Heating of tissues by microwaves: A model analysis

We consider the thermal response times for heating of tissue subject to nonionizing (microwave or infrared) radiation. The analysis is based on a dimensionless form of the bioheat equation. The thermal response is governed by two time constants: one(τ₁) pertains to heat convection by blood flow, and is of the order of 20–30 min for physiologically normal perfusion rates; the second (τ₂) characterizes heat conduction and varies as the square of a distance that characterizes the spatial extent of the heating. Two idealized cases are examined. The first is a tissue block with an insulated surface, subject to irradiation with an exponentially decreasing specific absorption rate, which models a large surface area of tissue exposed to microwaves. The second is a hemispherical region of tissue exposed at a spatially uniform specific absorption rate, which models localized exposure. In both cases, the steady-state temperature increase can be written as the product of the incident power density and an effective time constant τ_eff, which is defined for each geometry as an appropriate function of τ₁ and τ₂. In appropriate limits of the ratio of these time constants, the local temperature rise is dominated by conductive or convective heat transport. Predictions of the block model agree well with recent data for the thresholds for perception of warmth or pain from exposure to microwave energy. Using these concepts, we developed a thermal averaging time that might be used in standards for human exposure to microwave radiation, to limit the temperature rise in tissue from radiation by pulsed sources. We compare the ANSI exposure standards for microwaves and infrared laser radiation with respect to the maximal increase in tissue temperature that would be allowed at the maximal permissible exposures. A historical appendix presents the origin of the 6-min averaging time used in the microwave standard. Bioelectromagnetics 19:420–428, 1998. © 1998 Wiley-Liss, Inc.     

SAR versus Sinc: What is the appropriate RF exposure metric in the range 1–10 GHz? Part I: Using planar body models

This is the first of two articles addressing the most appropriate crossover frequency at which incident power flux density (S_inc) replaces the spatial peak value of the specific energy absorption rate (SAR) averaged over 1 or 10 g (i.e., peak 1 or 10 g SAR) as the basic restriction for protecting against radiofrequency (RF) heating effects in the 1–10 GHz range. Our general approach has been to compare the degree of correlation between these basic restrictions and the peak induced tissue temperature rise (ΔT) for a representative range of population/exposure scenarios. In this article we particularly address the effect of human population diversity in the thickness of body tissue layers at eight different sites of the body. We used a Monte Carlo approach to specify 32000 models (400 models for each of 8 body sites for 10 frequencies) which were representative of tissue thicknesses for age (18–74 years) and sex at the eight body sites. Histogram distributions of S_inc and peak 1 and 10 g SAR corresponding to a peak 1 °C temperature rise were obtained from RF and thermal analyses of 1D multiplanar models exposed to a normally incident plane wave ranging from 1 to 10 GHz in thermo‐neutral environmental conditions. Examination of the distribution spread of the histograms indicated that peak SAR was a better predictor of peak tissue temperature rise across the entire 1–10 GHz frequency range than S_inc, as indicated by the smaller spread in its histogram distributions, and that peak 10 g SAR was a slightly better predictor than peak 1 g SAR. However, this result must be weighed against partly conflicting indications from complex body modeling in the second article of this series, which incorporates near‐field effects and the influence of complex body geometries. Bioelectromagnetics 31:454–466, 2010. © 2010 Wiley‐Liss, Inc.     

A need to provide explanations for observed biological effects of radiofrequency exposure

Abstract

Although there is scientific consensus that radiofrequency (RF) exposure at high intensity can cause thermal effects, including well-established adverse health effects, there is still considerable controversy on whether low-intensity RF exposure can cause biological effects, especially adverse health effects. The objective of this paper is to describe several reported “non-thermal” effects that were later shown to be due to a weak thermal effect or an experimental artifact by properly conducted and thorough follow-on scientific research. First, the multiple factors that can cause different RF energy absorption in biological tissues are reviewed and second, several examples of experimental artifacts in published papers are described to demonstrate the importance of paying attention to dosimetry and temperature control. For example, isolated nerve response studies show that when temperature of the RF-exposed tissues is controlled, effects disappeared. During RF exposure, conductive electrodes routinely used in physiological studies have been shown to cause field intensification at the tips or contacts of the electrodes with biological tissue; thus, the RF exposure at the site of measurement could be much higher than the incident field. In some in vitro studies, a lack of temperature uniformity in RF-exposed cell cultures and rate of heating explain changes originally reported to be due to low-level RF exposure. In other studies, detailed dosimetry studies have identified artifacts that explain the reasons why so-called “non-thermal” effects were mistakenly reported. Researchers should look for explanations for their own findings, and not expect others to figure out what was the reason for their observed effects.     

