Publications by authors named "Stephen L Lake"

21 Publications

  • Page 1 of 1

A flexible multi-domain test with adaptive weights and its application to clinical trials.

Authors:
Yang Zhao Qifeng Yu Stephen L Lake

Pharm Stat 2020 05 30;19(3):315-325. Epub 2019 Dec 30.

Wave Life Sciences, Lexington, Massachusetts.

The design of a clinical trial is often complicated by the multi-systemic nature of the disease; a single endpoint often cannot capture the spectrum of potential therapeutic benefits. Multi-domain outcomes which take into account patient heterogeneity of disease presentation through measurements of multiple symptom/functional domains are an attractive alternative to a single endpoint. A multi-domain test with adaptive weights is proposed to synthesize the evidence of treatment efficacy over numerous disease domains. The test is a weighted sum of domain-specific test statistics with weights selected adaptively via a data-driven algorithm. The null distribution of the test statistic is constructed empirically through resampling and does not require estimation of the covariance structure of domain-specific test statistics. Simulations show that the proposed test controls the type I error rate, and has increased power over other methods such as the O'Brien and Wei-Lachin tests in scenarios reflective of clinical trial settings. Data from a clinical trial in a rare lysosomal storage disorder were used to illustrate the properties of the proposed test. As a strategy of combining marginal test statistics, the proposed test is flexible and readily applicable to a variety of clinical trial scenarios.
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http://dx.doi.org/10.1002/pst.1993DOI Listing
May 2020

Alemtuzumab improves quality-of-life outcomes compared with subcutaneous interferon beta-1a in patients with active relapsing-remitting multiple sclerosis.

Authors:
Rafael Arroyo González Mariko Kita Heidi Crayton Eva Havrdova David H Margolin Stephen L Lake Gavin Giovannoni

Mult Scler 2017 Sep 25;23(10):1367-1376. Epub 2016 Nov 25.

Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Background: Alemtuzumab was superior on clinical and magnetic resonance imaging (MRI) outcomes versus subcutaneous interferon beta-1a in phase 3 trials in patients with relapsing-remitting multiple sclerosis.

Objective: To examine quality-of-life (QoL) outcomes in the alemtuzumab phase 3 trials.

Methods: Patients who were treatment naive (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I [CARE-MS I]) or had an inadequate response to prior therapy (CARE-MS II) received annual courses of alemtuzumab 12 mg/day at baseline (5 days) and Month 12 (3 days) or subcutaneous interferon beta-1a 44 µg three times/week. QoL was measured every 6 or 12 months using Functional Assessment of Multiple Sclerosis (FAMS), European Quality of Life-5 Dimensions (EQ-5D) and its visual analog scale (EQ-VAS), and 36-Item Short-Form Survey (SF-36).

Results: Statistically significant improvements from baseline with alemtuzumab were observed on all three QoL instruments at the earliest post-baseline assessment and sustained through Year 2. Statistically significant greater QoL improvements over subcutaneous interferon beta-1a were seen at all time points in CARE-MS II with FAMS, EQ-VAS and SF-36 physical component summary, and in CARE-MS I with FAMS.

Conclusion: Patients treated with alemtuzumab had improvements in physical, mental, and emotional QoL regardless of treatment history. Improvements were significantly greater with alemtuzumab versus subcutaneous interferon beta-1a on both disease-specific and general measures of QoL.
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http://dx.doi.org/10.1177/1352458516677589DOI Listing
September 2017

Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients.

Authors:
Gavin Giovannoni Jeffrey A Cohen Alasdair J Coles Hans-Peter Hartung Eva Havrdova Krzysztof W Selmaj David H Margolin Stephen L Lake Susan M Kaup Michael A Panzara D Alastair S Compston

Neurology 2016 Nov 12;87(19):1985-1992. Epub 2016 Oct 12.

From Queen Mary University of London (G.G.), Barts and The London School of Medicine, UK; Mellen Center (J.A.C.), Cleveland Clinic, OH; Department of Clinical Neurosciences (A.J.C., D.A.S.C.), University of Cambridge, UK; Department of Neurology and Center for Neuropsychiatry (H.-P.H.), Heinrich-Heine University, Düsseldorf, Germany; Department of Neurology and Center for Clinical Neuroscience (E.H.), First Medical Faculty, Charles University in Prague, Czech Republic; Department of Neurology (K.W.S.), Medical University of Łódź, Poland; Sanofi Genzyme (D.H.M., S.L.L., M.A.P.), Cambridge, MA; and Evidence Scientific Solutions (S.M.K.), Philadelphia, PA (at the time the work was conducted).

Objective: To characterize effects of alemtuzumab treatment on measures of disability improvement in patients with relapsing-remitting multiple sclerosis (RRMS) with inadequate response (≥1 relapse) to prior therapy.

Methods: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II, a 2-year randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial, compared efficacy and safety of alemtuzumab 12 mg with subcutaneous interferon-β-1a (SC IFN-β-1a) 44 μg in patients with RRMS. Prespecified and post hoc disability outcomes based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Sloan low-contrast letter acuity (SLCLA) are reported, focusing on improvement of preexisting disability in addition to slowing of disability accumulation.

