When Daniel Judge, MD, director of the Cardiovascular Genetics program and fellowship director for cardiovascular disease at The Medical University of South Carolina (MUSC), moved over from John Hopkins a bit over five years ago, the use of genetics in clinical practice was absent in South Carolina.
“When you ask a clinician what genetics means, it’s often infants with phenylketonuria (PKU) or inherited disorders of metabolism,” Judge told Inside Precision Medicine. “But for adults with cardiovascular, pulmonary, or renal disease, not everyone uses genetics routinely in practice.”
So when the opportunity arose to work with population genomics company Helix on a large genomic screening program, Judge was incredibly enthusiastic.
“Here’s an opportunity for us and MUSC to stand apart from the large for-profit hospital centers that operate around the state, and for us to provide an academic and improved healthcare approach to things,” said Judge. “This was the opportunity for clinicians who have been doing good clinical work to bring genetics into their practice.”
In 2021, MUSC launched “In Our DNA, SC,” a first-of-its-kind genomics program to drive preventive, precision health care for South Carolinians. The statewide initiative has set out to enroll 100,000 patients in genetic testing over the next four years at no cost to the patients.
Walking the walk
Excluding COVID-19, the top cause of death in South Carolina is heart disease, followed by cancer. In the time that In Our DNA SC has been up and running, the cancer and heart disease rates haven’t yet begun to go down, but that’s the goal. Judge estimates that the program has detected about 175 positive results, which are split across breast cancer, colon cancer, and hyperlipidemia.
“Many of those patients with those results were quite surprised because they don’t have a family history of cancer or heart disease,” said Judge. “It’s nice to diagnose it because we’re seeing the ability to prescribe medications on the clinical side that are available more readily for people with familial hyperlipidemia or hypercholesterolemia.”
Judge is excited about the opportunity to provide an academic and improved healthcare approach. “It’s an opportunity for clinicians who have been doing great clinical work but haven’t integrated genetics into their primary care, or whatever that practice might be,” he said. “I think the use of genetics in clinical practice…is entering that mainstream. The patient benefits, and the family benefits.”
Judge’s experience in clinical genetics started about twenty years ago, and “I’ve always seen this pattern: once people see a successful use of something like this, they want to do more of it,” he said. “I think our clinicians will witness success with their patients and will want to see more.”
Making genomics part of real-time care
Behind the scenes of the In Our DNA SC initiative is a population genomics company called Helix that strives to accelerate the integration of genomic data into patient care and public health decision-making. Founder James Lu, MD, PhD, has dreamt of a world where genetic testing will provide a real-time response versus one that takes weeks. He set his sights on offering top-tier provider and patient experiences by making genomics a part of the healthcare fabric.
Lu thinks the best way to deliver genomics as a data stream or operating system within healthcare is to work with health systems. “Most of our partnerships are with large-scale health systems and are focused on large-scale, population-level programs,” said Lu. “Typically, a hundred thousand people plus, where they inevitably believe that this is going to become the standard of care over time.”
Lu believes that health systems will want to do this because it allows them to identify patients who are clearly at risk and are hiding in plain sight, such as carriers of well-established deleterious DNA variants. Helix went the route of whole exome sequencing (WES) rather than looking at an entire genome, as Lu believes that the coding regions contain almost all the relevant genomic data for clinical decision-making.
With its genomics data, Helix is currently narrowly focused on the diseases that are part of the CDC Tier 1 genomic application toolkit. This set addresses the nearly two million people in the United States who are at increased risk for adverse health outcomes because they have genetic mutations that predispose them to one of three conditions: hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), or familial hypercholesterolemia (FH). The healthcare system currently has a poor understanding of these conditions, and many affected people and their families are unaware that they are at risk; however, early detection and intervention could significantly lower morbidity and mortality.
The type of work that Helix is doing enables health systems to create fresh population health and value-based care algorithms to manage the health of larger populations. Over time, health systems want to drive the cost of care down while improving the quality of patient experiences.
From sea to shining sea
In addition to In Our DNA, SC, Helix currently has five other major programs running across the country that represent over 100,000 people in total, representing potentially one of the largest-scale programs across America’s health systems.
In addition to South Carolina, Helix is located in Minnesota, where it is working with HealthPartners on a program called “myGenetics.” This large-scale community health research program, which launched in May 2022, is a first of its kind in Minnesota. Implementing this requires knowing what information to analyze, interpret, and communicate to patients, which Leslie Dockan, VP of primary care, clinic operations, and laboratories at HealthPartners, said aligns nicely with its and Helix’s core principle of providing clinicians with clear decision support.
