as myocardial uptake overlying the left CT lung in fused PET/CT images. This study evaluates three postimaging registration techniques to correct PET/CT misalignment by altering the transmission map to match myocardial uptake. Simulated misalignment studies were performed with a cardiac torso phantom filled with [F18]FDG at 10:1 myocardium/background. An air‐filled saline bag affixed to the medial left lung surface served as a distensible lung. An initial CT acquisition was followed by successive PET acquisitions consisting of small displacements of the cardiac insert into the left lung. Phantom transmission scans were aligned to the myocardial uptake in the emission scans by applying 1) full rigid‐body translations and rotations, 2) rigid‐body restricted to medial / lateral and superior / inferior translation, or 3) an emission‐driven method that adds myocardial tissue to the transmission scan. These methods were also applied to 10 low‐likelihood coronary artery disease (CAD) patients showing signs of cardiac drift. Full rigid‐body registration showed significant over‐correction (p<0.004) of activity concentrations in the artifact areas of the phantom data due the relocation of highly attenuating structures . Inaccurate regional activity distributions were also observed as streaks extending from the spine and these results were replicated in the patient population. There was no significant difference between the true phantom activity concentration after correction with the emission‐driven method. Misalignment corrected with the rigid‐body registration results in an increase in activity concentration but fails to accurately recover the true concentration. These data suggest that a nonlinear image registration approach such as an emission‐driven method results in a more uniform activity distribution throughout the myocardium, and is more appropriate for addressing the cardiac drift misalignment problem.Myocardial perfusion studies suffer from artifacts caused by misalignment of the transmission and emission data due to the influences of voluntary and involuntary patient motion. Regardless of PACS number(s): 87.57.uk, 87.57.Q, 87.57.nj, 87.57.C, 87.19.Hh Cardiac imaging with positron emission tomography (PET) can provide quantitative information on myocardial perfusion and metabolism.G68e transmission sources results in nearly equivalent respiratory and cardiac temporal resolution. With the introduction of computed tomography (CT) for attenuation correction, the acquisition speed of helical CT fails to account for the time averaging observed in the emission acquisition.Registration artifacts that arise from misalignment of cardiac tissue boundaries are caused by voluntary patient motion, respiratory motion, contractile cardiac motion, and drift of the thoracic cavity contents. Voluntary patient motion commonly occurs in response to patient discomfort and rigid‐body transformations applied to the transmission image to match regions of myocardial uptake have resulted in the recovery of artificially low count regions.Approximately one‐quarter of the PET/CT cardiac studies exhibit misalignment due to the slow, continuous movement of the thoracic cavity contents,4.0×8.1×30 mm bismuth germanate (BGO) block detector ring of 150 mm field‐of‐view operating in the 2D mode.6.0×6.0×30 mm BGO block detector ring of 157 mm FOV also operating in the 2D mode.Phantom studies were acquired on a GE Discovery LS , comprised of a full Simulations of cardiac drift between the transmission and emission sequences were performed with an anthropomorphic torso phantom  using a cardiac insert without defects. Lung inserts were filled with Styrofoam beads and back‐filled with water. The sharp left ventricular/left lung interface observed in clinical studies was reproduced by affixing a 250 mL air‐filled saline bag to the medial surface of the left lung. Access to the saline bag from outside the phantom was accomplished by a bored cap screw threaded with a tube allowing for adjustment of the air volume such that it contoured the cardiac insert. The cardiac insert was secured to the phantom with a modified screw that included an extension with a handle permitting rotation in situ of the insert towards and away from the distensible saline bag. The cardiac insert was joined to the torso phantom at its base permitting rotations that appear as movement of the left ventricle apex away from the medial plane and into the left lung .18F]‐fluoro‐2‐deoxy‐glucose at a concentration of 10:1 relative to the background regions  with the phantom oriented in the supine position on the scanner bed. Cardiac drift was simulated by first acquiring an early CT with the cardiac insert positioned away from the left lung. The cardiac insert was then rotated into the air‐filled saline bag and an emission study was collected consisting of a 10‐minute acquisition. A late CT exam was acquired following the emission with the cardiac insert in the rotated position. Four scans were performed in total, beginning with the cardiac insert in the out position and applying four graduated rotations of the cardiac insert into the distensible saline bag. Three reconstructions were performed: 1) the early CT with the emission, which mimics the cardiac drift observed in patient studies and results in an artificial defect, 2) the early CT registered to the emission using one of the three methods discussed below, and 3) the late CT with the emission, which provides a true