Skin temperature increase caused by a mobile phone: a methodological infrared camera study

Mobile phone users often complain about burning sensations or a heating of the ear region. The increase in temperature may be due to thermal insulation by the phone, heating of the mobile phone resulting from its electrical power dissipation, and radio frequency (RF) exposure. The main objective of this study was to use infrared (IR) camera techniques to find how much each of these factors contributes to the increase in skin temperature resulting from the use of one GSM 900 phone. One subject, a healthy male, took part in the study. He was holding the phone in a normal position when the phone was switched off, when it was switched on but with the antenna replaced by a 50 Omega load to eliminate the RF exposure, and when it was transmitting RF fields. The output power could be fixed, and the minimal and the maximal power levels of the phone were used. The study was designed as a double blind experiment. The changes in temperature after 15 and 30 min of mobile phone use were calculated on the exposed side of the head relative to the unexposed side. The insulation and the electrical power dissipation led to statistically significant rises in the skin temperature, while the RF exposure did not.     

Low-level exposure to radiofrequency electromagnetic fields: Health effects and research needs

The World Health Organization (WHO), the International Commission on Non-Ionizing Radiation Protection (ICNIRP), and the German and Austrian Governments jointly sponsored an international seminar in November of 1996 on the biological effects of low-level radiofrequency (RF) electromagnetic fields. For purposes of this seminar, RF fields having frequencies only in the range of about 10 MHz to 300 GHz were considered. This is one of a series of scientific review seminars held under the International Electromagnetic Field (EMF) Project to identify any health hazards from EMF exposure. The scientific literature was reviewed during the seminar and expert working groups formed to provide a status report on possible health effects from exposure to low-level RF fields and identify gaps in knowledge requiring more research to improve health risk assessments. It was concluded that, although hazards from exposure to high-level (thermal) RF fields were established, no known health hazards were associated with exposure to RF sources emitting fields too low to cause a significant temperature rise in tissue. Biological effects from low-level RF exposure were identified needing replication and further study. These included in vitro studies of cell kinetics and proliferation effects, effects on genes, signal transduction effects and alterations in membrane structure and function, and biophysical and biochemical mechanisms for RF field effects. In vivo studies should focus on the potential for cancer promotion, co-promotion and progression, as well as possible synergistic, genotoxic, immunological, and carcinogenic effects associated with chronic low-level RF exposure. Research is needed to determine whether low-level RF exposure causes DNA damage or influences central nervous system function, melatonin synthesis, permeability of the blood brain barrier (BBB), or reaction to neurotropic drugs. Reported RF-induced changes to eye structure and function should also be investigated. Epidemiological studies should investigate: the use of mobile telephones with hand-held antennae and incidence of various cancers; reports of headache, sleep disturbance, and other subjective effects that may arise from proximity to RF emitters, and laboratory studies should be conducted on people reporting these effects; cohorts with high occupational RF exposure for changes in cancer incidence; adverse pregnancy outcomes in various highly RF exposed occupational groups; and ocular pathologies in mobile telephone users and in highly RF exposed occupational groups. Studies of populations with residential exposure from point sources, such as broadcasting transmitters or mobile telephone base stations have caused widespread health concerns among the public, even though RF exposures are very low. Recent studies that may indicate an increased incidence of cancer in exposed populations should be investigated further. Bioelectromagnetics 19:1–19, 1998. © 1998 Wiley-Liss, Inc.     

Radio-frequency exposure of the yellow fever mosquito (A. aegypti) from 2 to 240 GHz

Fifth generation networks (5G) will be associated with a partial shift to higher carrier frequencies, including wavelengths comparable in size to insects. This may lead to higher absorption of radio frequency (RF) electromagnetic fields (EMF) by insects and could cause dielectric heating. The yellow fever mosquito (Aedes aegypti), a vector for diseases such as yellow and dengue fever, favors warm climates. Being exposed to higher frequency RF EMFs causing possible dielectric heating, could have an influence on behavior, physiology and morphology, and could be a possible factor for introduction of the species in regions where the yellow fever mosquito normally does not appear. In this study, the influence of far field RF exposure on A. aegypti was examined between 2 and 240 GHz. Using Finite Difference Time Domain (FDTD) simulations, the distribution of the electric field in and around the insect and the absorbed RF power were found for six different mosquito models (three male, three female). The 3D models were created from micro-CT scans of real mosquitoes. The dielectric properties used in the simulation were measured from a mixture of homogenized A. aegypti. For a given incident RF power, the absorption increases with increasing frequency between 2 and 90 GHz with a maximum between 90 and 240 GHz. The absorption was maximal in the region where the wavelength matches the size of the mosquito. For a same incident field strength, the power absorption by the mosquito is 16 times higher at 60 GHz than at 6 GHz. The higher absorption of RF power by future technologies can result in dielectric heating and potentially influence the biology of this mosquito.     