The myGenetics program is free to the patient, given that it is a research project and the goal is to further biomedical understanding. “We wanted to create workflows that were easy for patients and weren’t disruptive to patient visits in the clinic, because our primary care clinicians have so many responsibilities and so many things that are happening,” said Dockan. This required HealthPartners to work closely with its electronic medical group and Helix to create a seamless workflow.
A day in the myGenetics life
After signing up and consenting electronically, the patient gets an automatic email to schedule their lab appointment at a pace that suits them. “They can take their time, ask questions, and review the information at a time when they’re comfortable, not feeling pressured to move into this,” said Dockan.
Once the appointment is scheduled, the patient gives a blood sample and receives clear information on what to expect, including how long sample processing takes and the information researchers will be looking for. From the results, HealthPartners shares information with the patient about the genes that it has screened for and what the results mean, in addition to facts about the patient’s ancestry and other genetic insights.
While this is happening, the clinical results for the CDC Tier 1 Genomic Applications Toolkit gets fed into the patient’s clinical record for any positive results. In the case of such a result, a nurse calls the patient and notifies them of the result, and offers a no obligation appointment with a genetic counselor to talk about their risk, what their results mean, and any additional testing that might be needed. Direct referrals get set up with a specialist. “If you need an oncology, cardiac, or a gastroenterology referral, we do that work for them, put the referral in, order any follow-up labs that may be needed, and set them on a clear clinical pathway,” said Dockan.
This information also goes to the primary care physician as part of the patient’s medical record, which impacts their future health maintenance, namely, how often screening occurs. “If they have a genetic variant, it doesn’t necessarily mean that they have the disease or will get the disease,” said Dockan. “So, we follow them closely and then have that as a part of their ongoing health maintenance and preventative care.”
Dockan said that genomics will be brought into everyday care, such as with pharmacogenomics. “Physicians will be able to see that there are drug-gene interactions,” said Dockan. “If your physician starts to order a drug that’s not going to be compatible with your genetic makeup and how you metabolize drugs, then we want to be able to alert your clinician at the time of order and have them be able to give you an alternative. Today, we have many people on drugs that just don’t work for them, and no one knows why.”
Outreach in every corner
As of June 2023, myGenetics has had 25,000 people consent, which is about the annual number its organizers are shooting for. “We’re starting to see positive results and have more people who are benefiting from this work in a positive way and learning things about themselves,” said Dockan. “We just identified our first early cancer—someone who was underage and not yet even at screening age came back positive for BRCA2. We ended up doing follow-up screening and an MRI, and we found cancer. She’s crediting the program with potentially saving her life.”
Dockan would like to see the next step of the program’s outreach be to everyone who’s due for their annual physical or a preventative exam. “We want to offer it with all of our mammography screenings,” said Dockan. “We have amazing screening rates for mammography, and this is just another layer that takes it even further.”
Dockan also wants to make sure that myGenetics is reaching underserved communities. She tells a story about a black woman in her fifties who has a long history of breast cancer in her family and found out that she was positive for one of the gene variants that put her at higher risk. Dockan thinks that this story can have a major influence on the communities of black women in Minnesota. Not only is there a benefit in getting the word out so that people get better immediate treatment, but the myGenetics team knows that patients of color are underrepresented in a lot of research databases and wants to help fuel new therapies and other ways of fighting disease in local underserved populations.
Judge laments that the program wasn’t in place several years earlier so that it could have worked in time for a famous South Carolina resident, Chadwick Bozeman. The actor developed metastatic colon cancer in his late thirties, well before colon cancer screening was done. Part of the plan for In Our DNA SC is to become one of the top-enrolled genomic screening programs for non-white participants. “We are in the southeast U.S., and while we are in the 15–16% range, we want to be like 30% of our participants who are non-white, predominantly black, representing our state,” said Judge. “When we look at what our goal is for inclusion in this program, we want the demographics in our publications to look like the state of South Carolina. We’re not there yet.”
