Direct Treatment Effects Research Articles

Topical Nasal Steroids for Allergic Rhinitis in Children. Is One Better Than the Others? Protocol for a Systematic Review and Network Meta-analysis.

Background The present protocol is registered in the International Prospective Register of Systematic Reviews PROSPERO under de ID code CRD42023476313, and adheres the PRISMA-P 2015 statement. The complete checklist can be consulted in the extended data section. Allergic Rhinitis (AR) is the most common chronic disease in children worldwide. According to many guidelines topical nasal steroids (TNS) are the first-line treatment for moderate/severe AR in children, nevertheless there is no conclusive evidence about which of them is superior in terms of efficacy and safety, including their impact on child’s growth. Methods We will conduct a systematic review of randomized controlled trials evaluating TNS in the treatment of children with moderate/severe AR. The primary outcome is the efficacy measured with the Total Nasal Symptom Severity Score (TNSS). Secondary outcomes are quality of life, adverse events (AE), and growth velocity. We will search Medline, Embase, CENTRAL, LILACS, clinicaltrials.gov, WHO trials database and grey literature resources. Two reviewers will independently screen titles and abstracts, review full texts, extract information, and assess the risk of bias and the confidence in the estimate (with the grading of recommendations, assessment, development, and evaluation [GRADE] approach). We will conduct a random-effects NMA to combine the pooled direct and indirect treatment effect estimates for each outcome if adequate data is available and transitivity and coherence assumptions are considered justifiable. Subgroup and sensitivity analyses are planned to evaluate the impact of some potential effect modifiers such as doses, co-intervention with oral antihistamines, the type of AR (intermittent or persistent), sponsorship of the study, the time of outcomes measurement and the risk of bias. We will use GRADE approach to draw conclusions from NMA. Discussion This systematic review and network meta-analysis aims to determine the relative efficacy and safety of the TNS for treatment of children with moderate/severe AR. The results will provide valuable information to assist clinicians, guideline developers, patients, and policy makers about the management of these patients, based on the best available evidence. Systematic review registration: PROSPERO number: CRD42023476313.

Dynamic path analysis for exploring treatment effect mediation processes in clinical trials with time-to-event endpoints.

Why does a beneficial treatment effect on a longitudinal biomarker not translate into overall treatment benefit on survival, when the biomarker is in fact a prognostic factor of survival? In a recent exploratory data analysis in oncology, we were faced with this seemingly paradoxical result. To address this problem, we applied a theoretically principled methodology called dynamic path analysis, which allows us to perform mediation analysis with a longitudinal mediator and survival outcome. The aim of the analysis is to decompose the total treatment effect into a direct treatment effect and an indirect treatment effect mediated through a carefully constructed mediation path. The dynamic nature of the underlying methodology enables us to describe how these effects evolve over time, which can add to the mechanistic understanding of the underlying processes. In this paper, we present a detailed description of the dynamic path analysis framework and illustrate its application to survival mediation analysis using simulated and real data. The use case analysis provides clarity on the specific exploratory question of interest while the methodology generalizes to a wide range of applications in drug development where time-to-event is the primary clinical outcome of interest.

Network intervention analysis indicates that roluperidone achieves its effect on negative symptoms of schizophrenia by targeting avolition

Roluperidone, a 5-HT2A, sigma2, and ɑ1A-adrenergic receptor antagonist, has proven efficacious for treating negative symptoms of schizophrenia in phase 2b and phase 3 clinical trials. Using network analysis, we demonstrated that the improvements observed in the phase 2b trial resulted from targeting avolition which was highly central and spurred a cascading effect of global negative symptom reductions when successfully treated. The current study aims to replicate these network findings using the phase 3 roluperidone clinical trial data. Participants included 496 schizophrenia patients with moderate to severe negative symptoms who were randomized to either roluperidone 32 mg/day (n =167), 64 mg/day (n = 162), or placebo (n = 167). Negative symptoms were assessed at baseline and weeks 2,4,8, and 12. Network intervention analysis (NIA) evaluated treatment-induced symptom changes over time to identify direct and indirect treatment effects. This analytic approach extends prior work by determining whether the symptoms with highest centrality have causal effects on the entire negative symptom construct and directly lead to symptom improvement. NIA indicated that the efficacious 64 mg/day dose of roluperidone had a direct effect on avolition, suggesting that changes in avolition propels treatment effects across the entire negative symptom constellation. These phase 3 findings replicated the phase 2b findings, indicating that from a network perspective, roluperidone achieves its effect by influencing the extent to which avolition drives other negative symptoms. These findings are relevant for understanding negative symptoms and how to treat them in neuropsychiatric disorders.