Effect of insulating layer material on RF-induced heating for external fixation system in 1.5 T MRI system

The radio frequency (RF)-induced heating is a major concern when patients with medical devices are placed inside a magnetic resonance imaging (MRI) system. In this article, numerical studies are applied to investigate the potentials of using insulated materials to reduce the RF heating for external fixation devices. It is found that by changing the dielectric constant of the insulation material, the RF-induced heating at the tips of devices can be altered. This study indicates a potential technique of developing external fixation device with low MRI RF heating.     

Simultaneous measurements of local tissue temperature and blood perfusion rate in the canine prostate during radio frequency thermal therapy

Local tissue temperature and blood perfusion rate were measured simultaneously to study thermoregulation in the canine prostate during transurethral radio-frequency (RF) thermal therapy. Thermistor bead microprobes measured interstitial temperatures and a thermal clearance method measured the prostatic blood perfusion rate under both normal and hyperthermic conditions. Increase in local tissue temperature induced by the RF heating increased blood perfusion throughout the entirety of most prostates. The onset of the initial increase in blood perfusion was sometimes triggered by a temporal temperature gradient at low tissue temperatures. When tissue temperature was higher than 41°C, however, the magnitude and the spatial gradient of temperature may play significant roles. It was found that the temperature elevation in response to the RF heating was closely coupled with local blood flow. The resulting decrease in or stabilization of tissue temperature suggested that blood flow might act as a negative feedback of tissue temperature in a closed control system. Results from this experiment provide insights into the regulation of local perfusion under hyperthermia. The information is important for accurate predictions of temperature during transurethral RF thermal therapy.     

Inverse investigation of non-Fourier heat conduction in tissue

This paper attempts to describe the heat conduction in tissue using the dual-phase-lag mode. Evaluating the thermo-physical parameters is one of the ways to certify the thermal behavior. As a result, the paper simultaneously and inversely estimates the values of τ_q, τ_T and α for bologna based on the dual-phase-lag mode with the measurement data in the literature. The inconsistence in theory discovered in the literatures is eliminated. The calculated results of temperature variation with the estimated values of τ_q, τ_T and α at the measurement location are very close to the experimental data and address the rationality of the present results.     

The origin and theoretical correction of thermal gradients in thermocouple psychrometers

Temperature-compensated psychrometers are explained and a theoretical correction for temperature gradients, with its boundaries, is given. The correction was elaborated for in situ determination of water potential on soybean and tomato stems where it was indispensable. The origin of the thermal gradients in the psychrometric chamber is then discussed. Cooling of the conducting tissue by the circulation of xylem sap seemed to be the major cause for these gradients, while the heating of the psychrometer (thermally insulated) by the surroundings through radiative or conductive transfer was negligible.     

Design and Evaluation of a Hybrid Radiofrequency Applicator for Magnetic Resonance Imaging and RF Induced Hyperthermia: Electromagnetic Field Simulations up to 14.0 Tesla and Proof-of-Concept at 7.0 Tesla