Results: Alemtuzumab-treated patients were more likely than SC IFN-β-1a-treated patients to show improvement in EDSS scores (p < 0.0001) on all 7 functional systems. Significantly more alemtuzumab patients demonstrated 6-month confirmed disability improvement. The likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than SC IFN-β-1a (p = 0.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores (p = 0.0014) and MSFC + SLCLA composite scores (p = 0.0097) than SC IFN-β-1a-treated patients.

Conclusions: In patients with RRMS and inadequate response to prior disease-modifying therapies, alemtuzumab provides greater benefits than SC IFN-β-1a across several disability outcomes, reflecting improvement of preexisting disabilities.

Classification Of Evidence: This study provides Class I evidence (based on rater blinding and a balance in baseline characteristics between arms) that alemtuzumab modifies disability measures favorably compared with SC IFN-β-1a.
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http://dx.doi.org/10.1212/WNL.0000000000003319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109953PMC
November 2016

Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon β-1a in MS.

Authors:
Douglas L Arnold Elizabeth Fisher Vesna V Brinar Jeffrey A Cohen Alasdair J Coles Gavin Giovannoni Hans-Peter Hartung Eva Havrdova Krzysztof W Selmaj Miroslav Stojanovic Howard L Weiner Stephen L Lake David H Margolin David R Thomas Michael A Panzara D Alastair S Compston

Neurology 2016 Oct 2;87(14):1464-1472. Epub 2016 Sep 2.

From NeuroRx Research (D.L.A.) and Department of Neurology and Neurosurgery (D.L.A.), Montréal Neurological Institute, McGill University, Québec, Canada; Department of Biomedical Engineering (E.F.) and Mellen Center (J.A.C.), Cleveland Clinic, OH; Zagreb Medical School and University Hospital Center (V.V.B.), Croatia; Department of Clinical Neurosciences (A.J.C., D.A.S.C.), University of Cambridge, UK; Queen Mary University of London (G.G.), Barts and the London School of Medicine, UK; Department of Neurology and Center for Neuropsychiatry (H.-P.H.), Heinrich-Heine University, Düsseldorf, Germany; Department of Neurology (E.H.), First Medical Faculty, Charles University in Prague, Czech Republic; Department of Neurology (K.W.S.), Medical University of Łódź, Poland; Clinical Centre Kragujevac (M.S.), Clinic of Neurology, Serbia; Brigham and Women's Hospital Center for Neurologic Diseases (H.L.W.), Boston, MA; Sanofi Genzyme (S.L.L., D.H.M., M.A.P.), Cambridge, MA; and Evidence Scientific Solutions (D.R.T.), Horsham, West Sussex, UK. Dr. Panzara is currently with Wave Life Sciences, Cambridge, MA.

Objective: To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS).

Methods: The impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II).

Results: Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-β-1a.

Conclusions: Alemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS.

Clinicaltrialsgov Identifier: NCT00530348 and NCT00548405.

Classification Of Evidence: The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints.
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http://dx.doi.org/10.1212/WNL.0000000000003169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075976PMC
October 2016

Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.

Authors:
Jeffrey A Cohen Alasdair J Coles Douglas L Arnold Christian Confavreux Edward J Fox Hans-Peter Hartung Eva Havrdova Krzysztof W Selmaj Howard L Weiner Elizabeth Fisher Vesna V Brinar Gavin Giovannoni Miroslav Stojanovic Bella I Ertik Stephen L Lake David H Margolin Michael A Panzara D Alastair S Compston

Lancet 2012 Nov 1;380(9856):1819-28. Epub 2012 Nov 1.

Mellen Center, Cleveland Clinic, Cleveland, OH 44195, USA.

Background: The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial.

Methods: In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348.

Findings: 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32-0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40-1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma.

Interpretation: Alemtuzumab's consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here.

Funding: Genzyme (Sanofi) and Bayer Schering Pharma.
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http://dx.doi.org/10.1016/S0140-6736(12)61769-3DOI Listing
November 2012

Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial.

Authors:
Alasdair J Coles Cary L Twyman Douglas L Arnold Jeffrey A Cohen Christian Confavreux Edward J Fox Hans-Peter Hartung Eva Havrdova Krzysztof W Selmaj Howard L Weiner Tamara Miller Elizabeth Fisher Rupert Sandbrink Stephen L Lake David H Margolin Pedro Oyuela Michael A Panzara D Alastair S Compston

Lancet 2012 Nov 1;380(9856):1829-39. Epub 2012 Nov 1.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Background: The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment.

Methods: In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405.

Findings: 202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.

Interpretation: For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity.

Funding: Genzyme (Sanofi) and Bayer Schering Pharma.
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http://dx.doi.org/10.1016/S0140-6736(12)61768-1DOI Listing
November 2012

Alemtuzumab versus interferon β-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes.