representation of the attenuating structures and hence the true reconstructed activity concentration in the presence of the simulated cardiac drift. Emission data were corrected for attenuation, scatter, and randoms and reconstructed using a 2D ordered‐subsets expectation maximization (OS‐EM) algorithm.The myocardial cavity was filled with [−450 HU) to a value of one and all other pixels to zero. The emission and transmission binary representations were then overlaid using the native scanner registration. A watershed algorithm applied to the left lung of the transmission image identified shared pixels between the binary transmission lung field and binary myocardial uptake image. The number of emission pixels overlaying the transmission lung field yielded the magnitude of misalignment expressed in units of volume (mL).The amount of cardiac drift was assessed using a variation of the method presented by Loghin et al.,Three registration methods were employed to recover the activity distribution from regions of reduced counts resulting from the simulated cardiac drift. Each method consisted of manipulations applied to the early CT image, prior to rotation of the cardiac insert into the distensible air‐filled saline bag. This was analogous to acquiring a single CT prior to administration of a PET perfusion agent. The first registration method consisted of a full  rigid‐body transformation applied to the CT transmission image to match areas of cardiac tissue with that of myocardial uptake measured in the emission image. The second registration method was also a rigid‐body registration but limited to translation of the CT transmission image in the medial / lateral and superior / inferior direction  such that the entire myocardiac uptake region was placed in the mediastinal cavity of the phantom. This case attempts to replicate movements permissible on an imaging bed, which is restricted in the anterior / posterior direction. The third registration method was an emission‐driven approach that reassigns shared overlaying pixels in the early CT new Hounsfield values consistent with myocardial tissue.Difference Image=(emission data reconstructed with registered early CT AC)−(emission data reconstructed with late CT AC), were created to highlight areas of artificial uptake caused by erroneous registration of the PET and CT data.The late CT attenuation image represents the true reconstructed position of the attenuating structures following rotation of the cardiac insert. Therefore, emission data reconstructed with the late CT were used for comparison against the two rigid‐body and emission‐driven registration methods. Analysis of the registration techniques was performed by drawing regions of interest (ROI) over the lateral wall of the left‐ventricle insert in the reconstructed emission image using the late CT for attenuation correction. The same regions were then applied to the PET images reconstructed with each of the image registration methods. Percent recovery was calculated by dividing the ROI from the reconstructed emission data with the registered early CT data by the emission data reconstructed with the late CT data. Lastly absolute valued differences images, The methods performed in the phantom simulations were applied to 10 patients who had less than 5% likelihood of coronary artery disease (CAD) based on sequential Bayesian analysis of age, gender, and symptom classification.A linear mixed effects model was applied to the phantom data to evaluate differences between the true myocardial concentration and the rigid‐body registration method. The linear mixed model offers a flexible way of modeling the registration method while accounting for the serial correlations in the repeated measures for each individual phantom scan. We fit a model with the differences between methods quantified separately for each measurement point in each phantom orientation.t‐test, to avoid making the assumption that the patient data followed a normal probability distribution. To accommodate multiple comparisons, namely the three registration measures, a Bonferroni correction was applied adjusting the type‐I error threshold for significance to 0.83%. All statistical analyses were performed using SAS 9.1.3 .Given the small sample size, patient data were analyzed using a Wilcoxon signed‐rank test, the nonparametric analogue to the matched pairs Student's p≤0.004). Statistically significant differences were also observed between the late CT reconstruction and each of the two rigid‐body registration techniques employing the full (p<0.002) and medial‐axial (p<0.002) rigid‐body methods. Similarly, the emission‐driven method resulted in significant increased activity compared to the late CT images (p<0.002).The recovery of the phantom myocardial activity, expressed as percent recovery of the true myocardial activity concentration, is shown in Simulations of large cardiac drift artifacts required similarly large rotations and medial shifts to match regions of myocardiac tissue uptake and attenuating tissue, respectively. Close inspection of the rigid‐body registration reconstructions reveals the presence of artifacts caused by the relocation of highly attenuating structures, particularly the spine. As the spine moves towards the left lung, an artificial increase in activity was observed along the border of the left lung and extending down from the left ventricular wall . Regionsp<0.005). Application of the emission‐driven method resulted