This work demonstrates the feasibility of a hybrid radiofrequency (RF) applicator that supports magnetic resonance (MR) imaging and MR controlled targeted RF heating at ultrahigh magnetic fields (B₀≥7.0T). For this purpose a virtual and an experimental configuration of an 8-channel transmit/receive (TX/RX) hybrid RF applicator was designed. For TX/RX bow tie antenna electric dipoles were employed. Electromagnetic field simulations (EMF) were performed to study RF heating versus RF wavelength (frequency range: 64 MHz (1.5T) to 600 MHz (14.0T)). The experimental version of the applicator was implemented at B₀ = 7.0T. The applicators feasibility for targeted RF heating was evaluated in EMF simulations and in phantom studies. Temperature co-simulations were conducted in phantoms and in a human voxel model. Our results demonstrate that higher frequencies afford a reduction in the size of specific absorption rate (SAR) hotspots. At 7T (298 MHz) the hybrid applicator yielded a 50% iso-contour SAR (iso-SAR-50%) hotspot with a diameter of 43 mm. At 600 MHz an iso-SAR-50% hotspot of 26 mm in diameter was observed. RF power deposition per RF input power was found to increase with B₀ which makes targeted RF heating more efficient at higher frequencies. The applicator was capable of generating deep-seated temperature hotspots in phantoms. The feasibility of 2D steering of a SAR/temperature hotspot to a target location was demonstrated by the induction of a focal temperature increase (ΔT = 8.1 K) in an off-center region of the phantom. Temperature simulations in the human brain performed at 298 MHz showed a maximum temperature increase to 48.6C for a deep-seated hotspot in the brain with a size of (19×23×32)mm³ iso-temperature-90%. The hybrid applicator provided imaging capabilities that facilitate high spatial resolution brain MRI. To conclude, this study outlines the technical underpinnings and demonstrates the basic feasibility of an 8-channel hybrid TX/RX applicator that supports MR imaging, MR thermometry and targeted RF heating in one device.     

Reactive oxygen species formation is not enhanced by exposure to UMTS 1950 MHz radiation and co‐exposure to ferrous ions in Jurkat cells

This study was designed to assess if radiofrequency (RF) radiation induces oxidative stress in cultured mammalian cells when given alone or in combination with ferrous ions (FeSO₄). For this purpose the production of reactive oxygen species (ROS) was measured by flow cytometry in human lymphoblastoid cells exposed to 1950 MHz signal used by the third generation wireless technology of the Universal Mobile Telecommunication System (UMTS) at Specific Absorption Rate of 0.5 and 2.0 W/kg. Short (5–60 min) or long (24 h) duration exposures were carried out in a waveguide system under strictly controlled conditions of both dosimetry and environment. Cell viability was also measured after 24 h RF exposure using the Resazurin and Neutral Red assays. Several co‐exposure protocols were applied to test if RF radiation is able to alter ROS formation induced by FeSO₄ (RF given before or concurrently to FeSO₄). The results obtained indicate that non‐thermal RF exposures do not increase spontaneous ROS formation in any of the experimental conditions investigated. Consistent with the lack of ROS production, no change in cell viability was observed in Jurkat cells exposed to RF radiation for 24 h. Similar results were obtained when co‐exposures were considered: combined exposures to RF radiation and FeSO₄ did not increase ROS formation induced by the chemical treatment alone. In contrast, in cultures treated with FeSO₄ as positive control, a dose‐dependent increase in ROS formation was recorded, validating the sensitivity of the method employed. Bioelectromagnetics 30:525–535, 2009. © 2009 Wiley‐Liss, Inc.     

Scanning calorimetry measurements of the gas temperature in an RF-discharge fluorine-containing plasma

The neutral-gas temperature in a low-pressure (50 Pa) capacitive RF discharge in a CF₄+O₂ mixture is determined from the heating kinetics of a gallium arsenide single crystal, which is chemically inert to any radicals in a fluorine-containing plasma. Experimental methods are discussed that make it possible to confirm the absence of heat sources capable of additional heating of the calorimeter in the discharge. The features and applicability limits of the method of non-steady-state gas thermometry in a weakly ionized nonequilibrium plasma are discussed. The method proposed is compared with conventional steady-state methods based on measurements of the established temperature of a thermal probe in the discharge. Temperature scanning makes it possible to study dependences that cannot be investigated by steady-state methods, in particular, the temperature dependence of the calorimeter heating power, which is very important for diagnosing the processes of plasma-surface heat transfer.     

Three-dimensional reconstruction and averaging of 50 S ribosomal subunits of Escherichia coli from electron micrographs

The thermal stability and melting kinetics of the α-helical conformation within several regions of the rabbit myosin rod have been investigated. Cyanogen bromide cleavage of long myosin subfragment-2 produced one coiled-coil α-helical fragment corresponding to short subfragment-2 with molecular weight 90,000 (M_r = 45,000) and two fragments from the hinge region with molecular weights of 32,000 to 34,000 (M_r = 16,000 to 17,000) and 24,000 to 26,000 (M_r = 12,000 to 13,000). Optical rotation melting experiments and temperature-jump kinetic studies of long subfragment-2 and its cyanogen bromide fragments show that the hinge and the short subfragment-2 domains melt as quasi-independent co-operative units. The α-helical structure within the hinge has an appreciably lower thermal stability than the flanking short subfragment-2 and light meromyosin regions of the myosin rod. Two relaxation processes for helix-melting, one in the submillisecond range (τ_f) and the other in the millisecond range (τ_s), are observed in the light meromyosin and short subfragment-2 regions of the rod, but melting in the hinge domain is dominated by the fast (τ_f) process. Results suggest that the hinge domain of the subfragment-2 link may be the locus of force generation in a cycling cross-bridge.     