Authors:
Alasdair J Coles Edward Fox Anton Vladic Suzanne K Gazda Vesna Brinar Krzysztof W Selmaj Ann Doan-Do Bass Daniel R Wynn David H Margolin Stephen L Lake Susan Moran Jeffrey Palmer M Shelton Smith D Alastair S Compston

Lancet Neurol 2011 Apr;10(4):338-48

Department of Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Background: Alemtuzumab is a humanised monoclonal antibody that depletes lymphocytes, causing long-term immunomodulation. In a 3-year, rater-blinded phase 2 study (the CAMMS223 study) in patients with relapsing-remitting multiple sclerosis (RRMS), alemtuzumab reduced relapse rate and the risk of sustained accumulation of disability compared with subcutaneous interferon beta-1a, and the mean expanded disability status scale (EDSS) score of the alemtuzumab cohort improved compared with baseline. Adverse events included infusion-associated reactions, predominantly mild to moderate infections, thyroid disorders, and immune thrombocytopenia. In this study, we further analysed the CAMMS223 data with the aim of determining whether demographic and baseline disease-related characteristics affect the beneficial effects of alemtuzumab. Additionally, we aimed to describe a new outcome measure in multiple sclerosis research: sustained reduction in disability.

Methods: 334 treatment-naive patients with active, early RRMS were randomly assigned in a 1:1:1 ratio to receive interferon beta-1a (44 μg subcutaneously three times per week), or 24 mg per day or 12 mg per day alemtuzumab intravenously for 2 or 3 annual cycles. We analysed freedom from clinical disease activity (CDA; defined as no relapses and no sustained accumulation of disability) and occurrence of sustained reduction in disability (SRD; a ≥1 point decrease on the EDSS sustained for 6 consecutive months for patients with a baseline EDSS ≥2), and analysed efficacy outcomes for subgroups based on age, sex, geographic region, MRI-T1 brain volume, MRI-T2 lesion volume, disease duration, number of previous relapses within 2 years, and EDSS.

Findings: 322 patients were analysed. 161 of 215 patients treated with alemtuzumab were free of CDA at 36 months (Kaplan-Meier estimate 71·8%, 95% CI 63·1-78·8%) compared with 52 of 107 patients treated with interferon beta-1a (42·6%, 32·4-52·4%; hazard ratio [HR]=0·31, 0·20-0·46; p<0·0001). For the 199 patients with a baseline EDSS score greater than or equal to 2, SRD was more likely (HR=2·61, 1·54-4·43; p=0·0004) among patients treated with alemtuzumab (66 of 133 patients, Kaplan-Meier estimate 51·6%, 95% CI 43·2-60·7%) than patients treated with interferon beta-1a (15 of 66 patients, 27·2%, 17·2-41·4%). All disability and relapse outcomes showed evidence of beneficial effects of alemtuzumab compared with interferon beta-1a across all analysed patient subsets, and no subgroup of patients consistently responded better than others to alemtuzumab.

Interpretation: Alemtuzumab reduced disease activity compared with interferon beta-1a in most of the analysed subgroups. Significantly greater numbers of patients experienced sustained improvement in disability after treatment with alemtuzumab than interferon beta-1a. The efficacy offered by alemtuzumab is a substantial advance in the treatment of multiple sclerosis.

Funding: Genzyme and Bayer Schering Pharma.
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http://dx.doi.org/10.1016/S1474-4422(11)70020-5DOI Listing
April 2011

Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity.

Authors:
Joanne L Jones Jane M Anderson Chia-Ling Phuah Edward J Fox Krzysztof Selmaj David Margolin Stephen L Lake Jeffrey Palmer Sara J Thompson Alastair Wilkins Daniel J Webber D Alastair Compston Alasdair J Coles

Brain 2010 Aug 21;133(Pt 8):2232-47. Epub 2010 Jul 21.

Department of Clinical Neuroscience, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.

Treatment of early relapsing-remitting multiple sclerosis with the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath [registered trade mark]) significantly reduced the risk of relapse and accumulation of disability compared with interferon β-1a in a phase 2 trial [Coles et al., (Alemtuzumab vs. interferon β-1a in early multiple sclerosis. N Engl J Med 2008; 359: 1786-801)]. Patients treated with alemtuzumab experienced an improvement in disability at 6 months that was sustained for at least 3 years. In contrast, those treated with interferon β-1a steadily accumulated disability. Here, by post hoc subgroup analyses of the CAMMS223 trial, we show that among participants with no clinical disease activity immediately before treatment, or any clinical or radiological disease activity on-trial, disability improved after alemtuzumab but not following interferon β-1a. This suggests that disability improvement after alemtuzumab is not solely attributable to its anti-inflammatory effect. So we hypothesized that lymphocytes, reconstituting after alemtuzumab, permit or promote brain repair. Here we show that after alemtuzumab, and only when specifically stimulated with myelin basic protein, peripheral blood mononuclear cell cultures produced increased concentrations of brain-derived neurotrophic factor, platelet-derived growth factor and ciliary neurotrophic factor. Analysis by reverse transcriptase polymerase chain reaction of cell separations showed that the increased production of ciliary neurotrophic factor and brain-derived neurotrophic factor after alemtuzumab is attributable to increased production by T cells. Media from these post-alemtuzumab peripheral blood mononuclear cell cultures promoted survival of rat neurones and increased axonal length in vitro, effects that were partially reversed by neutralizing antibodies against brain-derived nerve growth factor and ciliary neurotrophic factor. This conditioned media also enhanced oligodendrocyte precursor cell survival, maturation and myelination. Taken together, the clinical analyses and laboratory findings support the interpretation that improvement in disability after alemtuzumab may result, in part, from neuroprotection associated with increased lymphocytic delivery of neurotrophins to the central nervous system.
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http://dx.doi.org/10.1093/brain/awq176DOI Listing
August 2010

Hylan G-F 20 improves hip osteoarthritis: a prospective, randomized study.