in increased activity concentration along the left ventricular lateral wall and was significant compared to the uncorrected images (p<0.005). No significant difference was observed between the medial‐axial rigid‐body registration and emission‐driven method, but the rigid‐body method trended higher (p=0.0195).Misalignment of the myocardium in the patient data was consistent with the phantom simulation experiments of cardiac drift between the CT transmission and emission acquisitions. Application of the full and medial‐axial rigid‐body registration resulted in repositioning of the spine towards the left lung and artificial uptake along the lung boundaries following reconstruction . The act±5% to 10%, depending on whether full or translation only rigid‐body registration is applied. The emission‐driven method performed better than rigid‐body registration at recovering the true activity concentration in the phantom simulations suggesting that a nonlinear registration approach is needed to address the cardiac drift problem.This study demonstrates that rigid‐body registration to correct PET/CT misalignment caused by cardiac drift does not result in accurate recovery of the true activity concentration. Our simulation studies in phantoms show that the error in myocardial activity concentration over the misaligned area may range between The failure of the rigid‐body registration methods to correctly recover the myocardial activity distribution of the phantom is due to the relocation of highly attenuating structures. The most significant attenuating structure is the spine and when relocated creates streaks extending from the spinal location to the heart. Medial shift of the spinal column over‐corrects lines‐of‐response falling over the left ventricular wall leading to an artificial increase in activity concentration. The rigid‐body registration methods show improved activity concentration recovery in the myocardium but either over‐ or undercorrected the activity concentration depending on the position of the spine. Although the true activity distribution in the patient studies is not precisely known, the phantom studies successfully simulated the artificially high uptake along the lateral wall and demonstrated potential complications of applying rigid‐body registrations.This work further suggests that a nonlinear registration approached is needed to estimate the appropriate transmission tissue distribution to accurately address the cardiac drift misalignment problem. The emission‐driven method is less technically difficult to implement compared to other deformable algorithms and groups have applied nonlinear warping algorithms to solve the PET/CT registration problem,The use of rigid‐body registration methods to correct the cardiac drift misalignment problem improves the myocardial activity distribution but fails to quantitatively recover the true activity concentration. Relocation of highly attenuating structures such as the spinal column results in artificial increases in uptake and regional artifacts. The data presented in this work show that a nonlinear image registration approach is more appropriate to correct the cardiac drift problem. Careful consideration must be taken when aligning PET and CT to judge good alignment in all areas of the thorax.Creative Commons Attribution 4.0 International License.This work is licensed under a


We investigated predictors of two increases in older people’s public transport use: initiating public transport use among non-users; and increasing public transport use amongst users. We also investigated associations of these changes with physical activity, Body Mass Index (BMI) and waist circumference.Data come from the 2008 and 2012 English Longitudinal Study of Ageing (ELSA). Logistic regression assessed predictors of increases in public transport use among adults aged ≥50 years. Gender-stratified logistic and linear models assessed associations of increases in public transport use with changes in physical activity and adiposity.Those becoming eligible for a free older person’s bus pass were more likely to both initiate and increase public transport use (e.g. for initiating public transport use Adjusted Odds Ratio (AORs) 1.77, 95% Confidence Interval 1.35; 2.33). Retiring from paid work was also associated with both initiating and increasing public transport use e.g. AOR 1.57  for initiating use.2 lower  at follow up than those who did not, although this was attenuated after adjusting for BMI at baseline . After adjustment for baseline physical activity those initiating public transport use were more likely to undertake at least some physical activity in 2012 .Women who increased public transport use had mean BMI 2.03 kg/mBoth initiating and increasing public transport use were associated with increased physical activity and may be associated with lower adiposity among women. These findings strengthen the case for considering public transport provision as an effective means of promoting healthier ageing. Increasing population levels of physical activity through the promotion of physically active forms of travel is now recognised as a potential mechanism to combat obesity levels and non-communicable diseases (NCDs) , 2. MetaPhysical activity is particularly important for those at older ages, being linked to healthy ageing and maintaining good physical functioning , 9 . NonInterventional studies among working adults have linked changes from inactive to active forms of travel