SAR versus VAR, and the size and shape that provide the most appropriate RF exposure metric in the range of 0.5-6 GHz

Basic restrictions for protecting against localized tissue heating induced from exposure to radiofrequency (RF) fields are typically specified as the specific energy absorption rate (SAR), which is mass averaged in recognition of the thermal diffusion properties of tissues. This article seeks to determine the most appropriate averaging mass (1, 3, 5, 7, or 10 g) and averaging shape (cube or sphere). We also consider an alternative metric, volumetric energy absorption rate (VAR), which uses volume averaging (over 1, 3, 5, 7, and 10 cm³; cube and sphere). The SAR and VAR averaging approaches were compared by considering which was a better predictor of tissue temperature rise (ΔT) induced by near‐ and far‐field RF exposures (0.5–6 GHz), calculated in a detailed human body model. For the exposure scenarios that we examined, VAR is better correlated with ΔT than SAR, though not at a statistically significant level for most of the metric types we studied. However, as VAR offers substantive advantages in ease of assessment we recommend this metric over SAR. Averaging over a cube or a sphere provides equivalent levels of correlation with ΔT, and so we recommend choosing the averaging shape on the basis of which is easier to assess. The optimal averaging volume is 10 cm³ for VAR, and the optimal mass is 10 g for SAR. The correlation between VAR or SAR and ΔT diminishes substantially at 6 GHz, where incident power flux density may be a better exposure metric. Bioelectromagnetics 32:312–321, 2011. © 2010 Wiley‐Liss, Inc.     

Influence of blood flow and millimeter wave exposure on skin temperature in different thermal models

Recently we showed that the Pennes bioheat transfer equation was not adequate to quantify mm wave heating of the skin at high blood flow rates. To do so, it is necessary to incorporate an "effective" thermal conductivity to obtain a hybrid bioheat equation (HBHE). The main aim of this study was to determine the relationship between non-specific tissue blood flow in a homogeneous unilayer model and dermal blood flow in multilayer models providing that the skin surface temperatures before and following mm wave exposure were the same. This knowledge could be used to develop multilayer models based on the fitting parameters obtained with the homogeneous tissue models. We tested four tissue models consisting of 1-4 layers and applied the one-dimensional steady-state HBHE. To understand the role of the epidermis in skin models we added to the one- and three-layer models an external thin epidermal layer with no blood flow. Only the combination of models containing the epidermal layer was appropriate for determination of the relationship between non-specific tissue and dermal blood flows giving the same skin surface temperatures. In this case we obtained a linear relationship between non-specific tissue and dermal blood flows. The presence of the fat layer resulted in the appearance of a significant temperature gradient between the dermis and muscle layer which increased with the fat layer thickness.     

Electromagnetic simulation of RF burn injuries occurring at skin-skin and skin-bore wall contact points in an MRI scanner with a birdcage coil

PurposeTo simulate radiofrequency (RF) burns that frequently occur at skin–skin and skin–bore wall contact points.MethodsRF burn injuries (thumb–thigh and elbow–bore wall contacts) that typically occur on the lateral side of the body during 1.5 T magnetic resonance imaging (MRI) scans were simulated using a computational human model. The model was shifted to investigate the influence of the position of the patient in an MRI scanner. The specific absorption rate (SAR), electric field, and temperature were mapped.ResultsRegarding the contact points located near the edge of the birdcage transmission coil, under the allowable maximum RF power exposure i.e., the average whole-body SAR at the safety limit value (2 W/kg), the 10-g-tissue-averaged SAR (SAR_10g) at those points significantly increased for both the thumb–thigh (180 W/kg) and elbow–bore wall (48 W/kg) cases. Both values significantly exceeded the highest safety limit of the partial-body SAR (10 W/kg). The electric field, the square of which is proportional to SAR, was remarkably high near the edge of the birdcage transmission coil. The peak SAR_10g for each injury case was associated with contact-point peak temperatures that reached 52 °C at approximately 1 min following RF exposure onset; a 1-min period of exposure to this temperature causes a first-degree burn.ConclusionsWe demonstrated high heat generation in RF burn injury cases in silico. The RF heating occurring on the lateral side of the body was strongly dependent on the electric field distribution, which is dominantly determined by an RF transmission coil.     