Authors:
Andrew I Spitzer Barry I Bockow Victoria A Brander James W Yates Daryl K MacCarter Garland K Gudger Stephanie Haller Stephen L Lake Daniel B Magilavy

Phys Sportsmed 2010 Jun;38(2):35-47

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We compared the efficacy and safety of intra-articular hylan G-F 20 with methylprednisolone acetate (MPA) for treating symptomatic Kellgren-Lawrence grade (KLG) 2 or 3 hip osteoarthritis in a prospective, randomized, multicenter, double-blind trial (N = 313). Two injections of hylan G-F 20 were administered 2 weeks apart (n = 150), or 1 injection of 40 mg MPA and 1 sham injection 2 weeks later (n = 155). The Western Ontario and McMaster Universities Arthritis Index (WOMAC) (total and subscale), clinician observations, and patient global assessments were collected at baseline and at weeks 4, 8, 12, 16, 20, and 26 (intent-to-treat population was analyzed; n = 305). Responder rates were assessed by WOMAC domain A, and criteria were established by the Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI). At week 26, WOMAC A improved by 16.6 mm for hylan G-F 20 versus 13.6 mm for MPA. Response rates were higher with hylan G-F 20 versus MPA in patients with more advanced disease (KLG 3) and were similar between hylan G-F 20 and MPA in patients with less advanced disease (KLG 2). Adverse events were similar between groups and between patients with KLG 2 or 3. Hylan G-F 20 provided clinically meaningful improvements in pain and function, comparable with those of MPA, with good safety and tolerability. Thus, we conclude it is an appropriate option for treating hip osteoarthritis.
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http://dx.doi.org/10.3810/psm.2010.06.1781DOI Listing
June 2010

A randomized study of alglucosidase alfa in late-onset Pompe's disease.

Authors:
Ans T van der Ploeg Paula R Clemens Deyanira Corzo Diana M Escolar Julaine Florence Geert Jan Groeneveld Serge Herson Priya S Kishnani Pascal Laforet Stephen L Lake Dale J Lange Robert T Leshner Jill E Mayhew Claire Morgan Kenkichi Nozaki Dorothy J Park Alan Pestronk Barry Rosenbloom Alison Skrinar Carine I van Capelle Nadine A van der Beek Melissa Wasserstein Sasa A Zivkovic

N Engl J Med 2010 Apr;362(15):1396-406

Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Background: Pompe's disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe's disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe's disease.

Methods: Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC).

Results: At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients).

Conclusions: In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)
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http://dx.doi.org/10.1056/NEJMoa0909859DOI Listing
April 2010

Alemtuzumab vs. interferon beta-1a in early multiple sclerosis.

Authors:
Alasdair J Coles D Alastair S Compston Krzysztof W Selmaj Stephen L Lake Susan Moran David H Margolin Kim Norris P K Tandon

N Engl J Med 2008 Oct;359(17):1786-801

Background: Alemtuzumab, a humanized monoclonal antibody that targets CD52 on lymphocytes and monocytes, may be an effective treatment for early multiple sclerosis.

Methods: In this phase 2, randomized, blinded trial involving previously untreated, early, relapsing-remitting multiple sclerosis, we assigned 334 patients with scores of 3.0 or less on the Expanded Disability Status Scale and a disease duration of 3 years or less to receive either subcutaneous interferon beta-1a (at a dose of 44 microg) three times per week or annual intravenous cycles of alemtuzumab (at a dose of either 12 mg or 24 mg per day) for 36 months. In September 2005, alemtuzumab therapy was suspended after immune thrombocytopenic purpura developed in three patients, one of whom died. Treatment with interferon beta-1a continued throughout the study.

Results: Alemtuzumab significantly reduced the rate of sustained accumulation of disability, as compared with interferon beta-1a (9.0% vs. 26.2%; hazard ratio, 0.29; 95% confidence interval [CI], 0.16 to 0.54; P<0.001) and the annualized rate of relapse (0.10 vs. 0.36; hazard ratio, 0.26; 95% CI, 0.16 to 0.41; P<0.001). The mean disability score on a 10-point scale improved by 0.39 point in the alemtuzumab group and worsened by 0.38 point in the interferon beta-1a group (P<0.001). In the alemtuzumab group, the lesion burden (as seen on T(2)-weighted magnetic resonance imaging) was reduced, as compared with that in the interferon beta-1a group (P=0.005). From month 12 to month 36, brain volume (as seen on T(1)-weighted magnetic resonance imaging) increased in the alemtuzumab group but decreased in the interferon beta-1a group (P=0.02). Adverse events in the alemtuzumab group, as compared with the interferon beta-1a group, included autoimmunity (thyroid disorders [23% vs. 3%] and immune thrombocytopenic purpura [3% vs. 1%]) and infections (66% vs. 47%). There were no significant differences in outcomes between the 12-mg dose and the 24-mg dose of alemtuzumab.