Who is Mobilized to Vote by Short Text Messages? Evidence from a Nationwide Field Experiment with Young Voters

AbstractUsing a large randomized controlled trial and rich individual-level data on eligible voters and their household members, we evaluate how get-out-the-vote (GOTV) appeals affect inequalities in voting, transmit from treated to untreated individuals within households, and how the transmission of voting decisions through family networks influences inequalities in voting. We find that receiving a text message reminder before the Finnish county elections in 2022 mobilized mainly low-propensity voters. As a result, the GOTV intervention reduced existing social inequalities in voting within the target group of young voters. We remarkably find that over 100% of the direct treatment effect spilled over to untreated household members. These spillovers reduced inequality in political participation among the older voters who were not part of the target group. Overall, our results exemplify how randomized controlled trials with a limited focus on the analysis of individuals in the treatment and control groups alone may lead to misestimating the compositional effects of get-out-the-vote interventions.

Structural equation modeling for identifying the drivers of health-related quality of life improvement experienced by patients with migraine receiving eptinezumab

BackgroundAs new migraine therapies emerge, it is crucial for measures to capture the complexities of health-related quality of life (HRQoL) improvement beyond improvements in monthly migraine day (MMD) reduction. Investigations into the correlations between MMD reduction, symptom management, and HRQoL are lacking, particularly those that focus on improvements in canonical symptoms and improvement in patient-identified most-bothersome symptoms (PI-MBS), in patients treated with eptinezumab. This exploratory analysis identified efficacy measures mediating the effect of eptinezumab on HRQoL improvements in patients with migraine.MethodsData from the DELIVER study of patients with 2–4 prior preventive migraine treatment failures (NCT04418765) were inputted to two structural equation models describing sources of HRQoL improvement via Migraine-Specific Quality-of-Life Questionnaire (MSQ) scores. A single latent variable was defined to represent HRQoL and describe the sources of HRQoL in DELIVER. One model included all migraine symptoms while the second model included the PI-MBS as the only migraine symptom. Mediating variables capturing different aspects of efficacy included MMDs, other canonical symptoms, and PI-MBS.ResultsIn the first model, reductions in MMDs and other canonical symptoms accounted for 35% (standardized effect size [SES] − 0.11) and 25% (SES − 0.08) of HRQoL improvement, respectively, with 41% (SES − 0.13) of improvement comprising “direct treatment effect,” i.e., unexplained by mediators. In the second model, substantial HRQoL improvement with eptinezumab (86%; SES − 0.26) is due to MMD reduction (17%; SES − 0.05) and change in PI-MBS (69%; SES − 0.21).ConclusionsImprovements in HRQoL experienced by patients treated with eptinezumab can be substantially explained by its effect on migraine frequency and PI-MBS. Therefore, in addition to MMD reduction, healthcare providers should discuss PI-MBS improvements, since this may impact HRQoL. Health technology policymakers should consider implications of these findings in economic evaluation, as they point to alternative measurement of quality-adjusted life years to capture fully treatment benefits in cost-utility analyses.Trial registration ClinicalTrials.gov (Identifier: NCT04418765; EudraCT (Identifier: 2019–004497-25; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004497-25).Graphical

Mediating effect of craving on the impact of buprenorphine/naloxone and methadone treatment on opioid use: Results from a randomized controlled trial