Jonathan D. Grinstein’s wonder for the human mind and body led him to an undergraduate education in Neural Science and Philosophy and a doctorate in Biomedical science. He has 10 years of experience in experimental and computational research, during which he was a co-author on research articles in journals such as Nature and Cell. Since then, Jonathan hung up his lab coat and has explored positions in science writing and editing. Jonathan’s science writing work has been featured in Scientific American, Genetic Engineering and Biotechnology News (GEN), and NEO.LIFE.fed cdc treatment testing genetic dna mortality covid-19
A Calloused Market Heart
Calluses are generally a good thing, as they are the body’s response to help shield against pain and breach of the skin. Think of calluses as the tough…
Calluses are generally a good thing, as they are the body’s response to help shield against pain and breach of the skin. Think of calluses as the tough outer layer that stops the harshness and coldness of the world from hitting your nerve endings. Of course, calluses can also form in the heart, and for the same reason, i.e., to stop the harshness and coldness of the world from burrowing into our souls.
When it comes to financial markets, well, they, too, have calluses.
The latest atrocities in the Middle East tell us just that. You see, despite the fact the Hamas attacks on Israel and the future Israeli response to this conflict have dominated the mainstream and financial news, markets have largely remained callously indifferent.
Yet, the situation is set to potentially escalate in the coming days and weeks, so today, I want to provide a dedicated analysis to explain what this situation means for markets.
The following analysis was sent to subscribers of my Eagle Eye Opener, a publication that’s a collaboration with my “secret market insider” that explains what is going on in markets, what to look for that day and what the key events are that will move stocks, bonds, commodities and currencies. Perhaps most importantly, it’s presented in a quick, 10-minute, plain-English read that dispenses with the noise and tunes into the melody of the market.
From the Eagle Eye Opener…
First, we will not spend time addressing the human aspect of the Israel/Hamas situation other than to say it is a tragedy of epic proportions for all innocent civilians, and our hearts go out to the families that have lost loved ones and whose lives have been torn apart.
Yet, the reason we won’t spend time here on the human aspect of this situation is because it doesn’t matter to the markets.
The market is only focused on the economic impact of the conflict, and that’s why tragedies don’t usually impact markets unless they carry with them economic consequences.
Looking at the Israel/Hamas situation, like most geopolitical crises, the market views it through the lens of impact on energy commodities, and in this situation that means oil. For reference, the Ukraine/Russia war was viewed through the lens of a different commodity, natural gas.
So, for the Israel/Hamas conflict, here are the market truths:
- Anything that occurs that the market thinks might reduce the supply of oil will push oil prices higher and stocks lower.
- If the market does not think the events will impact the supply of oil, then the markets will largely ignore the war, regardless of the human tragedy or geopolitical upheaval that ensues.
Given those truths, here is the worst-case scenario for the market.
First, Israel invades Gaza. This is extremely likely to happen.
Second, Hezbollah attacks Israel in retaliation on their northern border through Lebanon, creating a two-front conflict for Israel.
Third (and this is the key point) Iran attacks Israel to support Hezbollah and Hamas, which prompts the United States to launch an attack on Iran, almost certainly destroying much of its oil infrastructure and removing supply from the market. To underscore this risk, South Carolina Sen. Graham will introduce legislation authorizing the president to destroy Iranian oil infrastructure in the event of an attack on Israel.
That is how this conflict goes from isolated (Israel versus Hamas or Israel versus Hamas/Hezbollah) to regional (Israel and the United States versus Iran, Hamas and Hezbollah). And that’s when this conflict would materially impact markets and send oil prices surging.
Absent this spiraling into a regional conflict (whereby Iran gets involved and the United States threatens to attack its oil infrastructure), then this conflict should not materially impact markets beyond the very short term.
Notably, this dynamic is why stocks rallied on Monday. President Biden’s trip to the region was seen as an effort to prevent a broader regional conflict, and as long as diplomatic progress occurs, that will pressure oil and help support markets.
Bottom line, for all the noise that will occur in the coming days/weeks, watch oil prices, because that is the barometer of the market’s worries about a regional conflict. If oil makes a fresh closing high above $87.72 on an Israel/Gaza/Hamas/Hezbollah/Iran headline, that’s a clear indicator the situation is legitimately deteriorating and increasing the risk of a pullback in stocks.
If you would like to get this kind of deep analysis on the economy, stocks, bonds and anything that makes the market move, each trading day 8 a.m. Eastern time, then I invite you to check out my Eagle Eye Opener, right now. I suspect it will be the best decision you make today!
Don’t Be A Bore
“A healthy male adult bore consumes each year one and a half times his own weight in other people’s patience.”
— John Updike
I have never been accused of being boring, and I’m not likely to ever suffer that accusation. The reason why is because I find everything about the world interesting, and people who are interested in the world are never bored.