Conclusions: In patients with early, relapsing-remitting multiple sclerosis, alemtuzumab was more effective than interferon beta-1a but was associated with autoimmunity, most seriously manifesting as immune thrombocytopenic purpura. The study was not powered to identify uncommon adverse events. (ClinicalTrials.gov number, NCT00050778.)
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http://dx.doi.org/10.1056/NEJMoa0802670DOI Listing
October 2008

Airway wall thickening and emphysema show independent familial aggregation in chronic obstructive pulmonary disease.

Authors:
Bipen D Patel Harvey O Coxson Sreekumar G Pillai Alvar G N Agustí Peter M A Calverley Claudio F Donner Barry J Make Nestor L Müller Stephen I Rennard Jørgen Vestbo Emiel F M Wouters Melanie P Hiorns Yasutaka Nakano Patricia G Camp Paola V Nasute Fauerbach Nicholas J Screaton Edward J Campbell Wayne H Anderson Peter D Paré Robert D Levy Stephen L Lake Edwin K Silverman David A Lomas

Am J Respir Crit Care Med 2008 Sep 19;178(5):500-5. Epub 2008 Jun 19.

Department of Medicine, University of Cambridge, Cambridge, UK.

Rationale: It is unclear whether airway wall thickening and emphysema make independent contributions to airflow limitation in chronic obstructive pulmonary disease (COPD) and whether these phenotypes cluster within families.

Objectives: To determine whether airway wall thickening and emphysema (1) make independent contributions to the severity of COPD and (2) show independent aggregation in families of individuals with COPD.

Methods: Index cases with COPD and their smoking siblings underwent spirometry and were offered high-resolution computed tomography scans of the thorax to assess the severity of airway wall thickening and emphysema.

Measurements And Main Results: A total of 3,096 individuals were recruited to the study, of whom 1,159 (519 probands and 640 siblings) had technically adequate high-resolution computed tomography scans without significant non-COPD-related thoracic disease. Airway wall thickness correlated with pack-years smoked (P < or = 0.001) and symptoms of chronic bronchitis (P < 0.001). FEV(1) (expressed as % predicted) was independently associated with airway wall thickness at a lumen perimeter of 10 mm (P = 0.0001) and 20 mm (P = 0.0013) and emphysema at -950 Hounsfield units (P < 0.0001). There was independent familial aggregation of both the emphysema (adjusted odds ratio, 2.1; 95% confidence interval, 1.1-4.0; P < or = 0.02) and airway disease phenotypes (P < 0.0001) of COPD.

Conclusions: Airway wall thickening and emphysema make independent contributions to airflow obstruction in COPD. These phenotypes show independent aggregation within families of individuals with COPD, suggesting that different genetic factors influence these disease processes.
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http://dx.doi.org/10.1164/rccm.200801-059OCDOI Listing
September 2008

Sex-stratified linkage analysis identifies a female-specific locus for IgE to cockroach in Costa Ricans.

Authors:
Gary M Hunninghake Jessica Lasky-Su Manuel E Soto-Quirós Lydiana Avila Catherine Liang Stephen L Lake Thomas J Hudson Mitzi Spesny Eduardo Fournier Jody S Sylvia Nelson B Freimer Barbara J Klanderman Benjamin A Raby Juan C Celedón

Am J Respir Crit Care Med 2008 Apr 31;177(8):830-6. Epub 2008 Jan 31.

Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115, USA.

Rationale: The basis for gender influences on allergen-specific IgEs is unclear.

Objectives: To perform regular and sex-stratified genomewide linkage analyses of IgE to each of three allergens (Ascaris lumbricoides, Blatella germanica [German cockroach]), and Dermatophagoides pteronyssinus [dust mite]) and to conduct an association study of a candidate gene in a linked genomic region.

Methods: Genomewide linkage analyses of allergen-specific IgEs were conducted in 653 members of eight large families of Costa Rican children with asthma. An analysis of the association between single-nucleotide polymorphisms in thymic stromal lymphopoietin (TSLP) and IgE measurements was conducted in 417 parent-child trios in Costa Rica. Significant results were replicated in 470 families of white children in the Childhood Asthma Management Program (CAMP).

Measurements And Main Results: Among all subjects, there was suggestive evidence of linkage (LOD >/= 2.72) to IgE to Ascaris (on chromosome 7q) and IgE to dust mite (on chromosomes 7p and 12q). In a sex-stratified analysis, there was significant evidence of linkage to IgE to cockroach on chromosome 5q23 (peak LOD, 4.14 at 127 cM) in female subjects. TSLP is located within the 1.5 LOD-unit support interval for this linkage peak and has female-specific effects on lung disease in mice. In a sex-stratified analysis, the T allele of single-nucleotide polymorphism rs2289276 in TSLP was associated with reductions in IgE to cockroach (in Costa Rican girls) and total IgE (in girls in Costa Rica and in CAMP; P value for sex-by-genotype interaction, <0.01 in both studies).

Conclusions: Consistent with findings in murine models, a variant in TSLP may have female-specific effects on allergic phenotypes.
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http://dx.doi.org/10.1164/rccm.200711-1697OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292826PMC
April 2008

Sex-specific linkage to total serum immunoglobulin E in families of children with asthma in Costa Rica.