BackgroundThe relationship between opioid craving and opioid use is unclear. We sought to determine to what extent craving mediated the relationship between opioid agonist therapy and changes in opioid use. MethodsData came from a pragmatic, 24-week, pan-Canadian, multi-centric, open-label, randomized controlled trial comparing flexible buprenorphine/naloxone take-home doses to standard supervised methadone models of care for the treatment of prescription-type opioid use disorder. Participants were randomly allocated to buprenorphine/naloxone or methadone models of care. 270 people with prescription-type opioid use disorder were included in analyses. There were 93 women (34.4%) and 2 transgender (0.7%) participants. Most participants were white (67.4%), 45.9% reported unstable living conditions, and 44.8% had psychiatric comorbidities. Generalized linear mixed models followed by mediation analysis estimated the direct effect of treatment group on Timeline Followback-reported next-week opioid use and the indirect effect through past 24-hour opioid craving measured using the Brief Substance Craving Scale at week 2, 6, 10, 14, 18 and 22. ResultsUpon mediation analysis, the average direct effect of treatment on opioid use was 0.465 (95 % CI = 0.183 to 0.751, p < 0.001). The average causal mediated effect was 0.144 (95 % CI = 0.021 to 0.110; p < 0.001). Craving accounted for 23.6 % of the effect of treatment on opioid use (p < 0.001). ConclusionsPast 24-hour craving was associated with increased next-week opioid use; however, craving only partially mediated the effect of buprenorphine/naloxone and methadone on next-week opioid use. Research is needed to develop a comprehensive understanding of factors mediating opioid use during opioid agonist therapy.

Direct and indirect treatment effects in the presence of semicompeting risks.

Semicompeting risks refer to the phenomenon that the terminal event (such as death) can censor the nonterminal event (such as disease progression) but not vice versa. The treatment effect on the terminal event can be delivered either directly following the treatment or indirectly through the nonterminal event. We consider 2 strategies to decompose the total effect into a direct effect and an indirect effect under the framework of mediation analysis in completely randomized experiments by adjusting the prevalence and hazard of nonterminal events, respectively. They require slightly different assumptions on cross-world quantities to achieve identifiability. We establish asymptotic properties for the estimated counterfactual cumulative incidences and decomposed treatment effects. We illustrate the subtle difference between these 2 decompositions through simulation studies and two real-data applications in the Supplementary Materials.

Direct, carryover, and maternal effects of ocean acidification on snow crab embryos and larvae.

Ocean acidification, a decrease in ocean pH with increasing anthropogenic CO2 concentrations, is expected to affect many marine animals. To examine the effects of decreased pH on snow crab (Chionoecetes opilio), a commercial species in Alaska, we reared ovigerous females in one of three treatments: Ambient pH (~8.1), pH 7.8, and pH 7.5, through two annual reproductive cycles. Morphometric changes during development and hatching success were measured for embryos both years and calcification was measured for the adult females at the end of the 2-year experiment. Embryos and larvae analyzed in year one were from oocytes developed, fertilized, and extruded in situ, whereas embryos and larvae in year two were from oocytes developed, fertilized, and extruded under acidified conditions in the laboratory. In both years, larvae were exposed to the same pH treatments in a fully crossed experimental design. Starvation-survival, morphology, condition, and calcium/magnesium content were assessed for larvae. Embryo morphology during development, hatching success, and fecundity were unaffected by pH during both years. Percent calcium in adult females' carapaces did not differ among treatments at the end of the experiment. In the first year, starvation-survival of larvae reared at Ambient pH but hatched from embryos reared at reduced pH was lowered; however, the negative effect was eliminated when the larvae were reared at reduced pH. In the second year, there was no direct effect of either embryo or larval pH treatment, but larvae reared as embryos at reduced pH survived longer if reared at reduced pH. Treatment either did not affect other measured larval parameters, or effect sizes were small. The results from this two-year study suggest that snow crabs are well adapted to projected ocean pH levels within the next two centuries, although other life-history stages still need to be examined for sensitivity and potential interactive effects with increasing temperatures should be investigated.

Assessing quality and quantity of cortical bone in childhood cancer survivors using anthropometric indices.

