Surface enhanced Raman scattering (SERS) is generally and widely used to enhance the vibrational fingerprint of molecules located at the vicinity of noble metal nanoparticles. In this work, SERS is originally used to enhance the own vibrational density of states (VDOS) of nude and isolated gold nanoparticles. This offers the opportunity of analyzing finite size effects on the lattice dynamics which remains unattainable with conventional techniques based on neutron or x-ray inelastic scattering. By reducing the size down to few nanometers, the role of surface atoms versus volume atoms become dominant, and the “text-book” 3D-2D transition on the dynamical behavior is experimentally emphasized. “Anomalies” that have been predicted by a large panel of simulations at the atomic scale, are really observed, like the enhancement of the VDOS at low frequencies or the occurrence of localized modes at frequencies beyond the cut-off in bulk. Consequences on the thermodynamic properties at the nanoscale, like the reduction of the Debye temperature or the excess of the specific heat, have been evaluated. Finally the high sensitivity of reminiscent bulk-like phonons on the arrangements at the atomic scale is used to access the morphology and internal disorder of the nanoparticles. In fact, all the vibrational modes are affected and a distortion of the vibrational density of states (VDOS) is observed. As a consequence, size reduction generates “anomalies” – et al.14Noble metal clusters, nanoparticles (NPs), nanowires or thin films have attracted a particular attention owing to their plasmonics properties. Among noble metals, gold plays a peculiar role due to its relative stability and the occurrence of both interband electronic transitions and localized surface plasmon resonance (LSPR) in the visible optical range. Numerous studies have concerned their structural and optical properties  corresponding to linear dispersion of sound waves. In this range, finite size effects lead to the discretization of spatially confined modes referred as Lamb modes. In an elastically isotropic sphere, they are labelled by quantum numbers n = 1) modes may efficiently modulate the high polarizability of the confined electron gas and are easily detected in time-resolved pump-probe experiments or using Raman-Brillouin spectroscopy: for recent reviews on these two types of investigations, see Crut et al.et al.19As the primitive cell of gold contains a single atom, only acoustic-like vibrations are present. Most of the published works deal with their low frequency range  modes in the bulk.The VDOS of nanoparticles is very sensitive to atomic arrangements (that may considerably differ between surface and inner atoms), twins and surface-disorder1112Some high frequency modes are observed beyond the cut-off of bulk VDOS and are generally attributed to a capillary pressure effect on the core atoms26 An enhancement of the VDOS is observed at low frequencies and is generally attributed to a contribution of atoms located on surface or grain boundaries22A question remains open concerning the frequency dependence in the Debye limit: does it evolves from quadratic to linear when reducing the size of the nanocrystals2223However, the description of a NP as made up of a continuous medium with a given shape is too idealized for a deep understanding of its vibrational and thus thermodynamic properties. Only its description as a cluster of atoms with a specific organization allows to calculate all the vibrational frequencies and associated displacement vectors. In that way, a lot of works dealing with determinations of entire or local VDOS in noble metal NPs have been achieved through atomic simulations51112192022232425262728Checking experimentally all these theoretical predictions is thus highly required. However exploring the whole VDOS of nanostructures is conceptually difficult because of their tiny volumes interacting with probes (neutrons or photons) and their instability under intense beams. Scarce results have been obtained on nanoclusters or nanocrystalline materials using nuclear resonant inelastic x-ray scattering (NRIXS) and inelastic neutron scattering (INS) techniques. The VDOS of nanocrystalline Ni and Fe4303128i.e. the concomitant increase of the surface over volume ratio, on thermodynamic properties. The third challenge was to get evidence of the “textbook 3D/2D transition” in the Debye regimeIn this context, the first objective of this work was to use plasmon resonant Raman scattering to get an image of the VDOS of nude Au NPs in order to avoid several drawbacks of earlier attempts, as the presence of foreign bonds at interfaces with the matrix (embedded NPs) or ligands (capped colloids) that is known to affect the lattice dynamics of NPsThe images of four samples of Au NPs assemblies and the corresponding size distribution histograms are reported in 2/Si bilayer when the dielectric thickness coincides with 3/4 or 1/4 of the light wavelength inside the dielectric, respectively. In between these minima, one identifies the singularities associated to direct optical transitions (at 295 and 365 nm) in the crystalline Si substrate.The optical reflectance spectra of the four samples are reported in R/R = 1 − R/R0 (R0 referring to sample S), are presented in the inset of The gold deposition is evidenced by its influence on these antireflective minima. On one hand, the increase of the gold equivalent thickness leads to a strong decrease (up to 80%) of the reflectance dip in the UV range. This simply reflects the absorption increase according to Lambert–Beer law, due to interband transitions in gold. On the other hand, a similar phenomenon is observed on the reflectance dip in the visible range, but with a more complex spectral signature. The differential reflectance spectra, defined as Δ−1. Some very weak structures are visible around 80 and 140 cm−1 superimposed on a strong quasi-elastic scattering tail which intensity increases rapidly with the Au equivalent thickness (from A to D). In order to verify that the collected signal comes from Raman processes, and not luminescence ones, the rough signal Iexp has been corrected by the Bose statistical population factor f of the whole experimental set-upTypical rough Raman spectra are displayed in 34ν is the Raman frequency shift , and νi the laser frequency.where D. Assuming an icosahedron ordering and neglecting intrinsic anisotropy, the following expression has been proposed theoretically and well verified experimentally for Au NPs−1, for sample A and B, respectively. One thus obtains D ≈ 7.3 ± 0.8 and 9.4 ± 1.2 nm, in rather good agreement with electron microscopy observations  is hidden by the filter cut-off near the Rayleigh line, at 3 cm−1.One clearly observes in 2829ions see . For sam−1 in −1 some weak features are due to overtones of Lamb modes and they will be discarded in the following discussion.We now focus on the numerous other vibrations of atoms that make up each NP. They only give a hardly noticeable signal that superimposes the electronic response below 200 cmi) the structures become better defined, (ii) the high frequency band (LA band) is less flat, and (iii) the frequency dependence of the low energy tail of the TA band evolves from linear to quadratic (see dotted lines in g(ν), following:When the mean size of the Au NPs increases, from sample A to D, one observes that (C(ν) is expected to be weakly dependent on the vibrational frequency out of very selective electronic transitions, and I(ν) has been shown to give a very accurate image of the VDOS2829The “coupling coefficient” Let us focus on the result concerning sample D where the signal is the most clearly defined. It is reported in 122028ie. with different sizes), all the integrated areas in Nm of vibrational modes of the NP composed with Nat atoms, excluding global translations and rotations:For an easier comparison between NPs with different ratio of surface atoms versus volume ones (−1) ending with a sharp cut-off at the LA(L) frequency at 4.70 GHz (158 cm−1)C(ν) is not too frequency- (or band-) dependent as this area ratio is not affected when going from the bulk to NPs . This lowering of TD versus the size reduction has been already observed experimentally in Au thin filmsTD for free nanocrystals because of the surface-stress effect11and thus deduce in each case an effective Debye temperature By examining more globally the VDOS in Au NPs reported in 28D, plane waves in the bulk are changed into wave packets in this NP: the resulting momentum spreading Δk ~ 2π/D would induce a frequency broadening Δω = vgΔk of each mode according to its specific group velocity vg. However the modes that give the higher contribution to the VDOS belong to high symmetry points of the Brillouin zone where vg is known to vanish. The confinement or disorder effect is not able to account alone for the strong distortion of the TA and LA bands. It also fails to explain specific observations  has been theoretically attributed to a global shrinking of the NPsThe broadening of the LA band (ii) which intensity maximum is lower than the TA band in a NP also appears in calculations as a signature of the ICO or DEC morphology−1, located in between the upper contribution of Lamb modes and the curvature of the TA branches. In this range the Debye approximation is thus fulfilled because all the dispersion curves are linearThe presence of excess modes at low frequencies has been already observed in INS in nanocrystalline Fe depositsn ≈ 2 (quadratic dependence) to n ≈ 1 (linear dependence). One thus confirms the prominent role of surface modes in the low frequency range for nanometer-sized nanoparticles. This transition has been predicted by some atomistic simulations but remains controversial in experiments42223242531n in the dependence of g(ν) ∝ vn at low frequencies is still the subject of debate mainly because the analysis performed on different assemblies of NPs suffer from the uncertainties on data corrections and heterogeneities of the samples. Very recently the 2D–3D transition has been clearly observed in ultrathin FeO films but it concerns nonmetallic systems containing also optical modes and whose acoustic modes are only confined in one directionTo exemplify these phenomena, the experimental VDOS are plotted in Cv(T) is essentially dominated by the lattice contribution at high temperature T because the electronic contribution becomes negligibleT is higher than the Debye temperature TD, Cv(T) tends toward the classical limit Cv,∞ = 3NmkB. In order to compare the thermal behavior of samples with different sizes, we define a normalized specific heat Cv(T), using The specific heat of a solid g(ν) deduced from Raman data, the selective resonant contribution of the few Lamb modes has been arbitrary subtracted (see dotted lines for samples A and D in νgap). Our calculation are thus obviously valid in the high temperature range (T > 10 K) where this quantized regime is blurred by the thermal effect (kBT ≳ hνgap). The calculated specific heat cv(T) corresponding to samples B and D is reported in T ≲ 30 K) whereas an excess specific heat is noted for Au NPs. This excess can be accounted for by introducing an “effective” Debye temperature, lower than in the bulk, as discussed previously.In the density of states T ≪ TD) because of the prominent role of surface contribution. As a matter of fact, the excess has more than doubled (3% to 7%) when the mean size is reduced from sample D to B. The excess specific heat has been already examined when going from bulk to nanocrystalline copper, either theoretically in clustersIn This work has thus experimentally confirmed a lot of theoretical phenomena predicted during the least decades, like the distortion of the VDOS induced by size reduction, internal disorder and strain, the 2D–3D transition when surface effects become prominent, and the resulting “anomalies” in thermodynamic properties.2(90 nm)/Si substrates by dc magnetron sputtering of a pure gold target in a Plassys ultra-high-vacuum device. The metallic layer was deposited at 600 °C in order to ensure the formation of NPs. The current was chosen to achieve a deposition rate of 0.027 nm/s. The amount of deposited gold was calibrated by the mass-equivalent thickness (The Au NPs were grown on specific SiOhickness . Four saA GEMINI field emission column integrated in a Zeiss CrossBeam 1540 was used for Scanning Electron Microscopy (SEM) imaging. The crystalline nature of the NPs has been demonstrated using high-resolution transmission electron microscopy (HRTEM) in a FEI Tecnai microscope equipped with a field emission gun and a spherical aberration corrector and operating at 200 keV.−1 from the Rayleigh line, the standard backscattering geometry is replaced by a two-objective system. The incoming laser beam is focused under an oblique incidence on the sample through a first objective ; the scattered light is collected in the normal direction by a long working distance microscope objective . Moreover, a specific optical and electronic filter is inserted into the spectrometer to limit the spectral window .Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