Local exposure of the rat cortex to radiofrequency electromagnetic fields increases local cerebral blood flow along with temperature

Few studies have shown that local exposure to radiofrequency electromagnetic fields (RF) induces intensity-dependent physiological changes, especially in the brain. The aim of the present study was to detect reproducible responses to local RF exposure in the parietal cortex of anesthetized rats and to determine their dependence on RF intensity. The target cortex tissue was locally exposed to 2-GHz RF using a figure-eight loop antenna within a range of averaged specific absorption rates (10.5, 40.3, 130, and 263 W/kg averaged over 4.04 mg) in the target area. Local cerebral blood flow (CBF) and temperatures in three regions (target area, rectum, and calf hypodermis) were measured using optical fiber blood flow meters and thermometers during RF exposure. All parameters except for the calf hypodermis temperature increased significantly in exposed animals compared with sham-exposed ones during 18-min exposures. Dependence of parameter values on exposure intensity was analyzed using linear regression models. The elevation of local CBF was correlated with temperature rise in both target and rectum at the end of RF exposure. However, the local CBF elevation seemed to be elevated by the rise in target temperature, but not by that of the rectal temperature, in the early part of RF exposure or at low-intensity RF exposure. These findings suggest that local RF exposure of the rat cortex drives a regulation of CBF accompanied by a local temperature rise, and our findings may be helpful for discussing physiological changes in the local cortex region, which is locally exposed to RF.     

Probing the fluorescence emission kinetics of the photosynthetic apparatus of Rhodopseudomonas sphaeroides, strain 1760-1, on a picosecond pulse fluorometer

Using the pulse picosecond fluorometric technique the fluorescence properties of intact cells, isolated chromatophores and photosynthetic reaction centres were studied in bacteria Rhodopseudomonas sphaeroides, strain 1760-1.The fluorescent emission from reduced reaction centres excited by 694.3 nm light has a biphasic character, the lifetimes of the components being τ₁ = 15±8 ps and τ₂ = 250 ps. The faster component, τ₁, contributes to the integral fluorescence in the long wavelength region. It disappears with oxidation of the reaction centres and is attributed to photoactive bacteriochlorophyll P870. The slow component, τ, is apparently due to both bacteriochlorophyll P800 and bacteriopheophytin. The fluorescence from intact cells exhibits a monophasic pattern and decays with τ = 200 ps.The fluorescence emitted by chromatophores comprises two components with τ₃ = 200 ps and τ₄ = 4200 ps. The duration of fluorescence τ₃ increases to its maximum of 500–550 ps, as P870 is oxidized chemically or photochemically, while τ₄ remains unchanged. The fluorescence with a lifetime of 200 ps was ascribed to the photosystem and the 4200-ps fluorescence to bacteriochlorophyll which had lost its functional links with the photosystem.The rise time of the fluorescence emitted by chromatophores varies from 60 or 70 ps to 350 ps depending on the wavelength of the exciting light and the recorded spectral region. On the basis of our findings the rate for energy migration was estimated to be 10⁹ s^?1.     

Multi-state survival models with treatment effects and biomarkers: Simulations for study design assessment

BackgroundComparative effectiveness studies of cancer therapeutics in observational data face confounding by patterns of clinical treatment over time. The validity of survival analysis in longitudinal health records depends on study design choices including index date definition and model specification for covariate adjustment.MethodsOverall survival in cancer is a multi-state transition process with mortality and treatment switching as competing risks. Parametric Weibull regression quantifies proportionality of hazards across lines of therapy in real-world cohorts of 12 solid tumor types. Study design assessments compare alternative analytic models in simulations with realistic disproportionality. The multi-state simulation framework is adaptable to alternative treatment effect profiles and exposure patterns.ResultsEvent-specific hazards of treatment-switching and death are not proportional across lines of therapy in 12 solid tumor types. Study designs that include all eligible lines of therapy per subject showed lower bias and variance than designs that select one line per subject. Confounding by line number was effectively mitigated across a range of simulation scenarios by Cox proportional hazards models with stratified baseline hazards and inverse probability of treatment weighting.ConclusionQuantitative study design assessment can inform the planning of observational research in clinical oncology by demonstrating the potential impact of model misspecification. Use of empirical parameter estimates in simulation designs adapts analytic recommendations to the clinical population of interest.