Evaluate mandibular cortical bone in childhood cancer survivors (CCS) and correlate findings with disease and treatment characteristics. Dental panoramic radiographs of 60 CCS and of 120 age and gender-matched healthy individuals were assessed by two independent observers. Bone was categorized as normal, moderately or severely eroded and its width was calculated at four sites bilaterally. Significant differences were tested using Chi-square and Pearson correlation co-efficient. Possible risk factors were detected by multivariate regression analysis. Forty five percent of CCS had moderately eroded bone, while 67% of healthy individuals normal bone. Mean width was 3.9mm in CCS (1.9mm-6.4mm) and 2.7mm in healthy controls (1.4mm-6mm). None of the above differences were significant. Survivors diagnosed at a younger age had a five times greater probability of presenting mildly eroded bone. No direct effect of antineoplastic treatment on cortical bone could be demonstrated in the current study, underlying the need for more well-designed studies.

Characterizing the Anchoring Effects of Official Forecasts on Private Expectations

The paper proposes a method for simultaneously estimating the treatment effects of a change in a policy variable on a numerable set of interrelated outcome variables (different moments from the same probability density function). Firstly, it defines a non-Gaussian probability density function as the outcome variable. Secondly, it uses a functional regression to explain the density in terms of a set of scalar variables. From both the observed and the fitted probability density functions, two sets of interrelated moments are then obtained by simulation. Finally, a set of difference-in-difference estimators can be defined from the available pairs of moments in the sample. A stylized application provides a 29-moment characterization of the direct treatment effects of the Peruvian Central Bank’s forecasts on two sequences of Peruvian firms’ probability densities of expectations (for inflation -π- and real growth -g-) during 2004-2015.

Pain and Inflammation as Mediators of Tofacitinib Treatment Effect on Fatigue in Patients with Ankylosing Spondylitis: A Mediation Analysis.

Tofacitinib is an oral Janus kinase inhibitor for treatment of ankylosing spondylitis (AS). Using mediation modelling, we describe interrelationships between fatigue, pain, morning stiffness, C-reactive protein (CRP) and tofacitinib treatment in patients with AS. Data from phase2 (NCT01786668)/phase3 (NCT03502616) studies of patients receiving tofacitinib 5mg twice daily (BID) or placebo were used. Initial models included treatment as the independent binary variable (tofacitinib 5mg BID versus placebo); fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F; modelA] or Bath AS Disease Activity Index [BASDAI] Q1 [modelB]) as the dependent variable; and pain (total back pain/nocturnal spinal pain [modelA] or pain measured by BASDAI Q2/3 [modelB]), morning stiffness (BASDAI Q5/6) and CRP as mediator variables. Pooled data from 370/371 patients were included in modelsA/B. Initial models demonstrated that tofacitinib treatment affects fatigue mainly indirectly via pain and morning stiffness. As a result, initial models were respecified to exclude direct treatment effect and the indirect effect via CRP. For respecified modelA, 44.0% of the indirect effect of tofacitinib treatment on fatigue was mediated via back pain/morning stiffness, 40.0% via morning stiffness alone and 16.0% via back pain alone (all P < 0.05). For respecified modelB, 80.8% of the indirect effect of tofacitinib treatment on fatigue was mediated via pain/morning stiffness and 19.2% via pain alone (both P < 0.05). In tofacitinib-treated patients with AS, improvements in fatigue were collectively mediated through combined treatment effects on morning stiffness and pain.

Semantic Feature Analysis (SFA) treatment in L1 and L2 in bilingual aphasia: Effects of cognitive and language factors