To present the implications of agency theory in microeconomics, augmented by behavioral economics, for different methods of value‐based payment in health care; and to derive a set of future research questions and policy recommendations based on that conceptual analysis.Original literature of agency theory, and secondarily behavioral economics, combined with applied research and empirical evidence on the application of those principles to value‐based payment.Conceptual analysis and targeted review of theoretical research and empirical literature relevant to value‐based payment in health care.Agency theory and secondarily behavioral economics have powerful implications for design of value‐based payment in health care. To achieve improved value—better patient experience, clinical quality, health outcomes, and lower costs of care—high‐powered incentives should directly target improved care processes, enhanced patient experience, and create achievable benchmarks for improved outcomes. Differing forms of value‐based payment , coupled with adjunct incentives for quality and efficiency, can be tailored to different market conditions and organizational settings.Payment contracts that are “incentive compatible”—which directly encourage better care and reduced cost, mitigate gaming, and selectively induce clinically efficient providers to participate—will focus differentially on evidence‐based care processes, will right‐size and structure incentives to avoid crowd‐out of providers’ intrinsic motivation, and will align patient incentives with value. Future research should address the details of putting these and related principles into practice; further, by deploying these insights in payment design, policy makers will improve health care value for patients and purchasers. This paper applies the economic theory of agency  to explicate the probable incentive effects of different models of “value‐based” payment in health care. Those forms of payment include recalibrated fee‐for‐service (FFS), bundled payment, capitation , and shared savings, coupled with adjunct performance incentives for quality and efficiency, including withhold and clawback provisions that shape ultimate incentive effects. “Value” is defined as maximum health benefit at minimum cost, and—operationally—better value translates into a combination of improved health outcomes and processes of care , better patient experience, and reduced costs of care.This paper examines a number of market and nonmarket mechanisms for improving agency and, correspondingly, enhancing the power of value‐based payment. I describe the hierarchy of incentives, the differential power of group and individual incentives, and the importance of aligning external (payer‐to‐provider organization) incentives with intraorganizational provider compensation. The conceptual analysis is joined with targeted, directly relevant empirical evidence to derive a set of research questions and policy recommendations that follow from the theory and extant evidence.This paper is a conceptual exposition of the application of principal–agent theory to medical care, reinforced by evidence relevant to the application of agency theory in designing payment incentives for health care organizations and individual providers. It is not a systematic review, but instead integrates theory with empirical evidence most germane to value‐based payment. As the principal objective of the paper was conceptual, not empirical, my presentation of empirical evidence is necessarily selective, but intended to be a representative sampling of the existing literature.Many of the concepts highlighted in this paper have been introduced previously in the theoretical and empirical literature  the role of loss aversion in reducing the optimal size of penalties and inducing greater participation of risk‐averse providers in two‐sided risk‐sharing contracts; (2) framing incentives as potential gains or losses to overcome status quo bias;Logic for incentive targets primarily based on the individual provider's and the organization's own level of performance rather than peer rankings;Implications of agency theory for design of incentive‐compatible contracts, and, in particular, the need to pay potentially more efficient providers and organizations an “information rent” to encourage them to participate and reveal their underlying efficiency;Use of clawback provisions as an alternative to withholds as adjunct incentives for quality and efficiency;Role of market mechanisms  in shaping the impact of value‐based payment on clinical quality, outcomes, and cost‐efficiency;Effects of ownership and organization structure on value‐based incentive effects.The section on future research questions identifies opportunities to advance knowledge regarding the impacts of value‐based payment incentives. Similarly, the policy recommendations reflect the implications of the author's analysis of theory and evidence relevant to the expected effects of value‐based payment.Agency theory is well suited to contracting and other economic relationships between a principal and the agent(s). This theory can be applied to payment arrangements between the principal  and the agent . Optimal provider payment incentive design seeks to align the principal's and agent's interests.One special feature of health care payment . This term is equivalent to “economic efficiency” or net benefit. As dimensions of health benefit, quality of patient experience and ultimate health outcomes (evidence‐based care processes) are inherently valued, whereas clinical quality (following evidence‐based care processes) is an instrumental value—useful as a means to the end of improved health. A recent systematic review  will be low, and the risk of false positives (rewarding good luck) or false negatives  will be high. One way to mitigate this sample size problem is to lengthen the interval between observation and incentive, but that potentially weakens the timeliness and impact of measurement . Valid, reliable, and timely measurement of each value dimension—costs, clinical quality (process of care), health outcomes, and patient experience—is necessary, but not sufficient, for success of value‐based payment.Tradeoffs in designing value‐based health care provider compensation are more complex. The time lag between ultimate health outcomes and multiple influences  beyond provider control implies that compensating providers on outcomes is potentially unreliable and unfair. This inherent measurement problem works against purely outcome‐based compensation. The asymmetry of quality, outcome, and price information between providers and health plan intermediaries and the patient or enrollee renders compensation based on clinical quality imperfect, but less so in terms of assessing the provider's actual contribution to patient health benefit. Finally, pure FFS payment stimulates quantity of service but fails to capture either quality of care or health outcomes.mixed payment model—based on measures of process quality, health outcomes, and transaction price measures—has the potential to improve the tradeoff between the higher relative measurement costs of paying on the basis of value and the potential patient health benefits of doing so. Optimal payment models will also be context‐dependent: baseline market conditions and structural relationships between purchasers, plans, provider organizations, and patients will vary geographically and over time, thus requiring a different mix of incentive size and structure.As long as measurement of process quality and outcomes is unbiased in its design, and conducted with sufficiently large samples to produce relatively precise estimates of performance, prospects for value‐based payment seem positive. This suggests that a In weighing use of process , patient experience, and health outcomes measures in incentive payment, the payer must balance the measurement costs of each performance attribute with relative benefits in terms of incentive effects on provider and patient behavior. I will argue that clinical quality and patient experience are more controllable by providers and provider organizations and measureable at relatively lower costs than outcomes  and desired provider behavior and outcomes. Relatively stronger value‐based payment incentives will be larger Financial incentive size must account both for the direct incentive effect, which elicits stronger response to those behaviors or outcomes that are relatively more rewarded or penalized relative to the alternative, and for diminishing marginal utility of net income, that is, the diminishing (but still positive) incremental value of net income to the provider. Diminishing marginal utility of net income implies that providers will be risk‐averse and will seek implicit or explicit “insurance” against the possibility of lower than expected net income.Behavioral economics suggests that a penalty of given size for failing to advance health benefit will more strongly encourage providers to deliver improved health than an equally large reward for advancing health benefit. This economic reasoning is supported by experiments in psychology , as well as a certain degree of performance risk .diagnostic and treatment uncertainty, which inherently cannot be diversified away by large numbers; this adds an additional layer of performance risk that suggests caution in implementing risk‐based payment. Provider organizations formed as partnerships, professional service corporations, and subchapter S corporations without outside, nonprovider owners will act as if they are risk‐averse to some extent, absent outside stockholders to diversify organizational risk.A corollary of this logic is that risk‐based payments  to larger provider organizations will be more sustainable, because those organizations will be more able to diversify individual provider‐level actuarial and performance risks. Given the incomplete evidence base for much of medical practice, providers and provider organizations face A fourth factor driving incentive strength is duration and stability of payment arrangements. Microeconomics has established that long‐run price elasticities of supply and demand are both greater in absolute value than the respective short‐run elasticities. In the short run, certain resources are fixed  and this dampens supply response to demand price; similarly, one's knowledge of and the availability of substitutes are limited in the short run, which attenuates demand response to suppliers’ price signals  , thereby reducing asymmetry of information between payer and individual provider or provider organization. Incentive‐compatible contracts between principal and agent must also satisfy the “participation constraint”—that is, to accept the contract, the agent must be at least as well off as under the next best available alternative contract. Thus, the size of payment incentives should be sufficient to yield an expected (but not guaranteed) competitive return on equity to the individual provider or provider organization.The payer's response to these challenges is to fashion a Given incomplete and asymmetric information, the principal's contract with the agent must generally pay an “information rent” to the more efficient agent: the provider with greater