So, if you don’t want to be accused of being a bore, and thereby consuming one and a half times your own weight in other people’s patience, then cultivate your interest and embrace all the wonder that life has to offer. If you don’t, you’re only depriving yourself of the tremendous beauty, truth and wisdom the world has to offer.
Wisdom about money, investing and life can be found anywhere. If you have a good quote that you’d like me to share with your fellow readers, send it to me, along with any comments, questions and suggestions you have about my newsletters, seminars or anything else. Click here to ask Jim.
In the name of the best within us,
Jim Woodsbonds stocks currencies commodities oil iran russia ukraine
‘It’s Electric!’ The Utility of Nuclear Power
Uranium and nuclear power are still on the menu for investors this week. Clean and green, nuclear power has come back into the global spotlight in recent…
Uranium and nuclear power are still on the menu for investors this week. Clean and green, nuclear power has come back into the global spotlight in recent months as an attractive alternative to fossil fuels and as the Russia-Ukraine conflict has prompted governments to prioritize energy security. This renewed interest in nuclear has increased demand for uranium.
In last week’s ETF Talk on Sprott Uranium Miners ETF (URNM), I mentioned that uranium is the fuel for nuclear fission, the process through which nuclear energy — mostly electricity — is produced. Nuclear is back in vogue for the first time since the 2011 Fukushima disaster that prompted a stall in new production for over a decade. While uranium is not a rare element, government investment in it has been low for years, negatively affecting the number of companies engaged in mining and exploration of the chemical element. But demand is now soaring in this niche industry and nuclear is on the rise.
The market is limited to just a few baskets of stocks from which to choose. Many have been seeing significant growth due to recent geopolitical events and a global focus on green climate policies. Uranium is vital to the green energy transition and increased demand has pushed uranium prices to their highest point since 2011. We’ve recently highlighted two funds in the uranium market, Global X Uranium ETF (URA) and Sprott Uranium Miners ETF (URNM). This week, I want to introduce another (mostly) pure-play nuclear fund.
VanEck Uranium+Nuclear Energy ETF (NYSE: NLR) is an exchange-traded fund (ETF) that targets companies across the uranium and nuclear energy industry. The portfolio focuses on companies expected to generate at least 50% of revenue or assets from mining, building and maintaining nuclear facilities, producing electricity using nuclear sources or providing services to the nuclear power industry. The fund seeks to replicate the price and yield performance of the Nuclear Energy Index, which is intended to track the overall performance of companies involved in uranium mining, the construction and maintenance of nuclear power facilities and related businesses in the production of nuclear power.
VanEck’s NLR is smaller than the other uranium ETFs and employs a different strategy. Unlike URA and URNM, NLR’s portfolio includes a hefty percentage of holdings in utilities. This makes it less of a pure-play option than the others and not quite as promising. Its growth has not matched URA and URNM, but investing so heavily in nuclear power utilities helps to stabilize the portfolio in a highly volatile market. It also provides a modest yield of 1.57%.
NLR fund has 28 positions, and its top 10 holdings account for 59.61% of assets. The fund’s sector weighting favors Energy at 47.64% and Utilities at 40.66% of the portfolio, rounded out by Industrials at 10.04% and Information Technology at 1.59%. Top holdings in the portfolio include Constellation Energy Group (NASDAQ: CEG), Public Service Enterprise Service Inc (NYSE: PEG), Pacific Gas & Electric Corp (NYSE: PCG), Cameco Corp (NYSE: CCJ) and Cez As (PSE: CEZ).
The fund is down 2.81% over the past month, up 13.90% over the last three months and jumped 25.21% year to date. NLR has a net asset value of $114.46 million and a net expense ratio of 0.61%.
While the energy sector is growing and the demand for nuclear power is on the rise, be aware that the uranium market is highly volatile and vulnerable on several national and international fronts, including geopolitical risks, regulatory action and competitive risk associated with the prices of other energy sources. As always, investors should do their due diligence before adding any stock, fund or ETF to their portfolio.
I am always happy to answer any of your questions about ETFs, so do not hesitate to send me an email. You may just see your question answered in a future ETF Talk.nasdaq stocks etf russia ukraine
Three learnings from Polen Capital’s recent Australia tour
You always learn a lot hearing from seasoned investors. The beauty of the Montgomery business as it has grown is that these nuggets of wisdom through our…
You always learn a lot hearing from seasoned investors. The beauty of the Montgomery business as it has grown is that these nuggets of wisdom through our partner managers are now spread across not only several asset classes but also across a number of geographies.