ABSTRACT Background Semantic Feature Analysis (SFA) treatment has been proven to be effective in alleviating word finding difficulties in individuals with aphasia. However, there is no consensus on the impact of SFA on naming abilities and general language skills in bilingual persons with aphasia (BiPWAs), nor on factors that determine the success of the SFA treatment. Aims This study aimed to investigate the efficacy of SFA treatment in a group of L1-Russian – L2-Hebrew chronic stage BiPWAs and to evaluate the contribution of background factors, language and cognitive measures on the treatment success. Methods & Procedures The current study included two groups of BiPWAs. In the experimental group (n=10), six individuals received SFA therapy in both languages and four individuals in L2. The delayed-treatment group (n=10) did not receive therapy and served as a control group. All BiPWAs completed the Bilingual Aphasia Test (BAT) in both languages, as well as a battery of 10 cognitive tests and linguistic background questionnaires. Outcome & Results The results indicated a direct effect of SFA treatment on naming as well as within-language generalization and cross-language transfer. Importantly, we found significant improvements of general language skills in the treated and untreated languages in BiPWAs who received SFA treatment, while no such improvement was observed in the control group. Non-verbal inhibition and verbal working memory in L1-Russian predicted success of SFA treatment in BiPWAs. Conclusions SFA therapy has positive effects on naming ability of BiPWAs. In addition, SFA therapy affects general language skills in BiPWAs. Yet, within-language generalization, cross-linguistic transfer, and maintenance of the treatment results vary across individuals. The success of SFA treatment in BiPWAs is predicted by cognitive functions rather than background factors of bilingualism.

Novel mathematical modeling approach finds Fortasyn Connect affects memory through reducing hippocampal atrophy in the LipiDiDiet trial

AbstractBackgroundLipiDiDiet is a 6‐year, randomized, double‐blind, placebo‐controlled intervention in 311 individuals with prodromal Alzheimer’s disease (AD)/mild cognitive impairment receiving the specific multinutrient combination Fortasyn Connect (Souvenaid) or a calorie‐matched placebo control once daily.1 AD is characterized by neurodegeneration including significant synapse loss, and the hippocampal formation is particularly vulnerable in the early stages of AD. Results over the first 2 and 3 years of intervention showed that Fortasyn Connect reduced hippocampal atrophy and slowed decline on clinical and other measures related to cognition, function, and disease progression.2,3 Here, possible mechanistic pathways through which the intervention may affect the risk of disease progression are being explored post‐hoc.MethodA new type of multivariate joint model was applied to the 3‐year LipiDiDiet clinical trial data in which the longitudinal outcomes MRI hippocampal volume (HCV) and neuropsychological test battery (NTB)‐memory are allowed to be associated with disease progression and dropout, and affect each other directly. Specifically, for each longitudinal outcome a linear mixed‐effects model is used to estimate its trajectory, where, for the second longitudinal outcome, the linear predictor of the first outcome is included as time‐varying covariate. Results are compared for both pathways (HCV and NTB‐memory and vice versa), and with results of existing multivariate joint models that have the form of so‐called parallel mediator models (i.e. longitudinal outcomes are merely allowed to be correlated but not to influence each other causally).ResultComparing the models, we observed a strong association between changes in NTB‐memory and disease progression and no direct treatment effect on NTB‐memory. Notably, there was a strong direct treatment effect for HCV changes, together with a direct effect of HCV on disease progression. Moreover, indirect effects of HCV changes on disease progression were mediated through NTB‐memory.ConclusionThis new multivariate joint model is useful in modeling possible mechanistic pathways. Overall results from application to the 3‐year data suggest that the observed intervention effects of Fortasyn Connect are partly mediated through reduction of hippocampal atrophy both directly and indirectly via NTB‐memory, in addition to yet to be defined other/complementary pathways. 1 Funding includes EU‐JPND. 2Lancet Neurol. 2017;16:965‐975. 3Alz &amp; Dementia. 2021;17:29‐40.

Patient-identified most bothersome symptom as a driver of health-related quality of life experienced by patients with migraine (P8-12.010)

Patient-identified most bothersome symptom as a driver of health-related quality of life experienced by patients with migraine (P8-12.010)

Nesfatin-1 peptide protects rat renal epithelial cells against high glucose and H2O2 induced injury via inhibition of oxidative stress, apoptosis, and fibrosis