skill who can, by definition, produce more of the principal's desired output with less effort. This information rent can be thought of as the excess payment above the efficient provider's marginal cost—to induce that clinician not to pretend to be a less efficient one and to hold out for a higher level of payment. For example, the physician with greater clinical skill will produce improved health outcomes and care processes with less time, effort, and practice inputs than will a less skillful clinician. Thus, higher quality providers will be differentially attracted to value‐based contracts.More efficient providers supply the optimal output desired by the payer; the payer accepts a below‐optimum level of output from less efficient providers.Only the efficient providers capture an excess payment, which equals the difference between the marginal productivity of the efficient and inefficient providers, multiplied by the below‐optimal level of output induced from less efficient providers.Payers face a tradeoff between productive efficiency of, and excess payment to, providers. Optimal contracts under conditions of asymmetric information can be characterized as follows: Another situation emerges wherein the payer decides to “shut down” any contracting with the less efficient providers. In that case, no excess payment is offered to more efficient  providers, but a below‐optimal level of output is supplied, given absence of production by less efficient providers. The payer has traded off some value to reduce the size of payment to higher quality providers. The inefficiency in this case equals the forgone health value and is solely attributable to asymmetry of information between the principal and agents  and provider organizational form . Ownership is an important financial incentive, in that owners capture their share of organization net income and are motivated to pursue maximum profit through cost minimization and strategic pricing. The implication for payers is that not‐for‐profit providers will have weaker incentives than for‐profits to hold out for above‐competitive prices, which will affect the  by Lynk  found th by Lynk  outlinesactuarial risk  and inducing the individual provider and organization to minimize performance risk . Table Organizational form influences incentive design. Guterman et al.  present The basic idea is that small independent medical practices are poorly equipped to bear significant actuarial risk for random variation in health status. Consequently, FFS arrangements will be most feasible for them, potentially tied to adjunct pay‐for‐performance (P4P) incentives based on measures of clinical quality and patient experience, but not to health outcomes or total cost per patient over time—reasoning that the smaller sample size would imply greater random variation in average cost and health outcomes.Put another way, small practices do not benefit from the “law of large numbers.” By the nature of their practice structure, small independent practices face greater costs of coordinating care for patients across different clinical conditions, which militates against placing them at risk for total care costs per person. Thus, risk‐adjusted primary care capitation, including withholds structured to guard against excess specialty referrals plus value‐based adjunct incentives, aligns well for these organizations. Paying single‐specialty groups per episode per referred patient (“contact capitation”) plus adjunct value incentives also discourages excess servicing and encourages value.Building on the base of diagnosis‐related group (DRG) payments, hospitals are poised to move to case rates for episodes of care, joined with adjunct value‐based incentives. Because of scale and internal capacity for cross‐specialty care coordination, larger multispecialty groups, integrated delivery systems, and ACOs are better positioned to accept risk under bundled payment and risk‐adjusted capitation, respectively. Depending on the extent of interpractice coordination of patient care protocols, information systems and contracting (IPAs) also have these capabilities. Ownership and organizational form thus significantly influence payment incentive design and the impact of financial incentives. In addition, market mechanisms also have the potential to significantly improve the agency between payers and their enrollees.Two mechanisms play a particularly important role in more closely aligning interests of payers and health plan enrollees. One is improved, more symmetric information on quality, outcomes, and prices relevant to health plans, their enrollees, and providers. As individual enrollees tend to be at an informational disadvantage relative to both health plans and providers, a health plan that offers publicly available, population‐based information on actual transaction prices , quality, and outcomes effectively narrows the informational gap between enrollees and providers.A second market mechanism—more effective competition within the markets for health care delivery (providers), health insurance (the plans), and integrated health plan‐provider organizations—also would improve agency of those intermediaries on behalf of their patients and enrollees. To the extent individual consumers are less attentive to such information—either because of first‐dollar health insurance benefit designs, loyalty to their current providers, or poor health care literacy—organized purchasers would have an interest in doing this on behalf of their workers, enrollees, and beneficiaries. However, given enrollee turnover and failure to assure uniform and unbiased information disclosure among competing insurers, there is a “public goods”  problem with voluntary disclosure. The insurer disclosing such information may not capture the benefits in cost, quality, or outcomes for the enrollees on whose behalf it originally invested. Similarly, asymmetric or biased information between the plan and its enrollees—by raising consumer search costs among alternative plans—can enhance a given plan's market power.Either government or an otherwise neutral organization is required to design and enforce these price and quality transparency mechanisms. Only government or a quasi‐governmental public–private partnership underpinned by organizational public commitments can monitor and regulate provision of “public goods,” such as common investments in public health information infrastructure; agreements on quality, outcomes, and patient experience measurement; and value‐based payment methods (not levels of payment).State action also has the capacity to create safe harbors (antitrust immunity) for collective agreement on payment method. As Enthoven  has arguA third market mechanism shaping agency is the intermediary role of public purchasers , private insurers, and employer–purchasers relative to their beneficiaries and enrollees. Public purchasers and private insurers will tend implicitly to weigh clinical quality, patient experience, and health outcomes less than direct patient beneficiaries of those components of value, whereas claims costs are a direct hit to public budgets. Moreover, because patients bear directly the opportunity costs of travel time and delays of treatment and enjoy the benefits of positive health outcomes and supportive caring patients, they will place greater weight on quality of experience and health outcomes than their insurer or public purchaser.current employees’ health and health care costs because, in a competitive labor market, improvements in value of employees’ health benefit package will be reflected in lower wage levels than would otherwise be demanded by employees: the employer fixes total compensation level, comprised of wages and employee benefits, so a rise in value of one component leads to a decrease in the other. This “compensating differential” has been demonstrated convincingly in health care  can be altered to influence volume incentives; specifically, if the margin on each service is equal and positive, the potential incentive for providers to “induce” demand for more profitable services is eliminated  schedule could be applied as a baseline for costing units of professional services, for example, for physicians and medical groups.Policy makers should deploy comparative effectiveness research to determine the marginal health benefits of different services. That comparative effectiveness research is directly applicable to VBID and should be deployed beyond the current emphasis on pharmaceuticals. Setting unit prices close to the unit cost of services solves the problem of “demand inducement.”If FFS payments were based on equating marginal expected health benefit with marginal cost per service, the provider would be induced to provide optimal value per service, but not to choose the optimal service mix per episode of illness or over calendar time . In that sense, FFS is best suited to acute, one‐time health problems.Patient copayments through value‐based insurance design (VBID) are unlikely to solve incentive problems with FFS because of the considerable asymmetry of information between providers and patients. Three corollaries emerge from this logic: Bundled, or episode‐based, payment implicitly assumes that the objective of the principal  is to maximize value from health care provision per episode of illness. The payer's definition of episode of care attempts to match the period of care with a clinically accurate period of the actual illness. Bundled payment places providers at risk for efficient care (often termed “performance risk”) of the patient during an episode of care. If the bundle includes multiple providers involved in provision of care during the episode, an added complication is articulating a payment sharing arrangement among the providers. Bundled payment incents cost reduction per episode, but one payer concern would be “unbundling” of care or repeated care episodes , particularly for procedure‐based care, for example, care episodes triggered by hospitalization for surgery. Unbundling might be addressed best by broad definition of an episode that includes preintervention (work‐up), intervention, and postintervention (follow‐up) periods, subject to adjunct incentives for total cost of care (TCOC) savings.To some extent, clinically appropriate classification of the episode adjusts for case mix variation and thus eliminates random, uncompensated variation in actuarial risk  across patients in the provider's panel. Another decision in bundled payment design is the extent to which the expected cost of potentially avoidable complications (PACs) is built into the prospective payment per episode. For example, the PROMETHEUS episode‐based system includes 50 percent of the expected cost of PACs in its prospective rates , places individual providers and provider organizations at greatest risk for cost variation. Providers bear both unit cost and volume risk for number and type of services per episode of care and for number of episodes over time. If better clinical (process) quality and patient experience reduce the number of care episodes and of additional services per episode, capitation offers the strongest positive incentive for health benefit if payments are “risk‐adjusted,” that is, pegged at higher levels for inherently more complex patients. Also, as payment is per person, provider organizations have the strongest incentive to accept more patients under this regime. Capitation is not a strong direct incentive for value unless capitation size is explicitly tied to expected patient health benefit (through risk adjustment and incentives for evidence‐based practice) and offers a large enough margin over cost to induce providers to attract new patients based on value. Use of a P4P quality incentive as an adjunct to the base, risk‐adjusted prospective capitation payment would also mitigate potential stinting in quality of care.Shared savings incentive models typically blend prospective FFS with sharing of retrospective, TCOC savings between payer and provider organization. By sharing in any total cost savings, the payer's intent is to attenuate providers’ potential tendency under FFS to overtreat and overprescribe. The strength of the incentive increases