to lower BMI , a findiWe used data from the English Longitudinal Study of Ageing (ELSA), a nationally representative cohort study of persons aged 50 years and older in England . Data foN = 4834). Individuals who reported the same level of public transport use at waves 4 and 6 were used as the reference group, while those who decreased their public transport use were excluded. Participants with the highest level of use at baseline were excluded due to being unable to increase their frequency of use (N = 364) Second, to assess initiating public transport use we further restricted the sample described above to include only individuals who reported not using public transport at baseline (N = 2064). A full breakdown of the levels of public transport use at baseline and follow up is presented in We focus here on increases in public transport use rather than changes in use generally. This is due to policies such as the free bus pass potentially driving increases in public transport use as well as concerns that any decreases in public transport use would be the result of natural disease processes or ageing, and that analyses may not be able to be adequately control for these factors. Two separate analytical samples were created to assess different aspects of increases in public transport use. First, to assess predictors of increases in public transport we analysed individuals with complete data on public transport use at waves 4 and 6 who had increased their monthly use of public transport , and mobility problems. ADLs are indicators of the functional status of older adults  and in EThe two analytic samples were analysed separately for analyses on increases in public transport analysis and the initiating public transport respectively. Descriptive characteristics were first described as frequencies for categorical variables or mean values for continuous variables. Logistic regression was used to assess predictors of initiating, and increasing, public transport use between baseline and follow up. Analyses of both initiating and increasing public transport use were adjusted for the covariates listed above, with the exception of adiposity models, which were not adjusted for changes in physical activity, which was considered to be on the causal pathway. Analyses of increases in public transport use were additionally adjusted for frequency of public transport use at baseline.p < 0.001). These models were subsequently stratified by gender. Logistic  and linear (BMI and waist circumference) regression models assessed the relationships with outcomes at follow-up, both unadjusted and adjusted for the potential confounders above. Outcomes at baseline were then added to these models to examine associations with changes over time. To examine whether any associations were mediated by non-transport physical activity we performed sensitivity analyses of the association between public transport use and adiposity, additionally adjusted for changes in physical activity levels.We identified the presence of statistically significant gender interactions for increases in public transport use with physical activity, BMI and waist circumference  at follow up than those who did not, although this was attenuated after adjusting for BMI at baseline . Results for waist circumference were similar to BMI findings, although not statistically significant for men.Associations of increasing levels of public transport use and health markers are shown in Table 2, − 2.75; − 1.15), although this association was not statistically significant after adjustment for BMI at baseline . Results for waist circumference were similar to BMI results for both genders and associations were not statistically significant for men.Associations of initiating public transport use with health markers are shown in Table Results from sensitivity analyses of adiposity additionally adjusted for physical activity were similar . The adiposity measures used were objective, and the use of both BMI and waist circumference strengthens our confidence in these findings. There are nevertheless some limitations. We have followed participants up over four years: however, we do not know at which point in these four years they have increased their public transport use. Also, assessment of public transport use and physical activity were both self-reported, although the physical activity measure has demonstrated excellent convergent validity with a variety of risk factors in previous work –29. ChanThis study highlights the potential role of public transport in increasing population levels of physical activity. The possibility of incorporating more walking or cycling into public transport journeys is noted in National Institute for Health and Clinical Excellence (NICE) guidance on walking and cycling , in partThe national free bus pass scheme is a universal benefit linked to the state pension age for women, and has been demonstrated here to increase public transport use among those becoming eligible. The scheme costs in the region of £1billion a year , but theThe key predictors of both initiating and increasing public transport among older adults were becoming eligible for a bus pass, retirement and moving house. Both initiating and increasing public transport use were associated with increased physical activity and may be associated with lower adiposity. These findings strengthen the case for considering public transport provision as an effective means of promoting healthier ageing.