Nesfatin-1 is a potent polypeptide and plays a crucial role in many physiological functions. Nesfatin-1 levels are reported in both the central nervous system and peripheral organs. However, the expression of nesfatin-1 in the renal system under chronic oxidative stress-induced conditions and the direct effect of nesfatin-1 treatment on stress-induced pathological damage are not reported. Thus, the present study aimed to explore the role of nesfatin-1 in vitro in oxidative stress-induced renal epithelial cells. High glucose (HG) and H2O2 combination were used to induce oxidative stress (OS). MTT, crystal violet, and H and E staining were used to measure cell viability, cytotoxicity, and morphology. FACS analysis and confocal microscopy were used to measure OS and apoptosis. RT-PCR was done for gene expression analysis. Decreased nesfatin-1 expression was observed in renal epithelial cells induced with HG and H2O2 compared to an untreated control (0.16; p < 0.0001). Nesfatin-1 co-treatment with HG and H2O2 attenuated ROS, apoptosis, and fibrosis. SOD, Catalase, and Bcl-2 expression decreased (p < 0.0001) and Caspase-3 and TGF-β1 expression increased in HG and H2O2-induced cells compared to control cells (p < 0.0001). Nesfatin-1 co-treatment attenuated these changes induced by HG and H2O2 (p < 0.0001). Nesfatin-1 expression was decreased in renal epithelial cells under stress-induced conditions. Moreover, nesfatin-1 co-treatment under stress-induced conditions protects the renal epithelial cells via inhibition of oxidative stress, apoptotic, and fibrotic signaling pathways.

The association of intensive blood pressure treatment and non-fatal cardiovascular or serious adverse events in older adults with mortality: mediation analysis in SPRINT.

Randomized clinical trials of hypertension treatment intensity evaluate the effects on incident major adverse cardiovascular events (MACEs) and serious adverse events (SAEs). Occurrences after a non-fatal index event have not been rigorously evaluated. The aim of this study was to evaluate the association of intensive (<120 mmHg) to standard (<140 mmHg) blood pressure (BP) treatment with mortality mediated through a non-fatal MACE or non-fatal SAE in 9361 participants in the Systolic Blood Pressure Intervention Trial. Logistic regression and causal mediation modelling to obtain direct and mediated effects of intensive BP treatment. Primary outcome was all-cause mortality (ACM). Secondary outcomes were cardiovascular (CVM) and non-CV mortality (non-CVM). The direct effect of intensive treatment was a lowering of ACM [odds ratio (OR) 0.75, 95% confidence interval (CI): 0.60-0.94]. The MACE-mediated effect substantially attenuated (OR 0.96, 95% CI: 0.92-0.99) ACM, while the SAE-mediated effect was associated with increased (OR 1.03, 95% CI: 1.01-1.05) ACM. Similar patterns were noted for intensive BP treatment on CVM and non-CVM. We also noted that SAE incidence was 3.9-fold higher than MACE incidence (13.7 vs. 3.5%), and there were a total of 365 (3.9%) ACM cases, with non-CVM being 2.6-fold higher than CVM [2.81% (263/9361) vs. 1.09% (102/9361)]. The SAE to MACE and non-CVM to CVM preponderance was found across all age groups, with the ≥80-year age group having the highest differences. The current analytic techniques demonstrated that intensive BP treatment was associated with an attenuated mortality benefit when it was MACE-mediated and possibly harmful when it was SAE-mediated. Current cardiovascular trial reporting of treatment effects does not allow expansion of the lens to focus on important occurrences after the index event.

Identifying causal effects in experiments with spillovers and non-compliance

This paper shows how to use a randomized saturation experimental design to identify and estimate causal effects in the presence of spillovers–one person’s treatment may affect another’s outcome–and one-sided non-compliance—subjects can only be offered treatment, not compelled to take it up. Two distinct causal effects are of interest in this setting: direct effects quantify how a person’s own treatment changes her outcome, while indirect effects quantify how her peers’ treatments change her outcome. We consider the case in which spillovers occur within known groups, and take-up decisions are invariant to peers’ realized offers. In this setting we point identify the effects of treatment-on-the-treated, both direct and indirect, in a flexible random coefficients model that allows for heterogeneous treatment effects and endogenous selection into treatment. We go on to propose a feasible estimator that is consistent and asymptotically normal as the number and size of groups increases. We apply our estimator to data from a large-scale job placement services experiment, and find negative indirect treatment effects on the likelihood of employment for those willing to take up the program. These negative spillovers are offset by positive direct treatment effects from own take-up.