Authors:
Benjamin A Raby Manuel E Soto-Quiros Lydiana Avila Stephen L Lake Amy Murphy Catherine Liang Eduardo Fournier Mitzi Spesny Jody S Sylvia Andrei Verner Thomas J Hudson Barbara J Klanderman Nelson B Freimer Edwin K Silverman Juan C Celedón

Hum Mol Genet 2007 Feb 1;16(3):243-53. Epub 2006 Dec 1.

Channing Laboratory and Respiratory Disorders Program, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA.

Serum total immunoglobulin E (IgE) is a critical intermediate phenotype of allergic diseases. Although total IgE exhibits sexual dimorphism in humans (with males demonstrating higher IgE than females), the molecular basis of this difference is unknown. A genome-wide scan of 380 short-tandem repeat (STR) markers was performed in eight extended pedigrees of asthmatic children (n=655) from the Central Valley of Costa Rica. Genome-wide linkage analysis of total IgE was performed by variance component models. Among all subjects, only one genomic region (chromosome 7p15) showed modest evidence of linkage to total IgE (LOD=1.60). In contrast, a sex-stratified analysis revealed distinct genetic architectures of total IgE in males and females and identified significant linkage to total IgE on a novel male-specific locus on chromosome 20p12 (LOD=3.63 at 36 cM). Genotyping of additional STRs on chromosome 20 resulted in improved evidence for linkage (LOD=3.75 at 33 cM) and a 1.5 LOD-unit support interval for the linkage peak between 26 and 38 cM. Three polymorphisms in two genes on chromosome 20p12 (JAG1 and ANKRD5) were then found to be associated with total IgE in 420 nuclear families of Costa Rican children with asthma. Two of these polymorphisms (in JAG1) were significantly associated with total IgE in families of boys (n=264) but not in families of girls (n=156) with asthma. JAG1 is a hematopoetic cell growth factor that may regulate normal B-cell development. This is the first demonstration of a possible genetic basis for differences in total IgE between sexes.
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http://dx.doi.org/10.1093/hmg/ddl447DOI Listing
February 2007

Genome-wide linkage analysis of pulmonary function in families of children with asthma in Costa Rica.

Authors:
Craig P Hersh Manuel E Soto-Quirós Lydiana Avila Stephen L Lake Catherine Liang Eduardo Fournier Mitzi Spesny Jody S Sylvia Ross Lazarus Thomas Hudson Andrei Verner Barbara J Klanderman Nelson B Freimer Edwin K Silverman Juan C Celedón

Thorax 2007 Mar 10;62(3):224-30. Epub 2006 Nov 10.

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA.

Background: Although asthma is highly prevalent among certain Hispanic subgroups, genetic determinants of asthma and asthma-related traits have not been conclusively identified in Hispanic populations. A study was undertaken to identify genomic regions containing susceptibility loci for pulmonary function and bronchodilator responsiveness (BDR) in Costa Ricans.

Methods: Eight extended pedigrees were ascertained through schoolchildren with asthma in the Central Valley of Costa Rica. Short tandem repeat (STR) markers were genotyped throughout the genome at an average spacing of 8.2 cM. Multipoint variance component linkage analyses of forced expiratory volume in 1 second (FEV(1)) and FEV(1)/ forced vital capacity (FVC; both pre-bronchodilator and post-bronchodilator) and BDR were performed in these eight families (pre-bronchodilator spirometry, n = 640; post-bronchodilator spirometry and BDR, n = 624). Nine additional STR markers were genotyped on chromosome 7. Secondary analyses were repeated after stratification by cigarette smoking.

Results: Among all subjects, the highest logarithm of the odds of linkage (LOD) score for FEV(1) (post-bronchodilator) was found on chromosome 7q34-35 (LOD = 2.45, including the additional markers). The highest LOD scores for FEV(1)/FVC (pre-bronchodilator) and BDR were found on chromosomes 2q (LOD = 1.53) and 9p (LOD = 1.53), respectively. Among former and current smokers there was near-significant evidence of linkage to FEV(1)/FVC (post-bronchodilator) on chromosome 5p (LOD = 3.27) and suggestive evidence of linkage to FEV(1) on chromosomes 3q (pre-bronchodilator, LOD = 2.74) and 4q (post-bronchodilator, LOD = 2.66).

Conclusions: In eight families of children with asthma in Costa Rica, there is suggestive evidence of linkage to FEV(1) on chromosome 7q34-35. In these families, FEV(1)/FVC may be influenced by an interaction between cigarette smoking and a locus (loci) on chromosome 5p.
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http://dx.doi.org/10.1136/thx.2006.067934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2117166PMC
March 2007

Significant linkage to airway responsiveness on chromosome 12q24 in families of children with asthma in Costa Rica.

Authors:
Juan C Celedón Manuel E Soto-Quiros Lydiana Avila Stephen L Lake Catherine Liang Eduardo Fournier Mitzi Spesny Craig P Hersh Jody S Sylvia Thomas J Hudson Andrei Verner Barbara J Klanderman Nelson B Freimer Edwin K Silverman Scott T Weiss

Hum Genet 2007 Jan 26;120(5):691-9. Epub 2006 Sep 26.