with the provider's share of any retrospective TCOC savings and with the level of TCOC savings expected by the provider. These shared savings models could be one‐sided , or two‐sided (both shared savings and shared downside risk). Schmidt and Emanuel  might be deployed to strengthen incentives for cost‐efficiency, and therefore improved value. Emanuel  delineatGiven the greater power of a loss compared to a gain of equal magnitude  that offers strong incentives for total savings, and to craft a valid and reliable method of attributing patients to the providers accepting payment based on shared savings. Such models assume that shared savings will derive mainly from reduced hospitalization and specialty costs, which are only partially under the control of the referring primary care provider (PCP). Often shared savings targets are tied either to overall PMPM costs in the local market or to those of another comparison group of provider organizations. Accordingly, the power of the shared savings incentive will depend on providers’ perceptions of validity and reliability of patient attribution and of TCOC performance targets.The other major challenge of shared savings models is that the predominant “frame” for payment is FFS, with retrospective “settling up” to determine whether savings have been achieved. Behavioral economics have shown that status quo bias and framing context are crucial determinants of decision making  can be deployed to offset some limitations of FFS as a general method for inducing value improvement. Withhold and “clawback” provisions also can be deployed to encourage value over volume. Withholds can be deployed to incent TCOC savings over the defined period or to return withheld payments in proportion to attainment of prospectively established quality or outcome targets. Clawback provisions retract a portion of previous payments over the performance period, based on retrospective determination of the provider's failure to achieve prospective cost, quality, or outcome objectives.Both provisions shift performance risk to providers; while the withhold's impact is spread over time, clawback provisions are executed only at the end of the performance period. Application of such a provision represents a loss of provider dollars. For payers imposing a clawback to achieve an incentive effect equal to that of a withhold, expected clawback size must balance the present value loss to the payer of deferring the clawback with the greater incentive power of the clawback due to provider loss aversion. While withhold and clawback provisions are generally tied to cost savings, they could be applied to stimulate improvements in care process and patient health outcomes by linkage to clinical performance. In that sense, quality‐ or outcome‐based withholds would be particularly useful adjuncts to episode‐based bundled payment or capitation incentives, for which concerns about stinting of care are more prominent than FFS.Provision of health care is a “team sport” requiring coordination between incentives and behavior of the group (or team) and the individual. Achieving the optimal balance between these incentives requires balancing cooperation and coordination among group members and strong individual‐level incentives. Group incentives are subject to a “public goods” problem: individual members may free‐ride on performance of other group members unless selective, individual‐level performance measures are applied to distribute a share of group incentive payment in proportion to individual provider contribution to the team's production Olson . Extant The weight of evidence and theory supports use of group‐level incentives to build improved information and care management infrastructure, rather than as a motivator for individual clinicians. One upside of group‐level incentives is that the actuarial and performance risk of unmeasured variation across team members in patient case mix and random variation in cost, quality, and outcomes is diversified. This allows the payer to apply stronger incentives dollar‐for‐dollar to risk‐averse providers acting as a group.Evidence from the contracts and labor economics literature strongly suggests that team‐based pay  is associated with lower average productivity and wider variance in output Lazear . While tGroup incentives will be more appropriate and sustainable for members of physician partnerships and integrated medical groups that share revenue, expense, and financial risk and are capable of coordinating patient care and clinical and economic information. IPAs and provider networks might be equally capable of sharing financial risk through value‐based capitation, bundled payment, mixed models, and shared savings. However, potentially higher costs of coordinating care and information among independent practices imply that individual provider‐level incentives will be necessary to augment group incentives. For similar reasons, individual‐level payment incentives should receive greater weight as group size increases  would look like this: severity‐adjusted DRG rates for hospitals and disincentives for readmissions, risk‐adjusted per episode payment to specialty providers (sometimes referred to as “contact capitation”), and salary compensation for PCPs—with all providers sharing in value‐based  incentives.Under health plan, risk‐adjusted capitation payments to an ACO, internal compensation structure for participating specialists, and PCPs, respectively, would be very similar to that for episode of care, bundled payment. The main differences would be that salary compensation for PCPs would include an adjunct incentive for risk‐adjusted panel size.Continued reliance on FFS would defeat movement toward value‐based payment. Consequently, more relevant examples of aligning external plan‐to‐organization payment with internal compensation incentives are those in which health plans are paying the organization on shared savings, bundled payment, or global payment (capitation). The core concept is to match internal compensation structure with external payment methods. Consider the following examples, in ascending order of strength of value‐based, person‐centered internal incentives  are more capable of diversifying population health risk and managing and coordinating the care of populations, which should position them to bear health risk and manage care under high‐powered incentive contracts .As individual providers, whether primary care or nonprimary care specialists, are particularly well‐positioned to influence patient experience, value‐based adjunct compensation incentives should place strong emphasis on patient experience. The experience dimensions of continuity of care, coordination of care, communication with the patient, shared decision making, communication among providers, access, and timeliness merit particular attention.What kind of incentives will work best for ACOs? ACOs are new, “virtual” forms of clinically and economically accountable entities attempting to replicate the cost‐efficiency, care coordination, and clinical quality advantages of vertically integrated, prepaid group practice. Their emergence raises several questions for research: What contract types are best for the ACO as umbrella entity, and which incentives will encourage the most clinically effective and economically efficient performance?Can ACOs borrow from successful practices in group model HMOs that unify the care continuum under one organizational umbrella?What practical incentive strategies will work best to mitigate gaming by different types of organizations? To what extent are regulatory, informational, and organizational designs likely to perform better than incentives in preventing gaming, risk selection, and “teaching to the test”? Regarding the latter, to what extent are high‐powered financial incentives inherently incompatible with building an organizational culture that supports altruism and intrinsic motivation among clinical professionals and other members of the health care team?What payment incentives best promote value and provider participation? Agency theory stresses appropriate design of incentives to solve adverse selection problems due to asymmetric information between patients and providers . Scott et al. , joined with P4P quality and efficiency incentives, replicate the cost‐efficiency of risk‐adjusted capitation, without potential stinting on care?What forms of value‐based contracts might replace the current encounter‐based and cost‐based payment arrangements of rural health clinics and critical access hospitals? Are regionally based ACOs a feasible structure for smaller rural providers to maintain population health collectively with virtual care coordination and health information exchanges? What type of entity is best structured to serve as the ACO's focal organization?What specific variables  explain why certain providers and provider organizations are willing to accept risk‐bearing, value‐based payment, while others prefer FFS? Prendergast  highlighWhat new forms of shared savings arrangements are likely to reduce total costs of care over time?How does “sharing ratio”  affect success of these arrangements in reducing cost without compromising quality? More fundamentally, do shared savings arrangements actually achieve cost reductions, or is the shared saving incentive simply not visible enough at the point of care to influence clinical behavior?Is there a “sweet spot” along the spectrum of risk‐bearing at which the comparative advantage of payers in bearing actuarial risk is balanced with the ability of individual providers and their provider organizations to manage performance risk? What mixed payment schemes would be optimal  achieved significant savings, with little on effect of patient outcomes. Among the others , the Physician Group Practice Demonstration showed little or no effect on Medicare expenditures and small improvement in care processes. Similar results were obtained for the Premier Hospital Quality Incentive Demonstration and the Medicare Home Health Pay for Performance Demonstration  should be fashioned within provider payment arrangements. Well‐designed practical trials and controlled before‐and‐after observational studies of different payment regimes in different settings should be conducted. These studies should evaluate such models as recalibrated FFS, bundled episode‐based payment, risk‐adjusted capitation, and shared savings arrangements in different organizational settings. In spite of the significant resources required to obtain efficient (precise) and unbiased estimates of practice costs, outcomes, and clinical quality, future studies of value‐based payment should incorporate all those metrics to paint a complete picture.Fee‐for‐service payment is likely to continue in the ongoing transition from “volume to value.” In that interim period, I recommend that private and public payers set FFS prices equal to their best estimate of efficient average production costs , including an estimate of the average risk‐adjusted return on equity for the provider.Allowing providers to vary their prices patient‐by‐patient  would be tantamount to price discrimination. Given imperfect competition among providers and asymmetric information between providers and patients regarding price and quality, individualized pricing patient‐by‐patient is inadvisable. In the limit, such “perfect” price discrimination by providers, while theoretically achieving an optimal level of output, would extract all consumer surplus from payers and patients and transfer those dollars to providers. Such a regime would approximate the usual, customary, and reasonable regime of physician pricing that predated the adoption of RBRVS.reference pricing, in which the external payer sets an estimated cost‐based price for the least costly, clinically equivalent service among different treatment options. This approach would require data from comparative effectiveness studies, which Pearson and Bach refer to in their 2010 article as “paying equally for services that provide equivalent results” (p. 1798). They discuss the case of different treatment options for low‐risk prostate cancer. For example, intensity‐modulated radiation therapy was reimbursed