The Montgomery team recently hosted Damon Ficklin and Rob Forker from Polen Capital, our U.S. based global equity partner manager. Damon is Head of the Large Company Growth Team based out of Florida who are responsible for running their flagship strategy, the Polen Capital Focus Growth Fund, along with the Polen Capital Global Growth Fund. Damon is also Polen’s longstanding investment team member with now over 20 years with the firm. Damon was joined by Rob from the Small Company Growth Team based out of Boston and is responsible for running the Polen Capital Global Small and Mid Cap Fund. Below is a summary of three key learnings from their briefings which I think are all timely reminders for investors in lieu of the world market back drop at present.
#1 Quality is a key driver of investment outcomes over the long term
Polen Capital’s process which has been in operation since 1989 is founded on the principle that investing in the highest quality companies works over the long-term. They define high quality companies initially via the following guardrails: sustained high returns on equity, exceptionally strong balance sheets, stable or growing profit margins, abundant free cashflow and real organic revenue growth. Although investing in high quality has been proven to work over extended periods of time, it doesn’t mean this factor is a driver of investment outcomes of every single time period. This has certainly been our experience at Montgomery working across Australian equities, both large and small.
According to Polen Capital’s research, quality was one of the worst performing investment factors over last calendar year. With that in mind, owning equities is a long-term proposition. As per Figure 1, over long periods of time investing in high quality businesses globally, both large and small, has been a clear driver of outperformance.
Figure 1: Global small and large cap returns by quality tercile (%)
Source: Asness, Frazzini and Pedersen, 2014. Data is publicly available and is updated and maintained by AQR, AQR.com. Dataset Is monthly from December 1994 to 31st May 2023. Methodology: Six portfolios are constructed based on size and quality. The small and large cap breakpoint is defined as: for the US small cap is below the median NYSE market equity and large cap is above and includes all US common stocks on the merged CRSP/XpressFeed data. For international stocks, the breakpoint is the 80th percentile by country and includes all available stocks on the CRSP and Compusta/XpressFeed Global database for 24 developed markets. The Quality measure is based on a score calculated by the average of four factors including Profitability, Growth, Safety and Payout, with high quality exhibiting these factors the most. No representation is being made that any investment will or is likely to achieve future results similar to those shown. Additional information regarding the analyses presented above is available upon request. Performance does not reflect any transaction costs, management fees, or taxes.
#2 The dispersion of returns between large cap and small cap equities is a global phenomenon
Roger has written at length about the differential of returns over the last 18 months between Australian large cap stocks versus their small cap equivalents which sit outside the ASX 100. In fact, as illustrated in Figure 2, this returns gap was close to 30 per cent as at 30 June this year. Interestingly, this is not a local anomaly. Rob from Polen Capital has observed a similar trend across a number of geographies that encompass his investment universe, whether it be U.S., Canada or even Japan. If we look to Figure 3, according to his research global small and mid cap stocks (SMID) are trading at a 10 per cent discount to their large cap equivalents also as at last fiscal year end. Moreover, historically global SMIDs have traded at a 15 per cent premium to their large cap equivalents. As an aside, this premium would be largely attributed to the superior earnings growth potential that these companies have offered investors historically.
Figure 2: Australian Small Ords Accumulation Index versus ASX 100 Accumulation Index
Source: Montgomery Lucent via IRESS, ASX 100 Accumulation Index, ASX Small Ords Accumulation Index returns over last 10 years
Figure 3: MSCI ACWI SMID Cap Index premium versus MSCI ACWI Index
Source: Polen Capital. SMID Cap Premium calculated by dividing the forward P/E multiple of the MSCI ACWI SMID Cap index by the forward P/E multiple of the MSCI ACWI index. Data for the longest available time periods available on Bloomberg; 31st March 2009 to 30th June 2023. Please see Disclosures page. Past performance is not indicative of future results.
#3 The importance of earnings
Said another way, fundamentals matter. Why do they matter? Well, investors can’t control the price movements of a company in the short-term which can often be divorced from the underlying performance of the business. However, if you get the earnings profile right, this can provide you an implicit margin of safety. For example, the Polen Capital Global Growth Fund is seeking to own a portfolio of high-quality businesses where their earnings are forecasted to grow on a blended average of 15 percent over the long term. With reference to Figure 4, if you purchase a business whose earnings over a five-year period (ex-dividends) are forecasted to grow at 15 per cent per annum and assuming the price to earnings (P/E) multiple you pay for this business remains unchanged at 0 per cent over this five-year period, your internal rate of return (IRR) upon selling will be 15 per cent per annum. However, if the P/E multiple was to compress 10 per cent over five years but yet the underlying earnings still grew at 15 per cent per annum over this same period, your IRR would still be 13 per cent. And again, even if the P/E multiple was to compress 25 per cent over five years but yet the underlying earning still grew at 15 per cent per annum over this same period, your IRR whilst not all inspiring would be a modest 9 per cent.