Channing Laboratory, Department of Medicine and Respiratory Disorders Program, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA.

Although asthma is a major public health problem in certain Hispanic subgroups in the United States and Latin America, only one genome scan for asthma has included Hispanic individuals. Because of small sample size, that study had limited statistical power to detect linkage to asthma and its intermediate phenotypes in Hispanic participants. To identify genomic regions that contain susceptibility genes for asthma and airway responsiveness in an isolated Hispanic population living in the Central Valley of Costa Rica, we conducted a genome-wide linkage analysis of asthma (n = 638) and airway responsiveness (n = 488) in members of eight large pedigrees of Costa Rican children with asthma. Nonparametric multipoint linkage analysis of asthma was conducted by the NPL-PAIR allele-sharing statistic, and variance component models were used for the multipoint linkage analysis of airway responsiveness as a quantitative phenotype. All linkage analyses were repeated after exclusion of the phenotypic data of former and current smokers. Chromosome 12q showed some evidence of linkage to asthma, particularly in nonsmokers (P < 0.01). Among nonsmokers, there was suggestive evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 2.33 at 146 cM). After genotyping 18 additional short-tandem repeat markers on chromosome 12q, there was significant evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 3.79 at 144 cM), with a relatively narrow 1.5-LOD unit support interval for the observed linkage peak (142-147 cM). Our results suggest that chromosome 12q24.31 contains a locus (or loci) that influence a critical intermediate phenotype of asthma (airway responsiveness) in Costa Ricans.
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http://dx.doi.org/10.1007/s00439-006-0255-5DOI Listing
January 2007

The SERPINE2 gene is associated with chronic obstructive pulmonary disease.

Authors:
Dawn L Demeo Thomas J Mariani Christoph Lange Sorachai Srisuma Augusto A Litonjua Juan C Celedon Stephen L Lake John J Reilly Harold A Chapman Brigham H Mecham Kathleen J Haley Jody S Sylvia David Sparrow Avrum E Spira Jennifer Beane Victor Pinto-Plata Frank E Speizer Steven D Shapiro Scott T Weiss Edwin K Silverman

Am J Hum Genet 2006 Feb 15;78(2):253-64. Epub 2005 Dec 15.

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

Chronic obstructive pulmonary disease (COPD) is a complex human disease likely influenced by multiple genes, cigarette smoking, and gene-by-smoking interactions, but only severe alpha 1-antitrypsin deficiency is a proven genetic risk factor for COPD. Prior linkage analyses in the Boston Early-Onset COPD Study have demonstrated significant linkage to a key intermediate phenotype of COPD on chromosome 2q. We integrated results from murine lung development and human COPD gene-expression microarray studies with human COPD linkage results on chromosome 2q to prioritize candidate-gene selection, thus identifying SERPINE2 as a positional candidate susceptibility gene for COPD. Immunohistochemistry demonstrated expression of serpine2 protein in mouse and human adult lung tissue. In family-based association testing of 127 severe, early-onset COPD pedigrees from the Boston Early-Onset COPD Study, we observed significant association with COPD phenotypes and 18 single-nucleotide polymorphisms (SNPs) in the SERPINE2 gene. Association of five of these SNPs with COPD was replicated in a case-control analysis, with cases from the National Emphysema Treatment Trial and controls from the Normative Aging Study. Family-based and case-control haplotype analyses supported similar regions of association within the SERPINE2 gene. When significantly associated SNPs in these haplotypic regions were included as covariates in linkage models, LOD score attenuation was observed most markedly in a smokers-only linkage model (LOD 4.41, attenuated to 1.74). After the integration of murine and human microarray data to inform candidate-gene selection, we observed significant family-based association and independent replication of association in a case-control study, suggesting that SERPINE2 is a COPD-susceptibility gene and is likely influenced by gene-by-smoking interaction.
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http://dx.doi.org/10.1086/499828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1380249PMC
February 2006

COMT genetic variation confers risk for psychotic and affective disorders: a case control study.

Authors:
Birgit Funke Anil K Malhotra Christine T Finn Alex M Plocik Stephen L Lake Todd Lencz Pamela DeRosse John M Kane Raju Kucherlapati

Behav Brain Funct 2005 Oct 18;1:19. Epub 2005 Oct 18.

Harvard Partners Center for Genetics and Genomics, Boston, USA.

Background: Variation in the COMT gene has been implicated in a number of psychiatric disorders, including psychotic, affective and anxiety disorders. The majority of these studies have focused on the functional Val108/158Met polymorphism and yielded conflicting results, with limited studies examining the relationship between other polymorphisms, or haplotypes, and psychiatric illness. We hypothesized that COMT variation may confer a general risk for psychiatric disorders and have genotyped four COMT variants (Val158Met, rs737865, rs165599, and a SNP in the P2 promoter [-278A/G; rs2097603]) in 394 Caucasian cases and 467 controls. Cases included patients with schizophrenia (n = 196), schizoaffective disorder (n = 62), bipolar disorder (n = 82), major depression (n = 30), and patients diagnosed with either psychotic disorder NOS or depressive disorder NOS (n = 24).