by Medicare at $42,000, compared to approximately $10,000 for traditional, three‐dimensional radiation therapy—without evidence regarding the comparative clinical effectiveness or potential toxicities of the alternate treatments (pp. 1799–1800).Instead, I recommend a form of There is no clear‐cut line of demarcation between areas appropriate versus inappropriate for applying strong incentives. Nevertheless, theory and evidence both suggest that small provider organizations are not equipped to assume actuarial risk. Random variation in population health is best borne by insurers. Well‐validated, person‐level health risk adjustment measures are a critical component of value‐based payment, so that all provider organizations are only bearing performance risk. Smaller provider organizations can band together in IPAs for risk contracting and economies of scale in management, information systems, and quality improvement initiatives, but whether such virtual integration can replicate the benefits of vertical integration and unified ownership remains an open question  incentives. The richest source of its explanatory power is focusing attention on the size and form of financial incentives required to induce participation by providers, as well as the elements of incentive contract design that will mitigate supply‐side moral hazard and adverse selection by providers. Future theoretical research and empirical testing should address the forms of per person, per episode, and per service payment and adjunct incentives  that result in superior outcomes and costs of care. Because incentives are not the whole game, future research should also explore the types of performance reporting, incentive measures, and regulatory oversight of market performance generate the best results—and under what circumstances.Mullen and colleagues’ study  of the PStrong pressure should be exerted by purchasers to encourage price and quality transparency and value‐based benefit design, and to eradicate barriers such as outdated, FFS‐based transactional systems and lack of transparency of total expected premium plus out‐of‐pocket costs under different health plans. The reasoning behind this policy recommendation is that strong provider payment incentives—absent supporting moves to reduce opacity of price, quality, and outcomes data and to align benefit design with value—are unlikely to achieve their full potential in improving value for patients .Deriving valid and reliable measures of value—a necessary antecedent to implementing value‐based payment—requires continued public investment of resources, especially given the public goods nature of information. Metrics developed by HEDIS, ongoing efforts at development of consensus quality and outcome measures by the National Quality Forum, patient experience survey items imbedded in CG‐CAHPS and other data collection metrics should be integrated within a broad national strategy for value‐based payment, underpinned by a scientific and professional consensus. Coordinated and sustained value‐based measurement and payment by CMS, the Veterans Health Administration, and the military health system, acting as “first movers,” can generate sufficient momentum to achieve consensus on value‐based payment and overcome inertia favoring volume‐based incentives.Finally, targeted public and private investment in technologies and systems required to integrate information and achieve interoperability among disparate health information systems is an absolute requisite for enabling value‐based payment incentives to be translated into action along the continuum of patient care. Current stages of meaningful use in electronic health record incentives and certification provide a useful policy implementation framework for information support needed to drive value‐based payment: data capture and sharing, advancing clinical processes, and improving outcomes. Real‐time, clinically and managerially actionable data at these three levels of utility would create a technical platform for value‐based payment and care. Without fundamental change in health information technology that unifies clinical and economic data for use at the point of care, value‐based payment will be limited to marginal adjustments to a FFS, encounter‐driven health care system.


Inbreeding depression  has long been a major focus of ecology, evolution, and conservation biology. Despite decades of research, we still have a limited understanding of the strength, underlying genetic mechanisms, and demographic consequences of inbreeding depression in the wild. Studying inbreeding depression in natural populations has been hampered by the inability to precisely measure individual inbreeding. Fortunately, the rapidly increasing availability of high‐throughput sequencing data means it is now feasible to measure the inbreeding of any individual with high precision. Here, we review how genomic data are advancing our understanding of inbreeding depression in the wild. Recent results show that individual inbreeding and inbreeding depression can be measured more precisely with genomic data than via traditional pedigree analysis. Additionally, the availability of genomic data has made it possible to pinpoint loci with large effects contributing to inbreeding depression in wild populations, although this will continue to be a challenging task in many study systems due to low statistical power. Now that reliably measuring individual inbreeding is no longer a limitation, a major focus of future studies should be to more accurately quantify effects of inbreeding depression on population growth and viability. IBD chrg generations ago are exponentially distributed with mean (100/2 g) cM  of the two homologous copies of DNA within an IBD chromosome segment.The length of IBD chromosome segments is strongly influenced by the number of generations separating the inbred individual from the common parental ancestor(s). Inbreeding due to recent ancestors usually generates quite long IBD chromosome segments, whereas IBD segments deriving from more distant ancestors tend to be shorter on average because of a greater number of meioses, and recombination events, separating the inbred individual from the parental ancestor Fig. . The mapith mean 00/2 g cMF relative to FP, and (iii) mapping loci responsible for inbreeding depression and how such approaches may be applied in natural populations. Throughout, we highlight the opportunities and challenges that genomics provides for the study of inbreeding and inbreeding depression in the wild.Given the rapid growth of genomic resources available for studies of nonmodel organisms, now is an excellent time to appraise the future prospects for molecular genetic‐ and pedigree‐based studies of inbreeding and inbreeding depression in the wild. Here, we review recent developments in (i) how the availability of large‐scale genomic data has led to a change in the way individual inbreeding is defined, (ii) the performance of molecular marker‐based measures of 2FP. Note that there are other definitions of inbreeding, and there has been considerable and persistent confusion in the interpretation of inbreeding coefficients  . Inbreeding arising from within‐population genetic drift and differentiation among subpopulations in the classic “infinite island” model of gene flow is quantified by Wright's FST is rarely useful in practice. First, high FST can result from rapid genetic differentiation among populations with very small Ne , or as a result of genetic drift over very long time spans among genetically diverse populations with large Ne and very little individual inbreeding arising from recent ancestors. Additionally, the assumptions of the infinite island model  are usually violated in real populations.Inferring the extent of individual inbreeding from FIS and FST requires careful definition of the base population. Estimates of individual genetic variation based on genomewide heterozygosity or ROH are much more informative of the extent of individual inbreeding than the population F‐statistics FIS and FST . An additional problem with defining individual inbreeding relative to a pedigree is that F can vary substantially among individuals with identical pedigrees because of the effects of linkage  is the most appropriate parameter for studies of inbreeding depression  for homologous loci across an individual's genome  is to define individual inbreeding parametrically in terms of the genomewide distribution of the TMRCA, an approach where it is unnecessary to categorize loci as being IBD or non‐IBD  are likely to miss many recent ancestors that contribute to contemporary inbreeding. Behavioral and molecular genetic data collected over long periods of time can be used to construct multigeneration pedigrees , which is calculated as the proportion of genotyped loci that are heterozygous , which is a function of F and the heterozygosity of noninbred individuals (H0): H = H0(1 − F)  ), with low values of r often interpreted as imprecision of MLH as a measure of individual inbreeding. However, r is expected to be less than the correlation between MLH and F ) because FP is really only an imprecise (and downwardly biased) measure of F.The availability of genomic resources and increasing recognition that F with essentially no error because an individual can in principle be scored as heterozygous or homozygous at nearly every position in the genome. Once genome resequencing becomes commonplace in studies of natural populations, it will clearly be unnecessary to construct pedigrees in order to study inbreeding and inbreeding depression. Studies based on genome resequencing of relatively large samples of individuals in natural populations are beginning to emerge  was more strongly correlated with FROH and two heterozygosity‐based measures of F than with FP calculated from five‐generation pedigrees in simulations meant to represent human populations. Kardos, Luikart, et al. , both in species with low and relatively high recombination rates (0.27 and 1.2 cM/Mb). For example, F was in some cases more strongly correlated with MLH measured with as few as 1,000 SNPs than with FP measured with twenty‐generation pedigrees  and a fitness component (w) is  and found that fitness traits tended to be more strongly correlated with heterozygosity at 11 microsatellites and at >1,300 SNPs than with FP, particularly when excluding highly inbred individuals (FP > 0.15) from the analysis. Huisman et al. (Cervus elaphus) that six fitness components were significantly associated with Fgrm , while only three fitness components were associated with FP. Pryce et al.  than when using FP as a measure of F. Bérénos et al. . Researchers can then determine whether actual genomewide heterozygosity (measured with the whole genome) and fitness components are most strongly associated with FP, or with marker‐based measures of F based on different numbers of loci sampled from throughout the genome.Resequencing the genomes of many individuals in wild pedigreed populations will provide perhaps the best opportunity to empirically evaluate the performance of pedigrees and molecular markers in estimating 3.8F, but this development has not changed the general approach to estimating effects of F on fitness components. The classical approach to estimate the strength of inbreeding depression is to perform a linear regression with a fitness component as the response, and FP as the predictor  has dramatically improved our ability to precisely measure Phoca vitulina) that the deviance in parasite infection explained by heterozygosity increased by nearly fivefold (to 49%) when >14,000 SNPs were used compared to when only 27 microsatellite loci were analyzed. Inbreeding depression also appeared to be very strong in red deer, with lifetime breeding success  reduced by 72% and 95%  among individuals with Fgrm = 0.125 compared to individuals with Fgrm = 0  < 1/2Ne, where h is the dominance coefficient, García‐Dorado, F is high can be accomplished by detecting populations with low mean genomewide heterozygosity. This approach is possible because the major effect of individual inbreeding is increased offspring homozygosity  typed in 30 individuals is sufficient to clearly