Shoot Emergence, Leaf Expansion, and Corm Growth in Amorphophallus muelleri Blume Treated with Hydropriming and Shading

A bulbil, as planting material, is difficult to stimulate to grow in a dormant state. This study examines the hydropriming effect on shoot emergence and the shading treatments on leaf and cormel growth during the vegetative stage. The priming was carried out by soaking the bulbils in distilled water for 0, 3, 6, 12, and 24 hours and the shading treatments at 0, 40, and 80 percent. The results show that the imbibition occurred immediately during the first 3 hours and continued to increase up to 24 hours. The bulbil re-drying process reached the pre-treatment water content in less than three days. Significantly the earlier emergence was observed in the plants exposed to the 80% shading. The petiole sheath breakup was not affected by the hydropriming and shading. The konjac planted in the shading treatment produced more sprouts, longer but slender petioles, larger but thinner leaves, and larger cormel size. The differences in fresh and dry weight were more related to tuber moisture content than the direct effect of the shading treatment. The SPAD value of konjac leaves immediately increased within a few days after the application of the NPK fertilizer and consistently lasted for four weeks.

Network experiment designs for inferring causal effects under interference.

Current approaches to A/B testing in networks focus on limiting interference, the concern that treatment effects can "spill over" from treatment nodes to control nodes and lead to biased causal effect estimation. In the presence of interference, two main types of causal effects are direct treatment effects and total treatment effects. In this paper, we propose two network experiment designs that increase the accuracy of direct and total effect estimations in network experiments through minimizing interference between treatment and control units. For direct treatment effect estimation, we present a framework that takes advantage of independent sets and assigns treatment and control only to a set of non-adjacent nodes in a graph, in order to disentangle peer effects from direct treatment effect estimation. For total treatment effect estimation, our framework combines weighted graph clustering and cluster matching approaches to jointly minimize interference and selection bias. Through a series of simulated experiments on synthetic and real-world network datasets, we show that our designs significantly increase the accuracy of direct and total treatment effect estimation in network experiments.

OS01.5.A Neuron-specific enolase (NSE) and S100 serum levels in patients with active brain metastases from HER2-positive breast cancer treated with trastuzumab-deruxtecan (T-DXd): A biomarker analysis from the TUXEDO-1 trial

Abstract Background T-DXd is a novel antibody-drug conjugate with high activity in HER2-positive metastatic breast cancer. The prospective, single-arm, single-centre phase II TUXEDO-1 trial showed clinically relevant activity of T-DXd in HER2-positive BC pts with active BM with an intracranial response rate of 73.3%. This biomarker sub-study of TUXEDO-1 aimed to investigate changes in the extent of metastases-induced brain damage in patients with and without response to therapy by measuring the serum levels of two proteins constitutively expressed in the human brain and measurable upon brain damage in the blood serum: NSE and S100. Material and Methods We assessed serum NSE (sNSE) and serum S100 (sS100) levels in a total of 37 blood samples drawn at cycles 1, 4 and end of treatment (EOT) in all patients of the intent-to-treat population of the TUXEDO-1 trial using commercially available ELISA assays. Intracranial radiological response was centrally assessed by a board-certified neuro-radiologist using RANO criteria. sNSE and sS100 levels were compared between responders and non-responders using the Mann Whitney U test and a significance level of 0.05. Results At baseline, we detected no significant difference of sNSE or sS100 levels between T-DXd responders and non-responders, respectively. Baseline median sNSE level was 10.6 ng/ml (interquartile range (IQR) 8.6-12.2) in T-DXd responders as compared with median 12.5 ng/ml (IQR 12.2-12.9) in the non-responder group (n.s.). At cycle 4, corresponding numbers were 8.1 ng/ml in responding patients (IQR 7-11.2) and 12.7 ng/ml (IQR 12.2-12.9) in non-responders, respectively (p=0.009). No differences in sS100 levels were observed between the groups at any time point. Conclusion In patients showing intracranial objective response to T-Dxd, sNSE levels were significantly lower at cycle 4 as compared with non-responders, suggesting a reduction in metastases-induced brain damage as a direct treatment effect. sNSE may be a clinically useful biomarker for longitudinal assessment of brain metastasis burden.