What does this look like in practice? If you take LVMH Group (EPA: MC) which is a current holding in the Polen Capital Global Growth Fund, this company has generated shareholders a total return of 15 per cent per annum since 1989. However, this is not without volatility. Over the last five years, the company has had six drawn downs in its share price north of 10 per cent. Despite this, Polen Capital’s long term earnings growth estimates for LVMH is 12 percent per annum. All of this noting they, at the end of the day, sell products that are non-discretionary. In the case of Louis Vuitton, I will leave you to debate whether their products are non-discretionary with my wife!
Figure 4: The Polen Capital heat map
Source: Polen Capital. This page is not intended as a guarantee of profitable outcomes. Any forward-looking estimates are based on certain expectations and assumptions that are susceptible to changes in circumstances. The y-axis = EPS CAGR over five-year period. EPS (earnings per share) measures a company’s profits per share of stock. CAGR (compounded annual growth rate) is the average annual growth rate over time. Together, the EPS CAGR is the annual rate at which a company grows it earnings per share. The x-axis = % change in P/E multiple for a five-year period. The P/E multiple or ratio measures the price investors are willing to pay per dollar of earnings. It can be used to determine a company’s valuation. In times of multiple expansion, investors pay more per dollar of earnings and the reverse is true in times of multiple contraction. This affects expected returns for a particular investment. Methodology and Assumptions: The calculation methodology assumes that the 5-year EPS CAGR will match 5-year annualized return excluding dividends if there no change in the P/E multiple. The calculation is as follows: [(1+% Change in PE Multiple)*[(1+EPS CAGR)5 ]1/5. There are numerous other factors which have not been fully accounted for in the preparation of these results which could adversely affect actual results. There is no guarantee that performance will follow earnings growth. This example is for illustrative purposes only and has been prepared based on assumptions believed to be reasonable; however, there is no guarantee that any forecasts made will come to pass. There may be several unexpected developments and market factors which may affect these scenarios, potentially adversely. There are certain inherent limitations. No representation is being made that any investment will or is likely to achieve future results similar to those shown. This information is not intended to be construed to equate to the expected or projected future performance/returns of a Polen Capital investment or portfolio. The opinions and views provided by Polen Capital constitute the judgment of Polen Capital as of the date of this article, may involve a number of assumptions and estimates which are not guaranteed, and are subject to change without notice. Although the information and any opinions or views given have been obtained from or based on sources believed to be reliable, no warranty or representation is made as to their correctness, completeness or accuracy. Opinions, estimates, forecasts, and statements of financial market trends that are based on current market conditions constitute our judgment and are subject to change without notice, including any forward-looking estimates or statements which are based on certain expectations and assumptions. The views and strategies described may not be suitable for all clients. References to specific securities, asset classes and financial markets are for illustrative purposes only and are not intended to be, and should not be interpreted as, recommendations. This document does not identify all the risks (direct or indirect) or other considerations which might be material when entering any financial transaction. The volatility and other material characteristics of the indices referenced may be materially different from the performance achieved by an individual investor. In addition, an investor’s holdings may be materially different from those within the index. Indices are unmanaged and one cannot invest directly in an index. MSCI ACWI SMID Cap is a market capitalization weighted equity index that measures the performance of the mid and small-cap segments across developed and emerging market countries. The index is maintained by Morgan Stanley Capital International. The MSCI ACWI Index is a market capitalization weighted equity index that measures the performance of large and mid-cap segments across developed and emerging market countries. The index is maintained by Morgan Stanley Capital International.
 Bloomberg and Polen Capital, as of December 31, 2022. 1 Factor Returns: Defined, modeled, and calculated by Bloomberg, help decompose returns into a combination of style, industry, geography, and currency exposures. Style factor exposures are estimated for the MSCI ACWI index based on underlying fundamental and security characteristics as defined by Bloomberg’s Equity Factor models. Relative factor returns calculated by Bloomberg as the top quintile returns minus the bottom quintile returns.
 Source: Polen Capital via company filings of March 31, 2023
 Source: Bloomberg, Polen Capital as of 30 June 2023.global growth equities stocks japan canada
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