differentiate populations with high versus low mean F  across populations.Mean genomewide heterozygosity among individuals within a population can be estimated precisely by genotyping a modest number of loci spread throughout the genome on a surprisingly small number of individuals  and in populations that have been small for a long time. The mean heterozygosity (and mean F) in a population is determined by the long‐term harmonic mean inbreeding effective population size (NeI)  methods  using large‐scale SNP or whole‐genome resequencing data  via quantitative trait locus mapping  or complex (i.e. governed by variation at multiple loci). For example, loci responsible for simple, recessive, monogenic diseases have been mapped in humans and livestock using homozygosity mapping  occurred at a frequency of 0.25 in affected families, consistent with the phenotype being caused by a single deleterious recessive allele. These are two examples of traits where homozygosity mapping based on a high‐density SNP array or whole‐genome resequencing could be helpful in efforts to localize the causal mutation, facilitating genetic management via identification of carriers. Kijas  can be identified via genomewide association (GWA) mapping of ROH with traits of interest—an approach that does not assume monogenic inheritance. This method involves identifying associations between trait values and the incidence of ROH across the genome and has been applied in studies of humans and livestock  being analyzed. For example, Keller et al.  used GWAAn important caveat regarding GWA approaches is that statistical power may be very low to identify loci contributing to inbreeding depression. Even whole‐genome resequencing and/or very large sample sizes do not ensure that any of the loci contributing to phenotypic variation will be detected via traditional GWA analyses , thus increasing the power to identify deleterious recessive alleles with large effects via GWA mapping.The ability to identify loci contributing to inbreeding depression via GWA association mapping will clearly depend on the allele frequencies and the magnitude of fitness effects at the causal loci. Deleterious alleles are expected to be initially rare. GWA mapping based on samples of unrelated individuals is likely to have low power when the causal deleterious recessive alleles occur at low frequencies because there will be few individuals affected by the causal allele. However, deleterious recessive alleles with large effects could reach high frequencies due to strong genetic drift in populations with very small Eucalyptus grandis progeny produced by self‐fertilization of a single individual that was heterozygous at 9,590 genes. Fifty percent of progeny are expected to be heterozygous at each locus that was heterozygous in the parent. However, heterozygosity was much higher—65.5% on average—suggesting very strong selection  against homozygotes. They identified six regions (up to 25 Mb in length) where one of the possible homozygotes was completely missing, which suggests that the missing haplotypes contained highly deleterious recessive alleles. A similar approach could be taken on progeny from a large number of parents in natural or seminatural experiments. Such studies would be enormously helpful for quantifying the frequency of highly deleterious alleles for viability in natural populations, and the variation in the strength of inbreeding depression among the offspring of selfing parents.Examining genomewide patterns of genetic variation in progeny produced by self‐fertilization can be used to test for inbreeding depression, and to identify genomic regions likely to contain large‐effect deleterious recessive alleles. Hedrick, Hellsten, and Grattapaglia  examined5.2A major focus in the study of inbreeding depression in model organisms has been to determine the relative contribution of heterozygous advantage  versus deleterious recessive alleles. The availability of large numbers of mapped genetic markers for nonmodel species will enable tests for evidence of heterozygous advantage in natural populations. However, it will be difficult to definitively exclude pseudo‐overdominance  as the underlying cause of apparent signatures of heterozygous advantage  using algorithms implemented in software such as PROVEAN  can still be used to estimate F and to detect inbreeding depression. However, the results of studies of inbreeding depression based on FP and small sets of markers should be cautiously interpreted considering that statistical power to detect inbreeding depression is likely to be low and that estimates of the effect sizes of inbreeding depression (i.e. proportion of variance in fitness explained by inbreeding) may be downwardly biased. Recent results from simulations (Kardos, Luikart, et al., F.Both 7F with far greater precision than was previously possible with only a handful of genetic markers or even with extensive pedigrees. This advancement could fundamentally change our understanding of inbreeding depression in the wild. The availability of genomic data means it is no longer necessary to construct pedigrees to study inbreeding depression in natural populations. Dramatically increased precision of estimates of genomewide heterozygosity and F based on large‐scale genomic data (Kardos, Luikart, et al., FP and genomic measures of F.Genomic data make it possible to measure F for many individuals. Because F can now be measured precisely for any individual, collecting data on enough fitness components from large numbers of individuals has become the biggest roadblock to a comprehensive understanding of the effects of inbreeding on individual fitness and population growth and viability. Thus, long‐term studies of natural populations still represent the greatest opportunity to further our understanding of the causes and consequences of inbreeding depression in the wild.A major priority for conservation biology is to more fully understand the effects of individual inbreeding on population growth and viability. Although it is clear that inbreeding depression is universal, there is still an insufficient understanding of the magnitude of the effects of inbreeding on individual fitness and, more importantly, on population growth and viability in natural populations (Allendorf et al., Simulation scripts for R are available in the Supporting Information. Click here for additional data file. Click here for additional data file. Click here for additional data file.


RNA sequencing to examine the transcriptional basis of temperature tolerance for round and tubenose goby, two nonindigenous fish species that differ dramatically in the extent of their Great Lakes invasions despite similar invasion dates. We used generalized linear models of read count data to compare gene transcription responses of organisms exposed to increased and decreased water temperature from those at ambient conditions. We identify greater response in the magnitude of transcriptional changes for the more successful round goby compared with the less successful tubenose goby. Round goby transcriptional responses reflect alteration of biological function consistent with adaptive responses to maintain or regain homeostatic function in other species. In contrast, tubenose goby transcription patterns indicate a response to stressful conditions, but the pattern of change in biological functions does not match those expected for a return to homeostatic status. Transcriptional plasticity plays an important role in the acute thermal tolerance for these species; however, the impaired response to stress we demonstrate in the tubenose goby may contribute to their limited invasion success relative to the round goby. Transcriptional profiling allows the simultaneous assessment of the magnitude of transcriptional response as well as the biological functions involved in the response to environmental stress and is thus a valuable approach for evaluating invasion potential.Phenotypic plasticity buffers organisms from environmental change and is hypothesized to aid the initial establishment of nonindigenous species in novel environments and postestablishment range expansion. The genetic mechanisms that underpin phenotypically plastic traits are generally poorly characterized; however, there is strong evidence that modulation of gene transcription is an important component of these responses. Here, we use  These species were both first detected in North America in the St. Clair River in 1990  following the manufacturer's protocol. RNA was dissolved in sterile water and treated with TURBO™ DNase  to remove genomic DNA contamination. RNA quality was assessed using the Eukaryotic RNA 6000 Nano assay on a 2100 Bioanalyzer . Only samples with an RIN > 7 and a 28S:18S rRNA ratio >1.0 were used to prepare sequencing libraries. RNA sequencing libraries  were prepared and sequenced at the McGill University and Genome Quebec Innovation Centre  using the TruSeq stranded mRNA library protocol and 100‐bp paired‐end sequencing in two lanes of an Illumina HiSeq 2000 sequencer .RNA was extracted from liver tissue using TRIzolRaw reads were pooled by species and de novo transcriptome assemblies were created for each species of goby using Trinity v3.0.3 . The second set of analyses focused on the function of responding genes, and whether genes with plastic responses to environmental perturbations represented relevant and coordinated biological functions for dealing with the temperature stress or random transcriptional changes lacking directed biological function.2.2.1p‐values for multiple comparisons  to identify differentially expressed genes in response to each temperature challenge for each species of goby separately. Negative binomial GLMs were implemented using the “edgeR” v3.8.6 package  and downregulated (negative Log2 fold change) genes separately in each treatment using nonparametric Wilcoxon rank‐sum tests in R v3.1.3  for response, we first compared the distribution of Log2 fold changes to temperature in each challenge (Log2 fold change from species‐specific one‐way GLMs above). We included only orthologous genes identified as statistically significantly responding to temperature challenge based on the two‐factor GLMs. Here, we analyzed the paired comparison of Log2 fold changes between the two species of goby for upregulated and downregulated genes separately in each treatment with Wilcoxon signed‐rank tests, a nonparametric analog of a paired t‐test.To further facilitate comparison of gene transcription variation between species and allow combining the species‐specific datasets, we identified putative orthologous genes using reciprocal best blast hits for round goby and tubenose goby transcripts using the blastn algorithm from BLAST+ v2.19 , Sj represents the effect of species, Iij the species × temperature interaction, and eijk the residual error. Genes exhibiting a species‐by‐treatment interaction could reflect transcriptional response capacity possessed or utilized by one species but not the other and may thus be the basis of differential invasion success. Additionally, maintenance of biological function may be more transcriptionally demanding and the scope for response may be limited due to higher levels of constitutive transcription for genes in one species. To assess this, we identified orthologous genes that were statistically significantly differentially transcribed between species based on the likelihood ratio test for the species term from the two‐factor GLMs. We then used the Log2 fold change associated with statistically significant genes to assess the magnitude that one species over‐transcribed a gene relative to the other. In this context, positive fold changes indicated genes consistently transcribed higher by tubenose goby irrespective of temperature treatment and negative fold changes indicated genes consistently transcribed higher by round goby. Wilcoxon rank‐sum tests were used to test for a difference between round and tubenose goby in the magnitude of over transcription between the two species. For this analysis, we only considered genes significantly differently transcribed between species and not exhibiting an interaction effect.We then combined the raw