The geographic ranges of taxa change in response to environmental conditions. Yet whether rates of range movement (biotic velocities) are phylogenetically conserved is not well known. Phylogenetic conservatism of biotic velocities could reflect similarities among related lineages in climatic tolerances and dispersal‐associated traits. We assess whether late Quaternary biotic velocities were phylogenetically conserved and whether they correlate with climatic tolerances and dispersal‐associated traits. We used phylogenetic regression and nonparametric correlation to evaluate associations between biotic velocities, dispersal‐associated traits, and climatic tolerances for 28 woody plant genera and subgenera in North America. The velocities with which woody plant taxa shifted their core geographic range limits were positively correlated from time step to time step between 16 and 7 ka. The strength of this correlation weakened after 7 ka as the pace of climate change slowed. Dispersal‐associated traits and climatic tolerances were not associated with biotic velocities. Although the biotic velocities of some genera were consistently fast and others consistently slow, biotic velocities were not phylogenetically conserved. The rapid late Quaternary range shifts of plants lacking traits that facilitate frequent long‐distance dispersal has long been noted . Our results are consistent with this paradox and show that it remains robust when phylogenetic information is taken into account. The lack of association between biotic velocities, dispersal‐associated traits, and climatic tolerances may reflect several, nonmutually exclusive processes, including rare long‐distance dispersal, biotic interactions, and cryptic refugia. Because late Quaternary biotic velocities were decoupled from dispersal‐associated traits, trait data for genera and subgenera cannot be used to predict longer‐term  floristic responses to climate change. This is evident in the recent shifts of species upslope along elevational gradients  fossil records have been widely used to understand the movements of plants  and Fagales .We analyzed the late Quaternary biotic velocities of 28 North American woody plant genera and subgenera using velocities estimated by Ordonez and Williams  from fosOrdonez and Williams  calculathttp://esp.cr.usgs.gov/data/little, accessed August 2013). Range maps for the two North American Sarcobatus species were digitized from range maps in the Flora of North America . Shapefiles of geographic ranges were transformed to an equal area projection (Goode homolosine) before calculating geographic range size and were logarithmically transformed prior to analysis.Because biotic velocities may also be correlated with range size, we tested whether present‐day range sizes are phylogenetically conserved and whether there are associations between present‐day range sizes and late Quaternary velocities. Present‐day geographic ranges of genera in North America were estimated using ESRI ArcGIS 10.0 by overlaying and merging digitized species‐level geographic range maps derived from the Atlas of United States Trees  and Flora of North America . For the phylogenetic comparative analyses, we calculated arithmetic mean velocities for each taxon across a predefined temporal interval, that is, (1) all six intervals (16–1 ka), (2) intervals >7 ka which were characterized by relatively fast velocities, and (3) intervals <7 ka characterized by relatively slow velocities  whereas others tended to move more slowly  , but not others  tended to be rapid movers whereas others tended to move at a slower pace . Rank order differences in genus biotic velocities were correlated between adjacent time intervals, although the absolute rates of range movement varied  on adjacent branches in the trimmed phylogeny  and Fagales . More broadly, because the range dynamics of higher taxa are a function of processes of speciation and extinction as well as the physiological tolerances of constituent species  vary considerably and are often comparable to those of plants that moved at faster rates. The decoupling of life history traits from late Quaternary biotic velocities, and specifically the rapid late Quaternary velocities of plants that possess heavier seeds and other dispersal‐limiting traits has been recognized by others previously as “Reid's paradox” , may have moved more slowly than pollen records would suggest because low‐density populations remained at higher latitudes. Recent studies combining molecular phylogeographic data with analyses of plant macro‐ and microfossils have identified cryptic refuges  used in our study, which was necessitated by the inability to differentiate pollen to species based on morphology alone, poses some limitations. Congeneric species can vary in range size, location, and rate of geographic range movement and thus the range dynamics of a genus do not scale down to all constituent species (Foote, Ritterbush, & Miller, We have assumed in this study that the biotic velocities estimated by Ordonez and Williams  reflect In conclusion, we assessed the relationships between phylogeny, biotic velocities, and life history traits and climatic tolerances, in North American woody plants, a system in which we can integrate data from the late Quaternary fossil record, phylogeny, and functional biology. We found that relative differences among woody plant genera in their biotic velocities were maintained through the Quaternary but were not phylogenetically conserved. Plant functional traits and climatic tolerances were not associated with Quaternary biotic velocities. These results provide a comparative phylogenetic perspective on the geographic range dynamics of woody plants and underscore the temporal scale‐dependence of range shifts for which functional traits may be predictive in the near term but less informative over longer time scales.None declared. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.