Results: SNP rs2097603, the Val/Met variant and SNP rs165599 were significantly associated (p = 0.004; p = 0.05; p = 0.035) with a broad "all affected" diagnosis. Haplotype analysis revealed a potentially protective G-A-A-A haplotype haplotype (-278A/G; rs737865; Val108/158Met; rs165599), which was significantly underrepresented in this group (p = 0.0033) and contained the opposite alleles of the risk haplotype previously described by Shifman et al. Analysis of diagnostic subgroups within the "all affecteds group" showed an association of COMT in patients with psychotic disorders as well as in cases with affective illness although the associated variants differed. The protective haplotype remained significantly underrepresented in most of these subgroups.

Conclusion: Our results support the view that COMT variation provides a weak general predisposition to neuropsychiatric disease including psychotic and affective disorders.
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http://dx.doi.org/10.1186/1744-9081-1-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1282571PMC
October 2005

Asthma steroid pharmacogenetics: a study strategy to identify replicated treatment responses.

Authors:
Scott T Weiss Stephen L Lake Eric S Silverman Edwin K Silverman Brent Richter Jeffrey M Drazen Kelan G Tantisira

Proc Am Thorac Soc 2004 ;1(4):364-7

Respiratory, Genetic, and Environmental Epidemiology, Channing Laboratory, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

Asthma treatment with inhaled steroids demonstrates significant between-person variability. Genetic variation could contribute to this response to inhaled glucocorticosteroids. Difficulties in performing genetic association studies are well known. We designed a test and validation strategy to assess steroid pathway candidate genes. One hundred thirty-one single nucleotide polymorphisms in 14 candidate genes in the steroid pathway were genotyped in an 8-week clinical trial of 470 adults with moderate to severe asthma. We then validated our findings in a second population of individuals with childhood asthma in a 4-year clinical trial of inhaled corticosteroids and a third population of adults with asthma. One gene, corticotrophin-releasing hormone receptor 1 (CRHR1, NM_004382), demonstrated multiple single nucleotide polymorphism associations within each of the three populations. The approach of a test and multiple replication populations is a valuable strategy in asthma pharmacogenetics, which can insure valid association findings.
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http://dx.doi.org/10.1513/pats.200409-043MSDOI Listing
October 2005

TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids.

Authors:
Kelan G Tantisira Eun Sook Hwang Benjamin A Raby Eric S Silverman Stephen L Lake Brent G Richter Stanford L Peng Jeffrey M Drazen Laurie H Glimcher Scott T Weiss

Proc Natl Acad Sci U S A 2004 Dec 16;101(52):18099-104. Epub 2004 Dec 16.

Channing Laboratory and Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

TBX21 encodes for the transcription factor T-bet (T-box expressed in T cells), which influences naive T lymphocyte development and has been implicated in asthma pathogenesis. Specifically, the T-bet knockout mouse spontaneously develops airway hyperresponsiveness and other changes consistent with asthma. Because airway responsiveness is moderated by the use of inhaled corticosteroids in asthma, it is conceivable that genetic variation in TBX21 may alter asthma phenotypes in a treatment-specific fashion. Here we demonstrate that the nonsynonymous variation in TBX21 coding for replacement of histidine 33 with glutamine is associated with significant improvement in the PC(20) (a measure of airway responsiveness) of asthmatic children in a large clinical trial spanning 4 years. We note that this increase occurs only in the children randomized to inhaled corticosteroids and that it dramatically enhances the overall improvement in PC(20) associated with inhaled corticosteroid usage. The average PC(20) at trial end for subjects on inhaled corticosteroids possessing a variant allele was in the normal range for nonasthmatics. In cellular models, we show that the TBX21 variant increases T helper 1 and decreases T helper 2 cytokine expression comparably with wild type. TBX21 may thus be an important determinant pharmacogenetic response to the therapy of asthma with inhaled corticosteroids.
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http://dx.doi.org/10.1073/pnas.0408532102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC539815PMC
December 2004

Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics.

Authors:
Steve Horvath Xin Xu Stephen L Lake Edwin K Silverman Scott T Weiss Nan M Laird

Genet Epidemiol 2004 Jan;26(1):61-9

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.

We provide a general purpose family-based testing strategy for associating disease phenotypes with haplotypes when phase may be ambiguous and parental genotype data may be missing. These tests for linkage and association can be used in candidate gene studies with tightly linked markers. Our proposed weighted conditional approach extends the method described in Rabinowitz and Laird to multiple markers. It is attractive because it provides haplotype tests for family-based studies that are efficient and robust to population admixture, phenotype distribution specification, and ascertainment based on phenotypes. It can handle missing parental genotypes and/or missing phase in both offspring and parents. It yields either haplotype-specific (univariate) tests or multi-haplotype (global) tests. This extension has been implemented in the freely available software haplotype FBAT. We used the haplotype FBAT program to test for associations between asthma phenotypes and single nucleotide polymorphisms (SNPs) in the beta-2 adrenergic receptor gene. Whereas no single SNP showed significant association with asthma diagnosis or bronchodilator responsiveness (quantitative trait), a haplotype-based global test found a highly significant association with asthma diagnosis (P value <0.00005) and the measure of bronchodilator responsiveness (P value =0.016).
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http://dx.doi.org/10.1002/gepi.10295DOI Listing
January 2004