gene transcription count data from both species for genes that were putatively orthologous and tested for species differences in transcription at the shared expressed genes using two‐factor GLMs for each temperature challenge. The two‐factor negative binomial GLMs were implemented in “edgeR,” with gene‐specific dispersion parameters estimated as described above, using the following model:2.3http://www.ncbi.nlm.nih.gov) using the blastx algorithm from BLAST+ v2.19  gene orthologs with a significant species‐by‐temperature interaction effect in the high‐temperature treatment and 823 (7.3%) gene orthologs in the cold temperature treatment. Functional annotation was available for 44 gene orthologs demonstrating a significant interaction in the high‐temperature treatment and 560 gene orthologs in the cold temperature treatment. The only biological process significantly over‐represented by any of these responses was present in response to cold temperature challenge and was for genes involved in steroid hormone‐mediated signaling  and 3,441 genes (50.7%) transcribed at a higher level in round goby (mean Log2 fold difference: 1.08). There is a significant difference in the magnitude of differential transcription between goby species . The genes that tubenose goby over‐transcribes relative to round goby are over‐transcribed to a greater degree than the genes that round goby over‐transcribes relative to tubenose goby  of them are significantly differently transcribed between the two species. These represent 3,346 genes (49.3%) transcribed at a higher level in tubenose goby , most of which were related to cell cycle, DNA replication, and cell division  mostly involved in rRNA and tRNA metabolic processes and tRNA activation , including carboxylic acid metabolic processes typical of phospholipid membrane alterations, transport of basic amino acids (arginine and lysine), and biosynthesis of carbohydrates typical of antifreeze functions, negative regulation of apoptosis, and proteosomal activity characteristic of targeted degradation or turnover of proteins  in response to decreased temperature, but with very different functional implications. The majority of upregulated processes were response to stimulus processes indicative of detection of stimulus, cell signaling cascades, regulation of gene expression, and immune system processes  within the significantly up‐ and downregulated genes separately in each temperature treatment  implies a reduced capacity to acclimate to a broad range of environments and may have limited the range expansion of tubenose goby. Indeed, Antarctic fishes that have evolved in very stable environments have completely lost a heat shock response (for a review, see: Logan & Buckley, In addition to increased capacity for transcriptional plasticity, the transcriptional changes exhibited by round goby are more consistent with adaptive responses to thermal challenge than those observed in the tubenose goby. Round goby altered biological processes that are characteristic of acute responses to temperature reported in other species with broad thermal tolerance (e.g., ubiquitin‐dependent protein degradation and negative regulation of apoptosis; Logan & Somero, The reduced scope of transcriptional response of tubenose goby suggests either that it lacked the biological mechanisms to respond to acute thermal stress or that tubenose goby found the handling procedures stressful and thus suffered reduced capacity to respond to the heat stress. While we could have conducted a laboratory acclimation experiment to isolate temperature as the sole factor driving transcriptional changes in our gobies, temperature is not the only environmental stressor encountered by these organisms. We provide a comparison of transcriptional response to temperature stressors that reflects the organisms' ecological context while controlling for prior environmental exposure by sampling these organisms from the same habitat at the same time. Presumably, sensitivity to the synergistic effects of multiple stressors expressed as a reduction in a potential aquatic invader's transcriptional capacity would not be adaptive for the invading species. Our use of three biological replicates has the potential to result in inflated variance estimates that inhibit our ability to detect more subtle differential expression; thus, our list of differentially transcribed genes should be considered conservative. Despite this limitation, we have characterized hundreds to thousands of differentially transcribed genes in each treatment Table  and our The process of invasion or range expansion often results in genetic founder effects and bottlenecks (Dlugosch & Parker, The lower transcriptional plasticity we found in the tubenose goby may reflect source population characteristics if selection pressures among assemblages of tubenose goby in their native range resulted in local adaptation, while the round goby in their native range are one broadly tolerant species. Round goby is known to exhibit broad environmental tolerance to other abiotic stressors, including salinity (Karsiotis, Pierce, Brown, & Stepien, There has been a tendency for invasion biologists to treat organisms as static entities and ignore the role of plasticity and evolution in determining invasion risk (Whitney & Gabler, https://doi.org/10.5061/dryad.408ht.Raw sequencing data for both species are available at the NCBI Sequence Read Archive under project accession numbers SRP075124 and SRP075141. Scripts used to process raw data, assemble the transcriptome, and generate the count data file as well as the count data file and R scripts used to perform the differential expression analysis are available on Dryad:  Click here for additional data file. Click here for additional data file.


High‐quality reporting of outbreak characteristics is fundamental to understand the behaviour of various strains of influenza virus and the impact of outbreak management strategies. However, few studies have systematically evaluated the quality of outbreak reporting.STROBE statement, and to examine characteristics associated with reporting quality.To conduct a systematic analysis and assessment for reporting quality of influenza outbreaks based on a modified version of the MEDLINE) for reports of influenza outbreaks . The quality of reports meeting our eligibility criteria was assessed using the Modified STROBE criteria and assigned a score of 30. Mean differences (MD) and 95% confidence intervals (CI) were reported for comparisons of study characteristics.A literature search was conducted across 3 online databases . Likewise, reports from authors affiliated with public health agencies were associated with better quality than those from academic institutions .Sixty‐four outbreak reports were available for analyses. The average Modified The development of explicit reporting guidelines specifically geared towards reporting of outbreak investigations proved to be useful. Providing information on patient characteristics, investigation details in introduction and results, as well as addressing limitations that could have biased the findings, were frequently missing in the published reports. However, due to literature including zoonotic diseases , investigations involving animal sources transmitting influenza virus to humans were eligible. We limited reports to those that at least described one or more of the following: onset of outbreak, clinical manifestations, control measures or specific diagnostic testing. Studies that evaluated surveillance systems or developed transmission models were not eligible for inclusion. We also excluded studies that did not provide a descriptive detailed account of individual outbreaks, such as annual surveillance reports.2.2Only English language papers were included.We searched PubMed, Web of Science and MEDLINE for reports published from 2000 to October 2015 using a basic combination of keywords and subject headings Figure . Our goa2.3To capture the key elements of outbreak reporting and enable effective assessment of reporting quality, we made several modifications to the original STROBE 2.4A potential association with the quality of reporting  was assessed for 7 variables: publication year, continent of outbreak, influenza strain, outbreak size, outbreak settings, author affiliation  and publication type (peer‐reviewed vs epidemiologic report). The predictor variables were selected a priori. We examined publications prior to and after 2009 on the basis of 2009 H1N1 pandemic given the large number of articles that followed the pandemic. Similarly, we sought to see differences by H1N1 vs seasonal or avian influenza. As STROBE  was developed in North America and Europe, we wanted to assess differences between these and other regions. We included outbreak size to assess differences between small  vs larger outbreaks that may have national teams involved. We were interested in seeing whether hospital staff fared differently in reporting compared to the community. Along a similar line, we wanted to see whether public health officials reported better/worse compared to academics. We expected better reporting with peer‐reviewed publications so aimed to assess this as well.P‐value of <.10 in the univariate analysis were included in the multivariate model. We chose the P < .10 threshold to maintain a balance between screening predictive factors for multivariate analysis but also ensuring adequate exclusion for factors deemed limited correlation with differences in quality scores. All statistical analyses were conducted using SPSS/PASW Version 18 . In the event that the investigation report involved both academic and public health institutions, the corresponding author of the report was used to determine author affiliation.Covariates with a 3A total of 64 of 174 37%) studies reviewed in full text met our eligibility criteria and underwent assessment for the quality of reporting.% studies3.1SD) ± 3.6) of 30. All studies provided scientific background and context to the reported outbreak (Item 2A) and quantitative data on affected patients/reported outbreaks (2C) (Table The mean Modified STROBE score of included studies was 20.0 (standard deviation (C) Table . SimilarC) Table . Sensiti3.2P = .010). Forty‐nine reports (77%) were peer‐reviewed publications. We found significantly higher scores with reports published in peer‐reviewed journals as opposed to public health epidemiologic reports . The remaining 5 predictors were not found to be significantly predictive for higher Modified STROBE scores  were published from 2009 and after. These reports had significantly higher Modified STROBE scores than those published prior to 2009  remained a significant predictor for higher Modified STROBE scores. While not associated with reporting quality in univariate analysis, affiliation with public health institutions (P = .035) was associated with significantly higher scores in the multivariate analysis. Meanwhile, the quality of reports published after 2009 was no longer significantly better than the quality of older reports (P = .076).In the multivariate model, only 4 covariates were retained as per our analysis plan: publication type, author affiliation, publication year and outbreak size. Peer‐reviewed journals  received greater attention and were reported in higher‐impact journals that would typically put more emphasis on appropriate reporting. This is in contrast to, for example, a school‐based outbreak that spanned several days and then posted in an epidemiologic journal as a brief weekly update. Reports by public health‐affiliated authors were superior in quality to those from academic institutions when included in our multivariate analysis, but not when assessed as an independent predictor. Although we referred to corresponding author's affiliation if an article had both academic and public health institutions, extensive resources for outbreak reporting and epidemiologic guidelines are likely to be consulted amongst authors regardless of institutional affiliation. With respect to our multivariate results, significantly greater scores could be related to the fact that >80% of our reports (53/64) involved help from public health authorities . Experts from these organizations are well versed in surveillance standards established by their affiliated organizations, for instance with extensive guidelines detailing the core concepts of surveillance systems and strategies to devise effective documentation of outbreak patterns.The quality of reports that have been published since 2009 was found to be higher compared to older reports in univariate, but not in the multivariate analysis. This may be related to the fact that our sample of publications since 2009 was more likely to be reported in peer‐reviewed journals  and involving investigators with public health affiliation . It is likely that this was an important source of confounding which was subsequently accounted for in our multivariate analysis. Furthermore, standardized methodology for transparent reporting has been available for outbreaks report and similar epidemiologic studies A possible explanation for similar scores in different geographic regions could be that there were no clear differences in terms of reporting protocol across international settings. Even for outbreaks outside of North America and Europe, investigators could have originated or trained from similar public health organizations  and hence proceed the investigation with limited deviations to their guidelines regardless of location. This is supported by several publications in the “non‐North American, non‐European” group which involved institutions such as WHO and CDC.We believe that our tool may be applicable to outbreaks of other respiratory viruses and pathogens. Further applications of our modified assessment tool will help determine its generalizability to other pathogens and outbreak settings as the scope of this study was limited to influenza outbreaks that were reported in English and may not be a collective representation of outbreak populations. Furthermore, our a priori criterion for differentiating affiliation (based on first/corresponding author) may not be exact enough in defining publications where authors were affiliated with both academic and public health institutions, and hence mutual exclusivity between comparison groups could not be established; this was supported by 8 of 19 publications in our “academic institution” group.Strengths of this review included a comprehensive search strategy, along with the incorporation of assessment criteria based on established grading tools for observational studies.In conclusion, development of explicit reporting guidelines specifically geared towards publication of outbreak investigations might be useful, given there were low to moderate (<70%) rates of reports providing information on patient characteristics, investigation details in crucial parts of the report  and in addressing limitations that could bias findings. If appropriately reported, evidence from outbreak reports can help in the management of similar outbreaks in the future and are as such an important tool for public health officials, hospital epidemiologists and other health professionals managing outbreaks.CKL, ML and DM drafted the protocol and collaboratively made modifications to the assessment tool (Modified STROBE). CKL conducted the literature search, reviewed articles for eligibility and computed individual scores for each report. All authors contributing to reviewing and finalizing specific components of the aforementioned steps. CKL conducted the data analysis and interpretation. DM and ML provided feedback on the interpretation of data. CKL, DM and ML drafted the manuscript. All authors critically reviewed the manuscript content and provided final approval of the version to publish.The authors have no competing interests. Click here for additional data file.


ART) in the “Treat All” era, there has been increasing emphasis on using differentiated models of HIV service delivery. The gaps within the clinical cascade for mothers and their infants suggest that current service delivery models are not meeting families' needs and prompt re‐consideration of how services are provided. This article will explore considerations for differentiated care and encourage the ongoing increase of ART coverage through innovative strategies while also addressing the unique needs of mothers and infants.With the rapid scale‐up of antiretroviral treatment (HIV diagnosis is a critical aspect of determining eligibility. Women newly diagnosed with HIV require a more intensive approach so that adequate counselling and monitoring of ART initiation and response can be provided. Women already on ART with evidence of virologic failure are also at high risk of transmitting HIV to their infants and require close follow‐up. However, women stable on ART with a suppressed viral load before conception have a very low likelihood of HIV transmission and thus are strong candidates for multi‐month ART dispensing, community‐based distribution of ART, adherence clubs, community adherence support groups and longer intervals between clinical visits. A number of other factors should be considered when defining eligibility of mothers and infants for differentiated care, including location of services, viral load monitoring and duration on ART. To provide differentiated care that is client‐centred and driven while encompassing a family‐based approach, it will be critical to engage mothers, families and communities in models that will optimize client satisfaction, retention in care and quality of services.Service delivery models should recognize that the timing of the mother's HIV incidence, and aspirations for sustainability, it is critical to consider efficient, customized and cost‐effective models of care for these populations as we aspire to eliminate mother‐to‐child transmission of HIV.Differentiated care for mothers and infants represents an opportunity to provide client‐centred care that reduces the burden on clients and health systems while improving the quality and uptake of services for families. However, with decreasing funding, stable  The intent of this differentiation is several‐fold: to improve client satisfaction and health outcomes, decrease the burden on congested health systems, reduce costs incurred by clients and health facilities, and develop more sustainable HIV programmes With the global expansion of “Option B+” for prevention of mother‐to‐child HIV transmission (PMTCT) and “Treat All” policies for people living with HIV, the number of women on ART in resource‐constrained settings has increased substantially; as a result, in many countries, at least half of HIV‐infected women presenting to antenatal (ANC) care know their HIV status and are stable on first‐line ART. Among these, the vast majority are virally suppressed 22.1In an effort to provide a more nuanced approach to differentiated care, the large umbrella term of “HIV‐infected pregnant and breastfeeding women” should be explored in greater detail. This dyad should not be grouped together and deemed inherently “unstable” in all contexts and circumstances. As the pregnancy and breastfeeding period can extend nearly three years in resource‐constrained settings, many women and infants will have prolonged periods of restricted access to differentiated care models with this approach, especially in areas of high fertility.Service delivery models should recognize that the timing of the mother's HIV diagnosis is a critical aspect of determining eligibility for differentiated care. Women newly diagnosed with HIV during ANC, delivery or breastfeeding inherently require a more intensive approach so that adequate counselling and monitoring of ART initiation and response can be provided. Women on ART with evidence of virologic failure are also at high risk of transmitting HIV to their infants and require close follow‐up, especially since infants require enhanced prophylaxis per the 2016 WHO guidelines A number of factors should be considered when defining eligibility of PBFW and infants for differentiated care. One consideration is the location of ANC and HIV services. Ideally, PBFW have access to an integrated, “one‐stop shop” model, but for women already on ART at pregnancy, providing ANC services in ART clinics is not the norm in resource‐constrained settings. HIV providers in ART clinics are rarely trained to provide routine obstetric care, so women are often referred to ANC for services, including HIV care and treatment. While this approach is still somewhat integrated, PBFW lose their “home” ART clinic and must temporarily re‐establish care in a different setting with a different provider. Although some PBFW may prefer this approach, it can be advantageous to keep stable PBFW on ART in their “home” clinic during pregnancy. It is recommended that if stable PBFW on ART are enrolled and choose to remain in a differentiated care model, they should be allowed to do so while still attending ANC services Another key factor in differentiated care for PBFW is access to HIV viral load monitoring. PBFW should be prioritized for viral load monitoring so that viraemia can be identified and acted upon quickly to prevent HIV transmission. By using viral load criteria to define stability, provider attention can be focused on PBFW with higher risk of transmission . In settings where viral load monitoring is not available, special consideration can be given to women with rising or stable CD4 per WHO guidelines, although such immunologic criteria are inferior and all efforts should be focused on providing the gold standard viral load monitoring WHO recommends at least 12 months on ART for non‐pregnant adults before being considered “stable” 2.2Although there is encouraging anecdotal evidence supporting inclusion of PBFW in differentiated care, there is limited experience and data. In Cote d'Ivoire, integration of ANC and postnatal care services at the ART clinic for women who become pregnant while on ART resulted in improved post‐partum retention and reduced mother‐to‐child transmission of HIV at six weeks after birth To provide differentiated care that is client‐centred and driven, it will be critical to engage mothers and communities in models that will optimize client satisfaction, retention in care and quality of services. Each country context and setting will vary, and multiple models may be needed within communities to address the diverse needs of PBFW and their infants. When developing local solutions and models, input on these issues can be obtained by leveraging existing community and peer support networks such as lay counsellors, mentor mothers and mother‐to‐mother networks 3Differentiated care for PBFW and their infants represents an opportunity to provide client‐centred care that reduces the burden on clients and health systems while improving the quality of care and uptake of services. It is also important to recognize that differentiated care will allow healthcare providers to focus their time on mother‐infant pairs requiring more attention and support. Although the PMTCT cascade is complex, building sustainable long‐term models will provide a solid foundation for efforts to improve the health of mothers and families and eliminate mother‐to‐child transmission of HIV. PMTCT programmes will continue to expand as HIV testing and treatment become more widespread in the era of 90‐90‐90. However, with decreased funding, stable incidence, and aspirations for sustainability, it is critical to consider efficient, customized, and cost‐effective models of care for these populations as we aspire to eliminate maternal‐to‐child transmission of HIV.The authors declare that they have no competing interests.BRP and SM conceived the topic for the commentary. MS, DS and LNB developed the initial outline and draft. All authors reviewed and provided revisions to the draft. MS incorporated revisions and coordinated approval from all authors prior to submission.This publication was supported by the U.S. President's Emergency Plan for AIDS Relief through the U.S. Agency for International Development and the U.S. Centers for Disease Control and Prevention.The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of participating federal agencies, including the U.S. Agency for International Development and the U.S. Centers for Disease Control and Prevention.